US20020077329A1 - EP4 receptor inhibitors to treat rheumatoid arthritis - Google Patents

EP4 receptor inhibitors to treat rheumatoid arthritis Download PDF

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US20020077329A1
US20020077329A1 US09/977,761 US97776101A US2002077329A1 US 20020077329 A1 US20020077329 A1 US 20020077329A1 US 97776101 A US97776101 A US 97776101A US 2002077329 A1 US2002077329 A1 US 2002077329A1
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ethyl
phenyl
alkyl
amino
imidazo
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Laurent Audoly
Takako Okumura
Masato Shimojo
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Pfizer Inc
Pfizer Pharmaceuticals LLC
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Assigned to PFIZER PHARMACEUTICALS INC. reassignment PFIZER PHARMACEUTICALS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AUDOLY, LAURENT, SHIMOJO, MASATO, Okumura, Takako
Assigned to PFIZER PHARMACEUTICALS INC. reassignment PFIZER PHARMACEUTICALS INC. CONSENT Assignors: PFIZER INC.
Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER PHARMACEUTICALS INC.
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Definitions

  • the present invention features methods of treating rheumatoid arthritis by administering an agent that inhibits prostaglandin EP4 receptor activity.
  • the invention also includes methods of identifying agents that selectively inhibit prostaglandin EP4 receptor activity in vivo.
  • Prostaglandin E 2 is a potent modulator involved in the pathogenesis of arthritis.
  • PGE 2 binds to at least four subtypes of PGE receptor, designated EP1, EP2, EP3, and EP4.
  • EP1, EP2, EP3, and EP4 subtypes of PGE receptors that belong to the G-protein coupled receptor superfamily.
  • EP1 activation stimulates the release of intracellular calcium via a G protein-mediated mechanism
  • EP2 and EP4 both activate adenylate cyclase via stimulatory G proteins, but differ in their response to certain ligands
  • EP3 inhibits adenylate cyclase via inhibitory G-proteins (Robert et al., supra, Negishi et al., Biochimica Biophys. Acta 1259:109-20, 1995).
  • the present invention features methods of treating rheumatoid arthritis.
  • the invention features a method of treating rheumatoid arthritis in a mammal involving administering an agent that inhibits prostaglandin EP4 receptor (EP4) activity.
  • the agent is administered in an amount sufficient to reduce interleukin (IL)-6 levels, reduce serum amyloid A (SAA) levels, reduce joint inflammation, reduce joint hyperplasia, reduce joint ankylosis, and/or increase joint mobility in the mammal.
  • the mammal is human and/or the agent is EP4 selective.
  • the agent is an aryl or heteroaryl fused imidazole compound of the following Formula I
  • Y 1 , Y 2 , Y 3 and Y 4 are independently selected from N, CH or C(L);
  • R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, C 1-8 alkoxy, halo-substituted C 1-8 alkoxy, C 1-8 alkyl-S(O)m-, Q 1 —, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8 alkyl)amino, C 1-4 alkyl-C( ⁇ O)—N(R 3 )— or C 1-4 alkyl-S(O)m-N(R 3 )—, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl are optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C 3-7
  • Q 1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, R 3 N(R 4 )C( ⁇ O)—, C 1-4 alkylsulfonylamino, C 3-7 cyclo
  • A is a 5-6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, acetyl, R 3 N(R 4 )C( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonyla
  • B is halo-substituted C 1-6 alkylene, C 3-7 cycloalkylene, C 2-6 alkenylene, C 2-6 alkynylene, —O—C 1-5 alkylene, C 1-2 alkylene-O—C 1-2 alkylene or C 1-6 alkylene optionally substituted with an oxo group or C 1-3 alkyl;
  • W is NH, N—C 1-4 alkyl, O, S, N—OR 5 or a covalent bond;
  • R 2 is H, C 1-4 alkyl, OH or C 1-4 alkoxy
  • Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1 4 alkynyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, R 3 C( ⁇ O)N(R 4 )—, HO(O ⁇ )C—, C 1-4
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C( ⁇ O)N(R 4 )—, NH 2 (HN ⁇ )C—, R 3 N(R 4 )C( ⁇ O)—, R 3 N(R 4 )S(O)m
  • m 0, 1 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • R 5 is H, C 1-4 alkyl, C 1-4 alkyl-(O ⁇ )C— or C 1-4 alkyl-O—(O ⁇ )C—;
  • Q 2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 5-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, hydroxy, C 1-4 alkoxy, halo-substituted Cl 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkyl-(O ⁇ )C—, R 3 (R 4 )C( ⁇ O
  • the invention provides a method of identifying an agent that selectively inhibits EP4 activity in vivo involving administering an agent to an animal model of rheumatoid arthritis, wherein the agent is identified as selectively inhibiting EP4 activity or selectively binding EP4, and measuring joint inflammation, joint swelling, joint ankylosis, interleukin (IL)-6, SAA protein, and/or joint mobility, wherein the agent is identified as selectively inhibiting EP4 activity in vivo if the agent causes reduced joint inflammation, reduced joint swelling, reduced joint ankylosis, reduced interleukin (IL)-6, reduced SAA protein, and/or increased joint mobility in the animal.
  • the agent is identified as selectively inhibiting EP4 activity in vivo involving administering an agent to an animal model of rheumatoid arthritis, wherein the agent is identified as selectively inhibiting EP4 activity or selectively binding EP4, and measuring joint inflammation, joint swelling, joint ankylosis, interleukin (IL)-6, SAA protein, and/or joint mobility, wherein
  • EP4 receptor activity or “EP4 activity” is meant an EP4-mediated increase in cAMP levels upon PGE 2 stimulation.
  • an agent that inhibits EP4 activity or an “EP4 inhibitor” is meant an agent that reduces or attenuates the biological activity of an EP4 receptor.
  • agents may include proteins such as anti-EP4 antibodies, nucleic acids, amino acids, peptides carbohydrates, small molecules (organic or inorganic), or any other compound or composition which decreases the activity of an EP4 receptor either by reducing the amount of EP4 receptor present in a cell, or by decreasing the binding or signaling activity of the EP4 receptor.
  • a “selective” EP4 inhibitor is an agent that inhibits EP4 activity with an IC 50 at least 10-fold less, preferably, at least 100-fold less than the IC 50 for inhibition of EP1, EP2, or EP3 activity, as determined by standard methods known in the art.
  • alkyl means a straight or branched saturated monovalent hydrocarbon radical including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl and the like.
  • alkenyl means a hydrocarbon radical having at least one double bond including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
  • alkynyl means a hydrocarbon radical having at least one triple bond including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.
  • halo refers to F, Cl, Br or I, preferably F or Cl.
  • cycloalkyl means a saturated carbocyclic radical including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • alkoxy means an O-alkyl group wherein “alkyl” is defined above.
  • the term “monocyclic aromatic ring”, as used herein, means a monocyclic aromatic carbocyclic or heterocyclic ring (and containing 0-4 heteroatoms selected from O, N and S) including, but not limited to, phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl and the like.
  • bicyclic aromatic ring means a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring (and containing 0-4 heteroatoms selected from O, N and S) including, but not limited to, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl quinoxalinyl and the like.
  • alkylene means saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons such as methylene, ethylene, propylene, butylene, pentylene, hexylene and the like.
  • cycloalkylene means divalent cycloalkyl groups including, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene and the like.
  • alkenylene means a straight or branched hydrocarbon chain spacer radical having at least one double bond including, but not limited to, —CH ⁇ CH—, —CH ⁇ CHCH—, —CH ⁇ CHCH(CH 3 )—, and the like.
  • alkynylene means a straight or branched hydrocarbon chain spacer radical having at least one triple bond including, but not limited to, —C ⁇ C—, —C—C ⁇ CCH 2 —, —C ⁇ CCH(CH 3 )—, and the like.
