EP1622916A2 - Heterocyclische cyclopentyltetrahydroisochinolin- und -tetrahydropyridopyridinmodulatoren der chemokinrezeptoraktivität - Google Patents

Heterocyclische cyclopentyltetrahydroisochinolin- und -tetrahydropyridopyridinmodulatoren der chemokinrezeptoraktivität

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Publication number
EP1622916A2
EP1622916A2 EP04750112A EP04750112A EP1622916A2 EP 1622916 A2 EP1622916 A2 EP 1622916A2 EP 04750112 A EP04750112 A EP 04750112A EP 04750112 A EP04750112 A EP 04750112A EP 1622916 A2 EP1622916 A2 EP 1622916A2
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European Patent Office
Prior art keywords
mmol
6alkyl
substituents
alkyl
substituted
Prior art date
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EP04750112A
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English (en)
French (fr)
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EP1622916A4 (de
Inventor
Gabor Butora
Stephen D. Goble
Alexander Pasternak
Lihu Yang
Changyou Zhou
Christopher R. Moyes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
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Merck Sharp and Dohme Ltd
Merck and Co Inc
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Publication of EP1622916A2 publication Critical patent/EP1622916A2/de
Publication of EP1622916A4 publication Critical patent/EP1622916A4/de
Withdrawn legal-status Critical Current

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Definitions

  • chemokines are a family of small (70-120 amino acids), proinflammatory cytokines, with potent chemotactic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall,
  • Cytokine 3, 165-183 (1991) and Murphy, Rev. Immun.. 12, 593-633 (1994)). These molecules were originally defined by four conserved cysteines and divided into two subfamilies based on the arrangement of the first cysteine pair. In the CXC-chemokine family, which includes IL-8, GRO ⁇ , NAP-2 and IP-10, these two cysteines are separated by a single amino acid, while in the CC-chemokine family, which includes RANTES, MCP-1, MCP-2, MCP-3, MTP-l ⁇ , MIP-l ⁇ and eotaxin, these two residues are adjacent.
  • ⁇ -chemokines such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas ⁇ -chemokines, such as RANTES, MEP-lcc, MlP-l ⁇ , monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, monocytes, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-666 (1996)).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • the chemokines are secreted by a wide variety of cell types and bind to specific G-protein coupled receptors (GPCRs) (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) present on leukocytes and other cells. These chemokine receptors form a sub-family of GPCRs, which, at present, consists of fifteen characterized members and a number of orphans. Unlike receptors for promiscuous chemoattractants such as C5a, fMLP, PAF, and LTB4, chemokine receptors are more selectively expressed on subsets of leukocytes. Thus, generation of specific chemokines provides a mechanism for recruitment of particular leukocyte subsets.
  • GPCRs G-protein coupled receptors
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • CCR-1 or "CKR-1" or "CC-CKR- 1" [MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem..
  • CCR-4 or "CKR-4" or "CC-CKR-4" [MTP-l ⁇ , RANTES, MCP-1] (Rollins, et al., Blood. 90, 908-928 (1997)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MlP-l ⁇ , RANTES, MlP-l ⁇ ] (Sanson, et al., Biochemistry. 35, 3362-3367 (1996)); and the Duffy blood- group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem.. 269, 7835-7838 (1994)).
  • the ⁇ -chemokines include eotaxin, MEP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted”) among other chemokines.
  • Chemokine receptors such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-
  • CCR-5, CXCR-3, CXCR-4 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • Humans who are homozygous for the 32-basepair deletion in the CCR-5 gene appear to have less susceptibility to rheumatoid arthritis (Gomez, et al., Arthritis & Rheumatism. 42, 989-992 (1999)).
  • chemokines are potent chemoattractants for monocytes and macrophages.
  • MCP-1 monocyte chemoattractant protein-1
  • CCR2 primary receptor for monocytes and macrophages.
  • MCP-1 is produced in a variety of cell types in response to inflammatory stimuli in various species, including rodents and humans, and stimulates chemotaxis in monocytes and a subset of lymphocytes. In particular, MCP-1 production correlates with monocyte and macrophage infiltration at inflammatory sites.
  • agents which modulate chemokine receptors such as the CCR-2 receptor would be useful in such disorders and diseases.
  • the recruitment of monocytes to inflammatory lesions in the vascular wall is a major component of the pathogenesis of atherogenic plaque formation.
  • MCP-1 is produced and secreted by endothelial cells and intimal smooth muscle cells after injury to the vascular wall in hypercholesterolemic conditions.
  • Monocytes recruited to the site of injury infiltrate the vascular wall and differentiate to foam cells in response to the released MCP-1.
  • CCR2 antagonists may inhibit atherosclerotic lesion formation and pathological progression by impairing monocyte recruitment and differentiation in the arterial wall.
  • the present invention is further directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
  • the present invention is directed to compounds of the formula I:
  • X is selected from: C, N, O, S and SO 2 ;
  • Y is selected from N or C.
  • R is selected from: hydrogen, -C ⁇ _6alkyl, -C ⁇ -6alkyl-O-Ci-6alkyl, -C ⁇ -6alkyl-S-Ci-6alkyl,
  • R 11 is independently selected from: hydroxy, hydrogen,
  • R 13 is selected from: hydrogen, Cl-6 alkyl, -O-C ⁇ -6 alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, Ci-3alkyl, Ci-3alkoxy, -CO2H, - CO2-C1-6 alkyl, and trifluoromethyl, and where R 14 is selected from: hydroxy, Ci-6 alkyl, -O-C 1-6 alkyl, benzyl, phenyl, C3-6 cycloalkyl where the alkyl, phenyl, benzyl, and cycloalkyl groups can be unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo
  • Ci-3alkyl where the alkyl is unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, and hydroxy,
  • R 3 is oxygen or is absent when Y is N;
  • R 3 is selected from the following list when Y is C:
  • Ci-3alkyl where the alkyl is unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, hydroxy, and -COR 11 ,
  • R5 is selected from:
  • Ci-6alkyl where alkyl may be unsubstituted or substituted with 1-6 fluoro and optionally substituted with hydroxyl
  • b -O-Ci-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro
  • c -CO-C ⁇ _6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro
  • d -S-Ci-6alkyl, where alkyl may be unsubstituted or substituted with 1-6 fluoro
  • (k) phenyl which may be unsubstituted or substituted with one or more substituents selected from the group consisting of : halo, trifluoromethyl,
  • R6 is selected from:
  • R 15 can be hydrogen, C ⁇ - alkyl, or where R 15 is joined via a 1-5 carbon tether to one of the carbons of V to form a ring, and where the C ⁇ -6 a lkyl is unsubstituted or substituted with 1-5 substituents, where the substituents are independently selected from:
  • R ⁇ and R ⁇ or R ⁇ and R 10 may be joined together to form a ring which is phenyl or heterocycle, wherein the ring is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
  • R ⁇ and R 1 ⁇ are independently selected from: (a) hydrogen,
  • n is selected from 0, 1 and 2; the dashed line represents a single or a double bond; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
  • R 1 , R , R 3 , R5, R ( ⁇ ; and n are defined herein, and wherein R 1 ⁇ and R 1 ⁇ are independently selected from: (a) hydrogen,
  • Another embidiment of the present invention include compounds of formula Id:
  • R 1 , R 2 , R 3 , R5, R9 ; Rl 1, Y, W, and n are defined herein and where the C ⁇ - carbon chain may be unsubstituted, or substituted with 1-4 substituents which are independently selected from:
  • R 1 , R 2 , R 3 , R5, R 7 , R ; R 10 , ⁇ ; a nd n are defined herein, and X is either N, or O (in which case R 7 is nothing).