  • tricyclic ring means a saturated carbocyclic radical including, but not limited to, adamantyl, tricyclo[5.2.1.0 2,6 ]decane, and the like.
  • two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms
  • oxygen atoms means, but not limited to, —O—CH 2 —O—, —CH 2 —O—CH 2 —, —O—CH 2 CH 2 —, —CH 2 CH 2 —O—, —O—CH 2 CH 2 —O—, —CH 2 CH 2 CH 2 —O—, —O—CH 2 CH 2 CH 2 —, —CH 2 —O—CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 —, and the like.
  • aryl means aromatic radicals including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl and the like.
  • protecting group means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1991);
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • nucleic acids and polypeptides are found in standard textbooks of molecular biology, protein science, and immunology (see, e.g., Davis et al., Basic Methods in Molecular Biology , Elsevir Sciences Publishing, Inc., New York, N.Y., 1986; Hames et al., Nucleic Acid Hybridization , IL Press, 1985; Molecular Cloning , Sambrook et al., Current Protocols in Molecular Biology , Eds. Ausubel et al., John Wiley and Sons; Current Protocols in Human Genetics , Eds. Dracopoli et al., John Wiley and Sons; Current Protocols in Protein Science , Eds. John E. Coligan et al., John Wiley and Sons; and Current Protocols in Immunology , Eds. John E. Coligan et al., John Wiley and Sons). All publications mentioned herein are incorporated by reference in their entireties.
  • FIG. 1 is a bar graph showing the severity of arthritic symptoms in wild type (filled bar) and EP receptor knockout (open bar) mice (*p ⁇ 0.05 by Mann-Whitney).
  • FIG. 2 is a bar graph showing the incidence of arthritic symptoms in wild type (filled bar) and EP receptor knockout (open bar) mice (*p ⁇ 0.05 by Chi-square test).
  • FIG. 3 is a bar graph showing the number of joints affected by arthritis in wild type (filled bar) and EP receptor knockout (open bar) mice.
  • FIG. 4 is a graph showing the time course for development of arthritic symtpoms in WT (filled square) and EP4 receptor knockout (open square) mice (*p ⁇ 0.05 by Student t-test on final day of study only).
  • FIG. 5 is a graph showing the effect of EP4 antagonist Compound A in reducing edema in the ipsilateral paw in rats with adjuvant-induced (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.005; significantly different from disease group untreated with compound, as determined by t-test or Mann-Whitney Rank Sum test).
  • FIG. 6 is a graph showing the effect of EP4 antagonist Compound B in reducing edema in the ipsilateral paw in rats with adjuvant-induced arthritis (*p ⁇ 0.05, **p ⁇ 0.01; significantly different from disease group untreated with compound, as determined by t-test or Mann-Whitney Rank Sum test).
  • FIG. 7 is a bar graph showing the effects of EP4 antagonist Compound A and Compound B in reducing arthritic scores in the limbs of rats with adjuvant-induced arthritis (*p ⁇ 0.05, **p ⁇ 0.01; significantly different from disease group untreated with compound, as determined by t-test or Mann-Whitney Rank Sum test).
  • the present invention is directed to a method of treating symptoms of rheumatoid arthritis by administering an agent that inhibits EP4 activity.
  • This invention is based upon the discovery that EP4 knockout mice are relatively resistant to developing symptoms of arthritis subsequent to disease induction with administration of an anti-type II collagen antibody (an experimental model for rheumatoid arthritis).
  • the invention also features screening methods to identify agents that inhibit EP4 activity in vivo for use, for example, as anti-rheumatoid arthritis therapeutics.
  • Agents identified as EP4 inhibitors are administered in a dose sufficient to reduce joint inflammation, joint swelling, joint ankylosis, interleukin (IL)-6, and/or serum amyloid A protein (SAA), and/or sufficient to increase joint mobility.
  • Such therapeutically effective amounts will be determined using routine optimization techniques that are dependent on the particular condition to be treated, the condition of the patient, the route of administration, the formulation, the judgment of the practitioner, and other factors evident to those skilled in the art in light of this disclosure.
  • An agent that inhibits EP4 activity can be incorporated into a therapeutic composition.
  • EP4 inhibitors can include small molecules, nucleic acids, e.g., EP4 antisense nucleic acids, amino acids, peptides, carbohydrates, and anti-EP4 antibodies.
  • agents are combined with a pharmaceutically acceptable delivery vehicle or carrier.
  • EP4 antibodies include, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, Fab, F(ab′) 2 , and Fab expression library fragments, scFV molecules, and epitope-binding fragments thereof.
  • An antisense oligonucleotide directed to the EP4 gene or mRNA to inhibit its expression is made according to standard techniques (see, e.g., Agrawal et al. Methods in Molecular Biology: Protocols for Oligonucleotides and Analogs , Vol. 20 (1993)).
  • a pharmaceutically acceptable delivery vehicle includes solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic and absorption delaying agents that are compatible with pharmaceutical administration.
  • the vehicle may also include other active or inert components, and/or may be targeted to joint tissue by virtue of its composition.
  • a therapeutic composition is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., by ingestion or inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions can be made as described in Remington's Pharmaceutical Sciences , (18 th ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., (1990)).
  • EP4 inhibitors can be determined in light of this disclosure by standard therapeutic procedures in cell cultures or experimental animals, e.g., for determining the ED 50 (the dose therapeutically effective in 50% of the population).
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage may vary depending upon the formulation and the route of administration.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • treatment of a mammal with a therapeutically effective amount of an EP4 inhibitor can include a single treatment or, preferably, can include a series of treatments.
  • the preferred dosage is generally 10 mg/kg to 20 mg/kg body weight.
  • partially humanized antibodies and filly human antibodies have a longer half-life within the human body than other antibodies. Accordingly, lower dosages and less frequent administration are possible.
  • Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration. A method for lipidation of antibodies is described in Cruikshank et al. (J. Acquired Immune Deficiency Syndromes Hum. Retrovirol. 14: 193, 1997).
  • EP4 inhibitors e.g., antagonists
  • EP4 inhibitors include the aryl and heteroaryl fused imidazole compounds of Formula I, as further described below, and as described in U.S. provisional application No. 60/241,825, filed Oct. 19, 2000, and in Akiyoshi et al., a non-provisional application filed on approximately Oct.
  • EP4 inhibitors that can be administered include those disclosed in EP 0985663, WO 00/15608, WO 00/03980, WO 98/55468, WO 00/01874, WO 01/42281, WO 01/02855, WO 01/10426, WO 00/16760, WO 00/18744, WO 00/16760, WO 00/21532, WO 00/18405, EP 0855389, GB 2330307, and GB 2075503.
  • EP1 receptor knockout (EP1-KO), EP2-KO, EP3-KO, and EP4-KO mice were generated as previously described (Stock et al., J. Clin. Invest. 107: 325-31, 2001; Tilley et al., J. Clin. Invest. 103: 1539-45, 1999; Fleming et al., Am. J. Physiol. 275: F955-61, 1998; Nguyen et al., Nature 390: 78-84,1997, respectively).
  • EP1-KO mice were maintained on a DBA1/lacJ genetic background.
  • EP2-KO and EP4-KO mice were maintained on a 129 ⁇ DBA/2 ⁇ C57/B16 genetic background.
  • EP2 and EP4 littermate wild type mice (WT) were used as controls.
  • EP3-KO animals were maintained on a 129Sv/Ev genetic background. All experiments were performed on 8-10 week old mice (approximate weight: 20 g).
  • mice Arthritis was induced in mice using a monoclonal antibody directed against Type II collagen (mAb treatment).
  • the mAb treatment involved an intraperitoneal (i.p.) injection (400 ⁇ l, 10 mg/ml) of a monoclonal antibody cocktail (Chemicon International Inc., Temecula, Calif.) in the mice on Day 0. After 24 hours, mice were injected i.p. with lipopolysaccharide (LPS) (100 ⁇ l, 0.25 mg/ml) (Chemicon International Inc.) For 10 days following the antibody injection, arthritis was assessed by the degree of swelling, redness, and ankylosis of the joints. All visual factors were combined into a score of 0-3 per paw and summed for a total score of 0-12 for each animal.
  • LPS lipopolysaccharide
  • mice were euthanized by CO 2 asphyxiation, and tissue samples were subjected to a comprehensive histological assessment that included evaluations of cartilage structure, cellularity, Safranin-O staining for acid mucopolysaccharides, and synovial inflammation and hyperplasia to develop Modified Mankin scores (Mankin, et al., J. Bone and Joint Surgery 53: 523-537, 1971).
  • Mankin scale was modified for rodents to reflect rodent size and to include synovial inflammation. The scores were based upon a scale of 0-4 (with 4 designated for the most severe form of arthritic symptoms) graded on a relative severity scale developed for the spectrum of lesions observed in these studies.
  • mice were bled by cardiac puncture. Using a gentle vacuum, blood was collected in Microtainer® serum separator tubes (Becton Dickenson, Franklin Lakes, N.J.) and spun at 1000 ⁇ g for 10 min. at 4° C. The serum fraction was collected and stored at ⁇ 20° C. until assayed for PGE 2 (Cayman Chemical, Ann Arbor, Mich.), IL-6 (R&D Systems, Inc., Minneapolis, Minn.), and serum amyloid A (SAA) (Biosource International, Camarillo, Calif.) levels.
  • PGE 2 Cayman Chemical, Ann Arbor, Mich.
  • IL-6 R&D Systems, Inc., Minneapolis, Minn.
  • SAA serum amyloid A
  • Peritoneal macrophages were collected by removing the skin from the abdomen of Day 10 euthanized mice, and injecting 8 ml of lavage fluid (500 ml Hanks's Balanced Salt Solution, 1 ml 1% EDTA) into the peritoneal cavity. The solution was collected from the peritoneal cavity and placed in 50 ml conical polystyrene tubes on ice. The samples were spun for 10 min. at 300 ⁇ g at room temperature. Lavage fluid (containing peritoneal exudates) was isolated and stored at ⁇ 20° C. until assayed. Interleukin (IL)-6 and PGE 2 levels were measured as described previously. Total protein content was determined by BCA assay (Pierce Chemical, Rockford, Ill.).
  • peritoneal macrophages After the collection of peritoneal macrophages as previously described, the cells were washed twice with lavage solution, and twice with modified DMEM (DMEM, 1% fetal bovine serum, 1% penicillin/streptomycin). The cells were resuspended in 10 ml modified DMEM and the cell concentration was diluted to 10 6 /ml in modified DMEM. Cells were plated in 96-well plates (100 ⁇ l/well), and incubated at 37° C., 95% O 2 , 5% CO 2 for 1-2 hours. After the incubation, the supernatant was removed from the plates by inversion in a sterile tissue culture hood.
  • modified DMEM DMEM, 1% fetal bovine serum, 1% penicillin/streptomycin
  • ⁇ -hexaminidase levels were measured in cell lysates from the remaining macrophages and used to normalize for variability in cell numbers. After collecting the supernatants, the peritoneal macrophages were lysed by adding 200 ⁇ l/well of lysis buffer (25 mM HEPES, pH 7, 0.5% Triton X-100, 250 mM NaCl and proteinase inhibitors (1 ⁇ g/ ⁇ l pepstatin, 1 ⁇ g/ ⁇ l leupeptin, 0.1 mM phenylmethylsulfonyl fluoride, all available from Sigma Chemical Co., St. Louis, Mo.). Plates were incubated on ice for 30 min., and lysates were collected.
  • lysis buffer 25 mM HEPES, pH 7, 0.5% Triton X-100, 250 mM NaCl and proteinase inhibitors (1 ⁇ g/ ⁇ l pepstatin, 1 ⁇ g/ ⁇ l leupeptin, 0.1 mM
  • the lysate sample (10 ⁇ l) was combined with 50 ⁇ l substrate (50 mM sodium citrate, pH 4, 0.2% Triton X-100, 2 mM p-nitrophenyl N-acetyl-beta-D-glucosamine (Sigma Chemical Co.) and incubated at 37° C. for 60 min. Reactions were stopped with 100 ⁇ l carbonate stop solution (0.11 M Na 2 CO 3 , 0.09 M NaHCO 3 , final pH about 10) and well absorbance was read at 415 nm.
  • RNA samples were harvested from Day 10 euthanized mice and snap frozen on dry ice.
  • Total RNA was isolated using Maxiprep columns (Qiagen, Valencia, Calif.) and stored at ⁇ 80° C. until assayed. Absorbance at 260 and 280 nm were determined to estimate RNA levels and purity. All samples had an A 260 to A 280 ratio greater or equal to 1.7.
  • Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and IL-1 mRNA levels were determined by enzyme immunoassay (Quantikine®, R&D systems). GADPH levels were used to normalize IL-1 mRNA levels.
  • EP4 mRNA was measured in WT and EP4-KO liver and peritoneal macrophages by reverse transcription polymerase chain reaction (RT-PCR), using the sense and antisense primers ggtcatcttactcatcgccacctctc (SEQ ID NO: 1) and tcccactaacctcatccaccaacag (SEQ ID NO: 2), respectively (Suzawa, et al. Endocrinology 141: 1554-1559, 2000). Cycling conditions were: 94° C. for 2 min.; 30 cycles at 94° C. for 30 seconds, 65° C. for 30 seconds, and 75° C. for 60 seconds; and 72° C. for 2 min.
  • EP1-KO, EP2-KO, and EP3-KO mAb-treated mice did not display any significant differences from their appropriate WT control in the incidence or severity of the arthritic symptoms.
  • EP4-KO mAb treated mice demonstrated a significant reduction in the severity of the symptoms (FIG. 1), in the number of mice that displayed arthritic symptoms (FIG. 2), and in the number of joints affected (FIG. 3) as compared to mAb-treated WT controls.
  • the differences in arthritis severity were evident throughout the time course of disease development (FIG. 4).
  • MAb-treated EP4-KO mice also displayed a significantly improved histology as compared to their mAb-treated WT controls as shown by Modified Mankin score (Table 1).
  • MAb-treated WT mice often developed a severe form of arthritis with the formation of multiple erosions on the cartilage surface, cellular hyperplasia, loss of proteoglycan, and pannus formation.
  • the articular cartilage of the mAb-treated EP4-KO mice were significantly protected from such damage (Table 1).
  • Non-treated MAb-treated WT EP4-KO WT EP4-KO collagen II 30 ⁇ 1 37 ⁇ 3 *2226 ⁇ 276 *2790 ⁇ 69 mAb (U/ ⁇ l) (6) (6) (8) (8) SAA ( ⁇ g/ml) 552 ⁇ 138 209 ⁇ 72 *3952 ⁇ 1555 293 ⁇ 57 (6) (6) (8) (8) serum IL-6 8 ⁇ 5 8 ⁇ 5 *159 ⁇ 69 *61 ⁇ 25 (pg/ml) (6) (6) (8) (8) exudate IL-6 1 ⁇ 1 1 ⁇ 1 *19 ⁇ 6 6 ⁇ 3 (pg/ml) (6) (6) (6) (6) exudate PGE 2 803 ⁇ 608 182 ⁇ 48 *3346 ⁇ 561 1541 ⁇ 415 (pg/ml) (6) (6) (8) (8)
  • EP4 antagonists included within Formula I as described above were each suspended in 0.1% methylcellulose (MC) and perorally administered separately in five groups of rats from day 0 to day 14 in a volume of 1 ml per 100 g body weight.