  • R 1 , R 5 , R 9 , R 16 , R 17 , and Y are defined herein, or where the R 16 and R 17 are joined together to form a heterocycle which is fused to the phenyl ring, and which itself may be unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, -COR 11 , and -C ⁇ -3 alkyl;
  • a further embodiment of the present invention includes compounds of formula Ih:
  • R 1 , R ⁇ , R9, R 1 " J R17 ; a nd Y are defined herein, and where H is a heterocycle; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • R 1 , R5, R9, R 11 , Y, and W are defined herein and where the C ⁇ _ carbon chain may be unsubstituted, or substituted with 1-4 substituents which are independently selected from:
  • X is C, O or N. In another embodiment of the present invention X is C or O.
  • R 1 is selected from: -C ⁇ _6alkyl, -C ⁇ -6alkyl-O-Ci-6alkyl, and
  • R 1 is selected from:
  • -Ci-6alkyl which is unsubstituted or substituted with 1-6 substituents where the substituents are independently selected from:
  • R 1 is selected from: (a) Ci-6alkyl,
  • Ci-6alkyl substituted with hydroxy Ci-6alkyl substituted with 1-6 fluoro.
  • R 1 is selected from:
  • R2 is selected from:
  • R2 is hydrogen.
  • R 3 is nothing or O (to give a N- oxide)
  • R 3 is nothing.
  • R 3 is selected from:
  • Ci-3alkyl where the alkyl is unsubstituted or substituted with 1-6 substituents independently selected from: fluoro, and hydroxy,
  • R 4 is hydrogen
  • R ⁇ is selected from:
  • R ⁇ is selected from:
  • R ⁇ is trifluoromethyl
  • R ⁇ is hydrogen-
  • R 7 is phenyl, heterocycle, C 3- cycloalkyl, C ⁇ . alkyl, - COR 11 , and -CONH-V-COR 1 1 , where V is selected from C 1-6 alkyl or phenyl, and
  • phenyl, heterocycle, C 3 . 7 cycloalkyl, and C ⁇ -6 alkyl is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
  • R 7 is phenyl, heterocycle, C 1-4 alkyl, -COR 11 , and -CONH-V-COR 11 , where V is selected from C h alky! or phenyl, and
  • phenyl, heterocycle, and C ⁇ -4 alkyl is unsubstituted or substituted with 1- 3 substituents where the substituents are independently selected from:
  • R 7 is selected from:
  • R ⁇ is selected from: (a) hydrogen, (b) hydroxy,
  • R 7 and R 8 may be joined together to form a ring which is selected from:
  • R9 and R 1 ⁇ are independently selected from: (a) hydrogen, (b) hydroxy,
  • n 1 or 2.
  • Representative compounds of the present invention include those presented in the Examples and pharmaceutically acceptable salts and individual diastereomers thereof.
  • the compounds of the instant invention have at least two asymmetric centers at the 1- and 3-positions of the cyclopentyl ring. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention.
  • the carbon bearing the amine substituent is designated as being of the (R) absolute configuration and the carbon bearing the amide subunit can be designated as being of either the (5) or (R) absolute configuration depending on the priority for R 1 .
  • R is isopropyl
  • the absolute stereochemistry at the carbon bearing the amide subunit would be (5) since the amide and amine units are preferred to have the cis arrangement on the cyclopentyl ring.
  • halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo.
  • alkyl is intended to mean linear, branched and cyclic structures having no double or triple bonds.
  • Ci-6alkyl is defined to identify the group as having 1, 2,
  • Ci-6alkyl specifically includes
  • Cycloalkyl is an alkyl, part or all of which which forms a ring of three or more atoms. Co or Coalkyl is
  • heterocycle as used herein is intended to include the following groups: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl,
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or 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, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Suitable salts are found, e.g. in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418. Exemplifying the invention is the use of the compounds disclosed in the
  • Specific compounds within the present invention include a compound which selected from the group consisting of: the title compounds of the Examples; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
  • the subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity.
  • these compounds are useful as modulators of the chemokine receptors, in particular CCR-2.
  • the utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for chemokine binding as disclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993) which may be readily adapted for measurement of CCR-2 binding.
  • Receptor affinity in a CCR-2 binding assay was determined by measuring inhibition of 125 I-MCP-1 to the endogenous CCR-2 receptor on various cell types including monocytes, THP-1 cells, or after heterologous expression of the cloned receptor in eukaryotic cells.
  • the cells were suspended in binding buffer (50 mM HEPES, pH 7.2, 5 mM MgCl 2 , 1 mM CaCl 2 , and 0.50% BSA) with and added to test compound or DMSO and 125 I-MCP-1 at room temperature for 1 h to allow binding. The cells were then collected on GFB filters, washed with 25 mM HEPES buffer containing 500 mM NaCl and cell bound 125 I-MCP-1 was quantified.
  • binding buffer 50 mM HEPES, pH 7.2, 5 mM MgCl 2 , 1 mM CaCl 2 , and 0.50% BSA
  • chemotaxis assay was performed using T cell depleted PBMC isolated from venous whole or leukophoresed blood and purified by Ficoll-Hypaque centrifugation followed by rosetting with neuraminidase-treated sheep erythrocytes. Once isolated, the cells were washed with HBSS containing 0.1 mg/ml BSA and suspended at lxlO 7 cells/ml. Cells were fluorescently labeled in the dark with 2 ⁇ M Calcien-AM (Molecular Probes), for 30 min at 37° C.
  • the compounds of the following examples had activity in binding to the CCR-2 receptor in the aforementioned assays, generally with an IC50 of less than about 1 ⁇ M. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity.
  • Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or lymphocyte function in a mammal, such as a human.
  • Compounds which inhibit or promote chemokine receptor function are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, compounds which inhibit or promote chemokine receptor function would be useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • an instant compound which inhibits one or more functions of a mammalian chemokine receptor may be administered to inhibit (i.e., reduce or prevent) inflammation.
  • a mammalian chemokine receptor e.g., a human chemokine receptor
  • one or more inflammatory processes such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited.
  • a variety of other mammals can be treated according to the method of the present invention.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • Diseases and conditions associated with inflammation and infection can be treated using the compounds of the present invention.
  • the disease or condition is one in which the actions of lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
  • Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ELD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as r
  • Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
  • Immunosuppression such as that in individuals with immunodeficiency syndromes such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infections diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms), (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis), trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis),
  • helminth infections such as nematodes (round worms), (Trichuriasis, Enterobia
  • treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for promoters of chemokine receptor function if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or delivery of compound in a manner that results in the misdirection of the migration of cells.
  • the compounds of the present invention are accordingly useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, as well as autoimmune pathologies.
  • the present invention is directed to the use of the subject compounds for treating, preventing, ameliorating, controlling or reducing the risk of autoimmune diseases, such as rheumatoid arthritis or psoriatic arthritis.
  • the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-2. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds that modulate the activity of chemokine receptors.
  • the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-2. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl
  • the present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the present invention is further directed to the use of the present compounds in treating, preventing, ameliorating, controlling or reducing the risk of infection by a retro virus, in particular, herpes virus or the human immunodeficiency virus (H1N) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS.
  • Treating ADDS or preventing or treating infection by HTV is defined as including, but not limited to, treating a wide range of states of HIV infection: ADDS, ARC (ADDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • a subject compound may be used in a method of inhibiting the binding of a chemokine to a chemokine receptor, such as CCR-2, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the chemokine to the chemokine receptor.
  • the subject treated in the methods above is a mammal, for instance a human being, male or female, in whom modulation of chemokine receptor activity is desired.
  • “Modulation” as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. In an aspect of the present invention, modulation refers to antagonism of chemokine receptor activity.
  • therapeutically effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • substituted in reference to substitution on alkyl, cycloalkyl, phenyl, heterocycle, or some other chemical group is intended to include mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed in any of the named chemical groups.