  • Hindpaw volume was measured by an hydroplethysmometer (Ugo Basile, Comerio, Italy) on Day 0, immediately before adjuvant injection, and on Days 1, 4, 7, 11 and 14 after injection. Paw swelling (%) was calculated as follows (Agents and Actions 34: 63-65, 1991):
  • the arthritic score of each paw was evaluated as described below.
  • the total arthritic score for each animal was the sum of the score for all four limbs (Agents and Actions 27: 356-358, 1989).
  • a score of 0 was used for limbs with no arthritic symptoms; a score of 1 was used for limbs with redness and swelling in two or less digits or locally in part of the foot pad; a score of 2 was used for limbs with redness and swelling of more than two digits, or in two or less digits and locally in part of the foot pad, or in the whole foot pad; a score of 3 was used for limbs with redness and swelling in more than two digits and locally in part of the foot pad, or in less than two digits and the whole foot pad; a score of 4 was used for limbs with redness and swelling in more than two digits and in the whole foot pad.
  • EP4 Antagonists Aryl and Heteroaryl Fused Imidazole Compounds of Formula I
  • Aryl and heteroaryl fused imidazole compounds of Formula I have the following formula:
  • Y 1 , Y 2 , Y 3 , and Y 4 are preferably independently selected from N, CH and C(L);
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, mono- or di-(C 1-4 alkyl)amino, halo-substituted C 1-4 alkoxy, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C( ⁇ O)N(R 4 )—, R 3 N(R 4 )C( ⁇ O)—, R 3 N(R 4 )S(O)m-, Q 2 —, Q 2 —C( ⁇ O)—, Q 2 —O—,
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkyl-(O ⁇ )C—, R 3 (R 4 )C( ⁇ O)N—,
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, mono- or di-(C 1-4 alkyl)amino, halo-substituted C 1-4 alkoxy, cyano, HO—C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C( ⁇ O)N(R 4 )—, R 3 N(R 4 )C( ⁇ O)—, R 3 N(R 4 )S(O)m-, Q 2 —, Q 2 —C( ⁇ O)—, Q 2 —O—, Q 2 —C 1-4 alkyl-O—
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is a 5 or 6 membered monocyclic aromatic ring, or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from N, CH and C(L);
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is 5 or 6 membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from N, CH and C(L);
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, cyano, HO—C 1-4 alkyl acetyl, R 3 N(R 4 )C( ⁇ O)—, R 3 N(R 4 )S(O)m-, Q 2 —, Q 2 —C( ⁇ O)—, Q 2 —O—, Q 2 —C 1-4 alkyl-O—, or two adjacent L groups are joined together to form a methylenedioxy group;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is 5 or 6 membered monocyclic aromatic ring system, more preferably Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from N, CH and C—L;
  • L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C( ⁇ O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group, more preferably Y 1 , Y 2 , Y 3 and Y 4 are selected from the group consisting of
  • Y 1 and Y 3 are C(L), Y 2 is CH and Y 4 is N;
  • Y 1 is CH, Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 , Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 and Y 3 are C(L), Y 2 is N and Y 4 is CH;
  • Y 1 is C(L) and Y 2 , Y 3 and Y 4 are CH;
  • Y 1 , Y 3 and Y 4 are CH, and Y 2 is C(L);
  • Y 1 , Y 2 and Y 3 are CH, and Y 4 is C(L);
  • Y 1 and Y 2 are C(L), and Y 3 and Y 4 are CH;
  • Y 1 and Y 3 are C(L), and Y 2 and Y 4 are CH;
  • Y 1 and Y 4 are CH, and Y 2 and Y 3 are C(L);
  • Y 1 and Y 2 are CH, Y 3 is C(L) and Y 4 is N;
  • Y 1 and Y 3 are CH, Y 2 is C(L) and Y 4 is N;
  • Y 1 , Y 2 , Y 3 and Y 4 are CH;
  • Y 1 and Y 2 are C(L), Y 3 is CH and Y 4 is N;
  • Y 1 , Y 2 and Y 4 are CH, and Y 3 is C(L);
  • Y 1 and Y 2 are C(L), Y 3 is N and Y 4 is CH;
  • Y 1 and Y 3 are C(L), and Y 2 and Y 4 are N;
  • Y 1 is C(L), Y 2 and Y 3 are CH, and Y 4 is N;
  • Y 2 is C(L), Y 1 and Y 3 are CH, and Y 4 is N;
  • Y 1 , Y 2 and Y 3 are C(L), and Y 4 is CH
  • L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C( ⁇ O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group, most preferably Y 1 , Y 2 , Y 3 and Y 4 are selected from the group consisting of
  • Y 1 and Y 3 are C(L), Y 2 is CH and Y 4 is N;
  • Y 1 is CH, Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 , Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 and Y 3 are C(L), Y 2 is N and Y 4 is CH;
  • Y 1 is C(L) and Y 2 , Y 3 and Y 4 are CH;
  • Y 1 , Y 3 and Y 4 are CH, and Y 2 is C(L);
  • Y 1 , Y 2 and Y 3 are CH, and Y 4 is C(L);
  • Y 1 and Y 2 are C(L), and Y 3 and Y 4 are CH;
  • Y 1 and Y 3 are C(L), and Y 2 and Y 4 are CH;
  • Y 1 and Y 4 are CH, and Y 2 and Y 3 are C(L);
  • Y 1 , Y 2 and Y 3 are C(L), and Y 4 is CH
  • L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C( ⁇ O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
  • R 1 is preferably H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, C 1-8 alkoxy, halo-substituted C 1-8 alkoxy, C 1-8 alkyl-S(O)m-, Q 1 —, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8 alkyl)amino, C 1-4 alkyl-C( ⁇ O)—N(R 3 )— or C 1-4 alkyl-S(O)m-N(R 3 )—, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl are optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C
  • Q 1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O)C—, R 3 N(R 4 )C( ⁇ O)—, C 1-4 alkylsulfonylamino, C 3-7 cyclo
  • m is 0 or 2;
  • R 3 is H or C 1-4 alkyl, more preferably R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, Q 1 —, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8 alkyl)amino, wherein said C 1-8 alkyl is optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C 3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 —, Q 1 —C(O)—, Q 1 —O—, Q 1 —S— or Q 1
  • Q 1 is a 5-12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and is optionally substituted with halo, C 1-4 alkyl, C 1-4 alkylsulfonyl and C 1-4 alkylC( ⁇ O)—;
  • m is 0 or 2, more preferably R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, Q 1 —, or mono- or di-(C 1-8 alkyl)amino wherein said C 1-8 alkyl is optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C 3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 —, Q 1 —C( ⁇ O)—, Q 1 —O—, Q 1 —S—, Q 1 —C 1-4 alkyl-O—, or C 1-4 alkyl-C(O)—N(H)—;
  • Q 1 is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S;
  • m is 0 or 2, more preferably R 1 is C 1-5 alkyl, C 3-7 cycloalkyl, or Q 1 —, mono- or di-(C 1-8 alkyl)amino wherein said C 1-5 alkyl is optionally substituted with C 1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 —, or C 1-4 alkyl-C(O)—N(H)—; and
  • Q 1 is 5-12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S, more preferably R 1 is C 1-5 alkyl, mono- or di-(C 1-8 alkyl)amino, pyrrolidinyl, or pyridyl optionally substituted with C 1-3 alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring is containing 1 or 2 heteroatoms selected from N and S, or C 1-4 alkyl-C(O)—N(H)—, most preferably R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1
  • R 2 is preferably H or C 1-4 alkyl, most preferably H.