  • each R12 is independently selected from the possible values thereof; i.e., each R12 can be the same as or different from any other R 12.
  • optionally substituted is intended to include both substituted and unsubstituted.
  • optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
  • Combined therapy to modulate chemokine receptor activity for thereby treating, preventing, ameliorating, controlling or reducing the risk of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
  • the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5- lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, usinel, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl
  • an antiinflammatory or analgesic agent such as an opiate agonist,
  • the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
  • a pain reliever such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinep
  • compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is typically employed.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists such as those described in US 5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216, WO96/22966, WO96/31206, WO96/40781, WO97/03094, WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818, WO98/54207, and WO98/58902; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSADD the weight ratio of the compound of the present invention to the NSADD will generally range from about 1000: 1 to about 1 : 1000, or from about 200: 1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing pr wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing pr wetting agents may be a naturally-occurring phosphatide, for example lecithin
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
  • topical application shall include mouthwashes and gargles.
  • compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; or about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, 2.0 to 500, 3.0 to 200, or 1, 5, 10, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 250, 300, 400, 500, 600, 750, 800, 900 and/or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • chemokine receptor modulators 1-5 This can be accomplished in various ways, including by first converting the acid to its acid chloride with a reagent such as oxalyl chloride, and then combining with amine 1-2 in the presence of a base such as triethylamine. Reductive amination of 1-3 with an amine 1-4 using, for example, NaB(OAc) 3 H or NaBH 3 CN as the reducing agent gives chemokine receptor modulators 1-5.
  • the compounds 1-9 which can be synthesized according to the chemistry described in Scheme 1 represent stereoisomeric mixtures (Eliel, E. E., Wilen, S. H., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York).
  • compounds 1-5 are often obtained as a mixture of cis and trans isomers.
  • 1-1 is a single stereoisomer (1-la) only 2 possible isomers of 1-5 can result (cis and trans); these can be separated by a variety of methods, including by preparative TLC, flash chromatography, MPLC, or by HPLC using a column with a chiral stationary phase.
  • 1-1 is racemic, a total of 4 possible isomers of 1-5 can be obtained. Again, these may be separated by HPLC using a column with a chiral stationary phase, or by a combination of the methods above.
  • the synthesis of racemic 1-1 is detailed in Scheme 2A, while syntheses of the chiral 1-la are described in Schemes 2B and 2C.
  • compounds 1-5 can themselves be modified to give new chemokine receptor modulators 1-5.1.
  • an ester functional group within a compound 1-5 can be hydrolyzed to the corresponding carboxylic acid, which also can be a chemokine receptor modulator.
  • the keto-ester 1-6 could be reductively aminated with amine 1-4 to form the amino ester 1-7 under a variety of conditions, including sodium triacetoxyborohydride or sodium cyanoborohydride.
  • alkylating agent such as an alkyl chloride, bromide or iodide in the presence of an appropriate base such as lithium bis(trimethylsilyl)amide
  • a similar diastereoisomeric separation could be also accomplished later, after the esters 1-8 were hydrolytically cleaved to yield the respective acids 1-9.
  • This hydrolysis was readily accomplished under usual conditions, including lithium, sodium or potassium hydroxide, at ambient to elevated temperatures, depending on the nature of the ester group and substituent R 1 .
  • These diastereoisomers could be separated by crystallization from a variety of solvents, taking advantage of the finding, that the s-diastereoisomeric acids are less soluble, when compared to their trans- epimers.
  • the compounds of formula 1-5 are then formed from the acids 1-9 and tetrahydroisoquinoline derivatives 1-2 under standard amide-bond forming reaction conditions, including carbodiimide reagents, such as DCC, EDC and catalysts such as DMAP, HOAT or HOBT.
  • carbodiimide reagents such as DCC, EDC and catalysts such as DMAP, HOAT or HOBT.