  • A is preferably a 5-6 membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N, and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy and halo-substituted C 1-4 alkoxy, more preferably 5-6 membered monocyclic aromatic ring optionally substituted with halo, C 1-4 alkyl or C 1-4 alkoxy, more preferably 5-6 membered monocyclic aromatic ring system optionally substituted with halo or C 1-4 alkyl, more preferably 5-6 membered err monocyclic aromatic ring system, most preferably phenyl or pyridyl.
  • B is preferably C 3-7 cycloalkylene or C 1-6 alkylene optionally substituted with an oxo group or C 1-3 alkyl, more preferably C 1-3 alkylene optionally substituted with C 1-3 alkyl, more preferably C 1-2 alkylene optionally substituted with methyl, most preferably ethylene or propylene.
  • W is preferably NH, N—C 1-4 alkyl, O or N—OH, more preferably NH, N—C 1-2 alkyl or O, most preferably NH, N—CH 3 or O.
  • Z is preferably a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from, N, O, and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, hydroxy, C 1-4 alkoxy, nitro, amino, cyano, HO—C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, R 3 C( ⁇ O)N(R 4 )—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 1-4 alkyl-C( ⁇ O)NH—, Q 2 —S(O)m-, Q 2 —O—, Q
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkyl-(O ⁇ )C—, R 3 (R 4 )C( ⁇ O)N—,
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is a 5 or 6 membered monocyclic aromatic ring, or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkoxy, nitro, amino, cyano, R 3 C( ⁇ O)N(R 4 )—, C 1-4 alkyl-O(O ⁇ )C—, Q 2 —S(O)m-, Q 2 —O—, Q 2 —N(R 3 )— or Q 2 —;
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is 5 or 6 membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, nitro, R 3 C( ⁇ O)N(R 4 )— or Q 2 —;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is 5 or 6 membered monocyclic aromatic ring system, more preferably Z is 5-10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-10 membered monocyclic aromatic ring is optionally substituted with chloro, bromo, methyl, nitro, CH 3 C( ⁇ O)NH—, tBuC( ⁇ O)NH— or phenyl, most preferably Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl.
  • a preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from N, CH and C(L);
  • R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, C 1-8 alkoxy, halo-substituted C 1-8 alkoxy, C 1-8 alkyl-S(O)m-, Q 1 —, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8 alkyl)amino, C 1-4 alkyl-C( ⁇ O)—N(R 3 )— or C 1-4 alkyl-S(O)m-N(R 3 )—, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl are optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C 3-7
  • Q 1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O)C—, R 3 N(R 4 )C( ⁇ O)—, C 1-4 alkylsulfonylamino, C 3-7 cyclo
  • A is a 5-6 membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N, and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy and halo-substituted C 1-4 alkoxy;
  • B is C 3-7 cycloalkylene or C 1-6 alkylene optionally substituted with an oxo group or C 1-3 alkyl;
  • W is NH, N—C 1-4 alkyl, O or N—OH;
  • R 2 is H or C 1-4 alkyl
  • Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, hydroxy, C 1-4 alkoxy, nitro, amino, cyano, HO—C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, R 3 C( ⁇ O)N(R 4 )—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 1-4 alkyl-C( ⁇ O)NH—, Q 2 —S(O)m-, Q 2 —O—, Q 2 —N(
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, mono- or di-(C 1-4 alkyl)amino, halo-substituted C 1-4 alkoxy, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C( ⁇ O)N(R 4 )—, R 3 N(R 4 )C( ⁇ O)—, R 3 N(R 4 )S(O)m-, Q 2 —, Q 2 —C( ⁇ O)—, Q 2 —O—
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkyl-(O ⁇ )C—, R 3 (R 4 )C( ⁇ O)N—,
  • a further preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from N, CH and C(L);
  • R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, Q 1 —, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8 alkyl)amino, wherein said C 1-8 alkyl is optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C 3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1—, Q 1 —C(O)—, Q 1 —O—, Q 1 —S—, Q 1 —C 1-4 alkyl-O—, or C 1-4
  • Q 1 is a 5-12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and is optionally substituted with halo, C 1-4 alkyl, C 1-4 alkylsulfonyl and C 1-4 alkylC( ⁇ O)—;
  • A is 5-6 membered monocyclic aromatic ring optionally substituted with halo, C 1-4 alkyl or C 1-4 alkoxy;
  • B is C 3-7 cycloalkylene or C 1-6 alkylene optionally substituted with an oxo group or C 1-3 alkyl;
  • W is NH, N—C 1-4 alkyl, O or N—OH;
  • R 2 is H or C 1-4 alkyl
  • Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkoxy, nitro, amino, cyano, R 3 C( ⁇ O)N(R 4 )—, C 1-4 alkyl-O(O ⁇ )C—, Q 2 —S(O)m-, Q 2 —O—, Q 2 —N(R 3 )— or Q 2 —;
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O)—, HO(O ⁇ )C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C( ⁇ O)N(R 4 )—, R 3 N(R 4 )C( ⁇ O)—, R 3 N(R 4 )S(O)m-, Q 2 —, Q 2 —C( ⁇ O)—, Q 2 —O—, Q 2 —C 14 alkyl-O—,
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is a 5 or 6 membered monocyclic aromatic ring, or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo.
  • a further preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 and Y 4 are independently selected from N, CH and C(L);
  • R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl or C 3-7 cycloalkyl, wherein said C 1-8 alkyl is optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C 3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 —, Q 1 —C( ⁇ O)—, Q 1 —O—, Q 1 —S—, Q 1 —C 1-4 alkyl-O—, or C 1-4 alkyl-C(O)—N(R 3 )—;
  • Q 1 is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S;
  • A is 5-6 membered monocyclic aromatic ring system optionally substituted with halo or C 1-4 alkyl;
  • B is or C 3-7 cycloalkylene or C 1-6 alkylene optionally substituted with an oxo group or C 1-3 alkyl;
  • W is NH, N—C 1-4 alkyl, O or N—OH;
  • R 2 is H or C 1-4 alkyl
  • Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkoxy, nitro, amino, cyano, R 3 C( ⁇ O)N(R 4 )—, C 1-4 alkyl-O(O ⁇ )C—, Q 2 —S(O)m-, Q 2 —O—, Q 2 —N(R 3 )— or Q 2 —;
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, cyano, HO—C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC( ⁇ O), HO(O ⁇ ) C—, C 1-4 alkyl-O(O ⁇ )C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C( ⁇ O)NR 4 —, R 3 N(R 4 )C( ⁇ O)—, R 3 N(R 4 )S(O)m-, Q 2 —, Q 2 —C( ⁇ O)—, Q 2 —O—, Q 2 —C 1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4
  • m is 0 or 2;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is 5 or 6 membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo.
  • a further preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 and Y 4 are independently selected from N, CH and C(L);
  • R 1 is C 1-5 alkyl or C 3-7 cycloalkyl, wherein said C 1-5 alkyl is optionally in substituted with C 1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 —, or C 1-4 alkyl-C(O)—N(H)—;
  • Q 1 is 5-12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S,
  • A is 5-6 membered monocyclic aromatic ring system
  • B is C 1-3 alkylene optionally substituted with C 1-3 alkyl
  • W is NH, N—C 1-2 alkyl or O;
  • R 2 is H
  • Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, nitro, R 3 C( ⁇ O)N(R 4 )— or Q 2 —;
  • L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl , hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, cyano, HO—C 1-4 alkyl, acetyl, R 3 N(R 4 )C( ⁇ O)—,
  • R 3 N(R 4 )S(O)m-, Q 2 —, Q 2 —C( ⁇ O)—, or two adjacent L groups are joined together to form a methylenedioxy group;
  • R 3 and R 4 are independently selected from H and C 1-4 alkyl
  • Q 2 is 5 or 6 membered monocyclic aromatic ring system.
  • a further preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 and Y 4 are independently selected from N, CH and C—L;
  • R 1 is C 1-5 alkyl optionally substituted with C 1-3 alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring is containing 1 or 2 heteroatoms selected from N and S, or C 1-4 alkyl-C(O)—N(R 3 )—;
  • A is phenyl
  • B is C 1-2 alkylene optionally substituted with methyl
  • W is NH, N—CH 3 or O
  • R 2 is H
  • Z is 5-10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-10 membered monocyclic aromatic ring is optionally substituted with chloro, bromo, methyl, nitro, CH 3 C( ⁇ O)NH—, tBuC( ⁇ O)NH— or phenyl; and
  • L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C( ⁇ O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
  • a further preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 and Y 4 are independently selected from N, CH and C—L;
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
  • A is phenyl
  • B is ethylene or propylene
  • W is NH, N—CH 3 or O
  • R 2 is H
  • Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
  • L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C( ⁇ O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
  • a further preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 and Y 4 are selected from the group consisting of
  • Y 1 and Y 3 are C(L), Y 2 is CH and Y 4 is N;
  • Y 1 is CH, Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 , Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 and Y 3 are C(L), Y 2 is N and Y 4 is CH;
  • Y 1 is C(L) and Y 2 , Y 3 and Y 4 are CH;
  • Y 1 , Y 3 and Y 4 are CH, and Y 2 is C(L);
  • Y 1 , Y 2 and Y 3 are CH, and Y 4 is C(L);
  • Y 1 and Y 2 are C(L), and Y 3 and Y 4 are CH;
  • Y 1 and Y 3 are C(L), and Y 2 and Y 4 are CH;
  • Y 1 and Y 4 are CH, and Y 2 and Y 3 are C(L);
  • Y 1 and Y 2 are CH, Y 3 is C(L) and Y 4 is N;
  • Y 1 and Y 3 are CH, Y 2 is C(L) and Y 4 is N;
  • Y 1 , Y 2 , Y 3 and Y 4 are CH;
  • Y 1 and Y 2 are C(L), Y 3 is CH and Y 4 is N;
  • Y 1 , Y 2 and Y 4 are CH, and Y 3 is C(L);
  • Y 1 and Y 2 are C(L), Y 3 is N and Y 4 is CH;
  • Y 1 and Y 3 are C(L), and Y 2 and Y 4 are N;
  • Y 1 is C(L), Y 2 and Y 3 are CH, and Y 4 is N;
  • Y 2 is C(L), Y 1 and Y 3 are CH, and Y 4 is N;
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
  • A is phenyl
  • B is ethylene or propylene
  • W is NH, N—CH 3 or O
  • R 2 is H
  • Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
  • L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C( ⁇ O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
  • a further preferred group of compounds of Formula I includes compounds wherein
  • Y 1 , Y 2 , Y 3 and Y 4 are selected from the group consisting of
  • Y 1 and Y 3 are C(L), Y 2 is CH and Y 4 is N;
  • Y 1 is CH, Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 , Y 2 and Y 3 are C(L) and Y 4 is N;
  • Y 1 and Y 3 are C(L), Y 2 is N and Y 4 is CH;
  • Y 1 is C(L) and Y 2 , Y 3 and Y 4 are CH;
  • Y 1 , Y 3 and Y 4 are CH, and Y 2 is C(L);
  • Y 1 , Y 2 and Y 3 are CH, and Y 4 is C(L);
  • Y 1 and Y 2 are C(L), and Y 3 and Y 4 are CH;
  • Y 1 and Y 3 are C(L), and Y 2 and Y 4 are CH;
  • Y 1 and Y 4 are CH, and Y 2 and Y 3 are C(L);
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
  • A is phenyl
  • B is ethylene or propylene
  • W is NH, N—CH 3 or O
  • R 2 is H
  • Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
  • L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C( ⁇ O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
  • Preferred individual compounds of Formula I are following:
  • Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM).
  • Low-resolution mass spectral data (EI) were obtained on a Automass 120 (JEOL) mass spectrometer.
  • Low-resolution mass spectral data (ESI) were obtained on a Quattro II (Micromass) mass spectrometer or a ZMD (Micromass).
  • IR spectra were measured by a Shimazu infrared spectrometer (IR-470).
  • step 3 To a stirred solution of 2- ⁇ 4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl ⁇ ethanol (step 3, 1.6 g, 5.6 mmol) in ethyl acetate (15 mL) was added 10% Pd—C (160 mg). The mixture was stirred at room temperature for 6 h under hydrogen atmosphere. The palladium catalyst was removed by filtration and washed with ethanol (100 mL).
  • Step 1 N- ⁇ 2-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyndin -3-yl)phenyl]ethyl ⁇ -N-methylamine
  • Step 8. 1-[4-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]2-propanamine
  • Step 1 2-[4-(5,7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridin -3-yl)phenyl]ethyl butyrate
  • Step 6 5,7-Dimethyl-3-(4- ⁇ 2-[( ⁇ [(4-methylphenyl)sulfonyl]amino ⁇ carbonyl)amino]ethyl ⁇ phenyl)-2-propyl -3H-imidazo[4.5-b]pyridine
  • Step 7 6-Bromo-3-[4-(2-chloroethyl)phenyl]-2-isopropyl-5,7-dimethyl -3H-imidazo[4,5-b]pyridine
  • Step 8 2-[4-(6-Bromo-2-isopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin -3-yl)phenyl]ethyl azide
  • Step 10 2-Isopropyl-5,7-dimethyl-3-(4- ⁇ 2-[( ⁇ [(4-methylphenyl)sulfonyl]amino ⁇ carbonyl)amino]ethyl ⁇ phenyl)-3H-imidazo[4,5-b]pyridine
  • Step 1 2-[4-(2-Isobutyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin -3-yl)phenyl]ethyl3-methylbutanoate
  • Step 2 N 2 -[4-(2-Chloroethyl)phenyl]-4,6-dimethyl-2,3-pyridinediamine
  • Step 4 2-(4- ⁇ 5,7-Dimethyl-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridin-3-yl ⁇ phenyl)ethyl azide
  • the title compound was prepared according to the procedure described in step 8 Example 1 from 3-[4-(2-chloroethyl)phenyl]-5,7-dimethyl-2-[2-(1,3-thiazol -2-yl)ethyl]-3H-imidazo[4,5-b]pyridine (step 3).
  • Step 6 5,7-Dimethyl-3-(4- ⁇ 2-[( ⁇ [(4-methylphenyl)sulfonyl]amino ⁇ carbonyl)amino]ethyl ⁇ phenyl)-2-[2-(1,3-thiazole -2-yl)ethyl]-3H-imidazo[4,5-b]pyridine
  • step 2 To a solution of 2- ⁇ 4-[(6-methyl-3-nitro-2-pyridinyl)amino]phenyl ⁇ ethanol (step 1, 4.6 g, 16.9 mmol) in methanol (100 mL) was added 10% Pd—C (300 mg). The resulting mixture was stirred for 2 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated.
  • TLC Rf 0.50 (hexane/ethyl acetate 2:1).
  • Step 7 6-Chloro-2-ethyl-3-(4- ⁇ 2-[( ⁇ [(4-methylphenyl)sulfonyl]amino ⁇ carbonyl)amino]ethyl ⁇ phenyl) -3H-imidazo[4,5-b]pyridine
  • the mixture was diluted with ethyl acetate (100 mL) and washed with 1N aqueous NaOH (50 mL) and brine (50 mL). The organic layer was dried (Na 2 SO 4 ), and concentrated.
  • Step 8 2-Ethyl-5,6-dimethyl-3-(4- ⁇ 2-[( ⁇ [(4-methylphenyl)sulfonyl]amino ⁇ carbonyl)amino]ethyl ⁇ phenyl)-3H-imidazo[4,5-b]pyridine
  • Step 8. 5,6-Dichloro-2-ethyl-3-(4- ⁇ 2-[( ⁇ [(4-methylphenyl)sulfonyl]amino ⁇ carbonyl)amino]ethyl ⁇ phenyl)-3H-imidazo[4,5-b]pyridine
  • Step 8 5-Chloro-2-ethyl-6-methyl-3-(4- ⁇ 2-[( ⁇ [(4-methylphenyl)sulfonyl]amino ⁇ carbonyl)amino]ethyl ⁇ phenyl)-3H-imidazo[4,5-b]pyridine
  • TLC Rf 0.05 (ethyl acetate).
  • TLC Rf 0.1 (ethyl acetate).

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040142034A1 (en) * 2002-12-20 2004-07-22 Dynogen Pharmaceuticals, Inc. Methods of treating non-painful bladder disorders using alpha2delta subunit calcium channel modulators
US20060069127A1 (en) * 2004-06-28 2006-03-30 Zice Fu Imidazolo-related compounds, compositions and methods for their use
US7074801B1 (en) * 2001-04-26 2006-07-11 Eisai Co., Ltd. Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof
WO2007073405A1 (en) * 2005-12-21 2007-06-28 Decode Genetics Ehf N-linked aryl heteroaryl inhibitors of lta4h for treating inflammation
US10059663B2 (en) 2013-08-29 2018-08-28 Kyoto Pharmaceutical Industries, Ltd. Aromatic compound and use thereof
RU2811411C2 (ru) * 2014-03-06 2024-01-11 Аратана Терапьютикс, Инк. Композиции грапипранта и способы их применения

Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7544511B2 (en) * 1996-09-25 2009-06-09 Neuralstem Biopharmaceuticals Ltd. Stable neural stem cell line methods
CA2482382A1 (en) * 2002-04-12 2003-10-23 Pfizer Inc. Pyrazole compounds as anti-inflammatory and analgesic agents
MXPA04009243A (es) 2002-04-12 2005-06-08 Pfizer Uso de ligandos para el receptor ep4 en el tratamiento de enfermedades vinculadas a il-6.
EP1494667A1 (en) * 2002-04-12 2005-01-12 Pfizer Japan Inc. Imidazole compounds as anti-inflammatory and analgesic agents
US8293488B2 (en) 2002-12-09 2012-10-23 Neuralstem, Inc. Method for screening neurogenic agents
WO2004053071A2 (en) * 2002-12-09 2004-06-24 Judith Kelleher-Andersson Method for discovering neurogenic agents
EP1593668A4 (en) * 2003-02-14 2007-07-11 Wako Pure Chem Ind Ltd METHOD FOR PRODUCING A HYDROXYLAMINE COMPOUND USING A PLATINATE CATALYST IMMOBILIZED ON AN ION EXCHANGE RESIN
EP1602648B1 (en) * 2003-03-13 2013-04-17 Idemitsu Kosan Co., Ltd. Nitrogen-containing heterocycle derivative and organic electroluminescent element using the same
US20070105931A1 (en) * 2003-08-04 2007-05-10 Mayo Foundation For Medical Education And Research Methods and compositions for inhibiting the proliferation of prostate cancer cells
FR2860514A1 (fr) * 2003-10-03 2005-04-08 Sanofi Synthelabo Derives d'arylalkylcarbamates, leur preparation et leur application en therapeutique
ATE458201T1 (de) * 2003-12-23 2010-03-15 Hoffmann La Roche Methode zur beurteilung von rheumatoider arthritis durch bestimmung von anti-ccp und interleukin 6
CN1946391A (zh) * 2004-04-20 2007-04-11 辉瑞产品公司 包含α－2－δ配体的组合
CN104042629A (zh) 2004-11-17 2014-09-17 神经干公司 用于治疗神经变性症状的人类神经细胞的移植
US7442716B2 (en) * 2004-12-17 2008-10-28 Merck Frosst Canada Ltd. 2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors
WO2006063466A1 (en) * 2004-12-17 2006-06-22 Merck Frosst Canada Ltd. 2-(phenyl or heterocyclic)-1h-phenantrho[9,10-d]imidazoles as mpges-1 inhibitors
WO2006095268A1 (en) * 2005-03-11 2006-09-14 Pfizer Japan Inc. Crystal forms of an imidazole derivative
EP2019675A4 (en) * 2006-05-02 2011-03-02 Merck Frosst Canada Ltd METHODS FOR TREATING OR PREVENTING NEOPLASIA
CL2007002994A1 (es) * 2006-10-19 2008-02-08 Wyeth Corp Compuestos derivados heterociclicos que contienen sulfamoilo, inhibidores de hsp90; composicion farmaceutica; y uso para el tratamiento del cancer, tal como cancer de mama, de colon y prostata, entre otros.
JP2010522218A (ja) * 2007-03-26 2010-07-01 メルク フロスト カナダ リミテツド Ｅｐ４受容体アンタゴニストとしてのナフタレン及びキノリンスルホニル尿素誘導体
DE102007037579B4 (de) 2007-08-09 2012-05-16 Emc Microcollections Gmbh Neue Benzimidazol-2-yl-alkylamine und ihre Anwendung als mikrobizide Wirkstoffe
CA2698075C (en) 2007-08-27 2016-04-12 Siga Technologies, Inc. Antiviral drugs for treatment of arenavirus infection
JP2011509990A (ja) 2008-01-22 2011-03-31 オキサジェン リミテッド Ｃｒｔｈ２アンタゴニスト活性を有する化合物
CN102224154A (zh) * 2008-09-25 2011-10-19 默克弗罗斯特加拿大有限公司 作为EP4受体拮抗剂的β-咔啉磺酰脲衍生物
WO2010087425A1 (ja) 2009-01-30 2010-08-05 国立大学法人京都大学 前立腺癌の進行抑制剤および進行抑制方法
ES2698508T3 (es) 2009-04-22 2019-02-05 Askat Inc Sustancia antagonista del receptor EP4 selectivo para el tratamiento del cáncer
KR101041561B1 (ko) * 2009-12-21 2011-06-15 짚라인코리아 (주) 비행용 착용복
US9457084B2 (en) * 2010-02-22 2016-10-04 Raqualia Pharma Inc. Use of EP4 receptor antagonists in the treatment of IL-23 mediated diseases
US9540611B2 (en) 2010-07-28 2017-01-10 Neuralstem, Inc. Methods for treating and/or reversing neurodegenerative diseases and/or disorders
PT2619182T (pt) 2010-09-21 2017-01-17 Eisai R&D Man Co Ltd Composição farmacêutica
CA2825134A1 (en) * 2011-01-25 2012-08-02 Kissei Pharmaceutical Co., Ltd. Indole derivative, and pharmacologically acceptable salt thereof
TW201326154A (zh) * 2011-11-28 2013-07-01 拜耳知識產權公司 作為ｅｐ２受體拮抗劑之新穎２ｈ－吲唑
UA115576C2 (uk) 2012-12-06 2017-11-27 Байєр Фарма Акцієнгезелльшафт Похідні бензимідазолу як антагоністи ер4
US10391086B2 (en) 2013-03-19 2019-08-27 Askat Inc. Use of EP4 receptor antagonists in the treatment of cartilage disease
EP2976105B1 (en) * 2013-03-19 2023-01-04 AskAt Inc. Use of ep4 receptor antagonists in the treatment of cartilage disease
WO2014153280A1 (en) * 2013-03-22 2014-09-25 Merck Sharp & Dohme Corp. 2-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors
TW201607943A (zh) 2013-12-19 2016-03-01 拜耳製藥公司 作為ｅｐ４配體之新穎苯并咪唑衍生物
EP3511000B1 (en) 2014-03-06 2022-04-27 Elanco Animal Health Incorporated Crystalline form x2 of grapiprant
WO2015134792A1 (en) * 2014-03-06 2015-09-11 Aratana Therapeutics, Inc. Compositions of grapiprant and methods for using the same
KR20190060016A (ko) 2014-10-20 2019-05-31 뉴럴스템, 인크. 성장 인자를 코딩하는 외인성 폴리뉴클레오티드를 포함하는 안정한 신경 줄기세포 및 그의 사용 방법
WO2017007755A1 (en) 2015-07-06 2017-01-12 Rodin Therapeutics, Inc. Heterobicyclic n-aminophenyl-amides as inhibitors of histone deacetylase
WO2017007756A1 (en) 2015-07-06 2017-01-12 Rodin Therapeutics, Inc Hetero-halo inhibitors of histone deacetylase
CN105486851A (zh) * 2015-11-20 2016-04-13 中国药科大学 一种基于荧光共振能量转移技术的前列腺素受体4筛选模型
CR20180323A (es) 2015-11-20 2018-08-06 Idorsia Pharmaceuticals Ltd Derivados de indol n-sustituídos como moduladores de los receptores de pge2
US10342785B2 (en) 2016-11-04 2019-07-09 Askat Inc. Use of EP4 receptor antagonists for the treatment of NASH-associated liver cancer
EP3570834B1 (en) 2017-01-11 2021-12-22 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
WO2018162562A1 (en) 2017-03-10 2018-09-13 Bayer Pharma Aktiengesellschaft Use of an ep4 antagonist for the treatment of inflammatory pain
KR102650756B1 (ko) 2017-05-18 2024-03-22 이도르시아 파마슈티컬스 리미티드 N-치환된 인돌 유도체
RS62398B1 (sr) 2017-05-18 2021-10-29 Idorsia Pharmaceuticals Ltd Derivati pirimidina kao modulatori receptora pge2
US11446298B2 (en) 2017-05-18 2022-09-20 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives
US11712438B2 (en) 2017-05-18 2023-08-01 Idorsia Pharmaceuticals Ltd Phenyl derivatives as PGE2 receptor modulators
CN110621671A (zh) 2017-05-18 2019-12-27 爱杜西亚药品有限公司 作为pge2受体调节剂的苯并呋喃及苯并噻吩衍生物
MA49839B1 (fr) 2017-08-07 2022-05-31 Alkermes Inc Inhibiteurs bicycliques de la histone déacétylase
WO2019038156A1 (en) 2017-08-22 2019-02-28 Bayer Pharma Aktiengesellschaft USE OF AN EP4 ANTAGONIST FOR THE TREATMENT OF ARTHRITIS
RU2659169C1 (ru) * 2017-10-31 2018-06-28 Федеральное бюджетное учреждение науки "Уфимский научно-исследовательский институт медицины труда и экологии человека" Способ прогнозирования риска развития иммуноопосредованных заболеваний у работающих в условиях обсеменённости воздуха рабочей зоны условно-патогенными микроорганизмами
EP3781162A1 (en) * 2018-04-16 2021-02-24 Arrys Therapeutics, Inc. Ep4 inhibitors and use thereof
WO2019245590A1 (en) 2018-06-18 2019-12-26 Avista Pharma Solutions, Inc. Chemical compounds
US20210300921A1 (en) * 2018-07-11 2021-09-30 Arrys Therapeutics, Inc. Ep4 inhibitors and synthesis thereof
US20210315909A1 (en) * 2018-07-11 2021-10-14 Arrys Therapeutics, Inc. Polymorphic compounds and uses thereof
KR20210125471A (ko) 2018-10-05 2021-10-18 안나푸르나 바이오, 인코포레이티드 Apj 수용체 활성과 관련된 병태를 치료하기 위한 화합물 및 조성물
CA3128346A1 (en) 2019-01-30 2020-08-06 Avista Pharma Solutions, Inc. Synthetic process and novel intermediates
US11459331B2 (en) 2019-01-30 2022-10-04 Avista Pharma Solutions, Inc. Chemical compounds
WO2021027722A1 (zh) * 2019-08-09 2021-02-18 成都先导药物开发股份有限公司 一种免疫调节剂
US11254675B2 (en) 2019-08-12 2022-02-22 Cadila Healthcare Limited Process for preparation of grapiprant
WO2021226162A1 (en) 2020-05-05 2021-11-11 Arrys Therapeutics, Inc. Ep4 antagonists and their use in the treatment of proliferative diseases
EP4245301A1 (en) 2020-11-13 2023-09-20 ONO Pharmaceutical Co., Ltd. Cancer treatment by combined use of ep4 antagonist and immune checkpoint inhibitor

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8804439D0 (en) * 1988-02-25 1988-03-23 Pfizer Ltd Dihydropyridines
IL94805A (en) 1989-06-28 1994-04-12 Ciba Geigy Ag Certain translocated carboxylic acids (a) Arylsulfonamide - and pyridyl - or imidazolil (), process for their preparation and pharmaceutical preparations containing them
GB9009469D0 (en) * 1990-04-27 1990-06-20 British Bio Technology Compounds
GB9010404D0 (en) * 1990-05-09 1990-06-27 Pfizer Ltd Therapeutic agents
GB2330307A (en) 1998-02-07 1999-04-21 Glaxo Group Ltd EP4 Receptor antagonists as bone resorption inhibitors
WO1999047497A2 (en) * 1998-03-13 1999-09-23 Merck Frosst Canada & Co. Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment
AU1444200A (en) 1998-10-15 2000-05-01 Merck & Co., Inc. Methods for inhibiting bone resorption
CA2346031A1 (en) * 1998-10-15 2000-04-20 Merck & Co., Inc. Methods for stimulating bone formation
JP2000191615A (ja) * 1998-10-20 2000-07-11 Takeda Chem Ind Ltd 芳香族アミン誘導体、その製造法および剤
PT1183245E (pt) 1999-04-22 2007-07-12 Lundbeck & Co As H Antagonistas selectivos de npy (y5)
BR0010605A (pt) 1999-04-28 2002-02-13 Aventis Pharma Gmbh Derivados ácidos de di-aril como ligantes de receptores ppar
GB0031295D0 (en) 2000-12-21 2001-01-31 Glaxo Group Ltd Naphthalene derivatives
GB0031302D0 (en) 2000-12-21 2001-01-31 Glaxo Group Ltd Napthalene derivatives
GB0031315D0 (en) 2000-12-21 2001-02-07 Glaxo Group Ltd Indole derivatives

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7074801B1 (en) * 2001-04-26 2006-07-11 Eisai Co., Ltd. Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof
US20040142034A1 (en) * 2002-12-20 2004-07-22 Dynogen Pharmaceuticals, Inc. Methods of treating non-painful bladder disorders using alpha2delta subunit calcium channel modulators
US20060069127A1 (en) * 2004-06-28 2006-03-30 Zice Fu Imidazolo-related compounds, compositions and methods for their use
US7271271B2 (en) * 2004-06-28 2007-09-18 Amgen Sf, Llc Imidazolo-related compounds, compositions and methods for their use
WO2007073405A1 (en) * 2005-12-21 2007-06-28 Decode Genetics Ehf N-linked aryl heteroaryl inhibitors of lta4h for treating inflammation
US7674802B2 (en) 2005-12-21 2010-03-09 Decode Genetics, Ehf N-linked aryl heteroaryl inhibitors of LTA4H for treating inflammation
US10059663B2 (en) 2013-08-29 2018-08-28 Kyoto Pharmaceutical Industries, Ltd. Aromatic compound and use thereof
RU2811411C2 (ru) * 2014-03-06 2024-01-11 Аратана Терапьютикс, Инк. Композиции грапипранта и способы их применения

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