  • the particularly suitable dimethyl acetal protecting group can be introduced using trimethyl orthoformate as a reagent in a suitable solvent such as dichloromethane and methyl alcohol in the presence of an acidic catalyst.
  • a suitable solvent such as dichloromethane and methyl alcohol
  • the acid 2-1 can be converted to 2-3 directly by using trimethyl orthoformate and an acidic catalyst, such as para-toluenesulfonic acid.
  • the ester protecting group present in 2-4 can be removed in a number of ways, depending on the nature of the ester.
  • Intermediate 1-1 can be prepared as a single stereoisomer (1-la) in various ways including those depicted in Schemes 2B and 2C.
  • racemic 1-1 can be converted to its benzyl ester.
  • There are many ways to effect this esterification one of which being by a sequence involving conversion to the corresponding acid chloride with, for example oxalyl chloride, followed by treatment with benzyl alcohol in the presence of a base such as triethylamine.
  • the racemic benzyl ester 2-5 can be separated by chiral preparative HPLC to give 2-5a as a single stereoisomer.
  • Removal of the benzyl group to give the chiral ketoacid 1-la can be accomplished in several ways.
  • One convenient way is by hydrogenolysis in the presence of a catalyst such as Pd/C.
  • chiral ketoacid intermediate 1-la can be prepared starting from commercially available optically pure amino acid 2-6. Protection of the carboxylic acid group can be achieved in a variety of ways.
  • esterification can be accomplished by treatment with methanol in the presence of an acid catalyst such as HCl. Treatment with Boc 2 O results in protection of the amine group of 2-7.
  • Hydrolysis of the ester to give 2-11 can be achieved under standard conditions depending on the R 18 group.
  • hydrolysis can be accomplished by treatment with a base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, with or without heating.
  • the Boc protecting group can be removed under standard acidic conditions, such as with HCl in a solvent such as dioxane, or with TFA.
  • Oxidation of 2-12 to give 1-la can be achieved in several ways, including by treatment with NBS, followed by treatment with sodium methoxide.
  • Amines 1-2 can be prepared in several ways as shown in schemes 3A-3G.
  • the 5-aza- tetrahydroisoquinoline fragment can be prepared in accordance to the literature methods of MarCoux, J-F. et al. (/. Chem. Lett., 2000, 2 (15), 2339-2341). Alternatively, it can be prepared as outlined in Scheme 3A.
  • Compound 3-1 normally obtained from commercial sources, is brominated (Br 2 , AcOH) to give 3-2.
  • Metal halogen exchange NaH, t-butyl lithium
  • DMF provides aldehyde 3-3.
  • Conversion of the aldehyde group to a nitrile can be achieved with sodium formate, hydroxylamine hydrochloride and formic acid.
  • the resulting nitrile 3-4 can be treated with phosphorous oxychloride to give 2-chloropyridine 3-5.
  • Displacement of the chloro group can be achieved with the sodium salt of a dialkylmalonate.
  • Reduction of the nitrile group of 3-6 with hydrogen and Raney Ni catalyst is accompanied by cyclization to afford compound 3-7.
  • Decarboxylation can be achieved in a variety of ways depending on the ester. In the case represented in Scheme 3A, the t-butyl ester was decarboxylated with TFA to give 3-8.
  • R 10c Removal of the protecting group R 10c is achieved in different ways depending upon the nature of R 10c . If R 10c is benzyl, hydrogenation in the presence of HCl and a catalyst such as Pd/C can be applied. If R 10c is benzoyl, hydrolysis can be achieved by heating in concentrated HCl solution. Installation of a
  • Boc protecting group on to 3-15 can be easily achieved with Boc 2 O to give 3-16.
  • Various R 10d can then be inco ⁇ orated generating ethers (see Scheme 3C).
  • the Boc protecting group on the resulting compounds 3-17 can finally be removed with HCl or TFA to give l-2b.
  • Compound 3-14 itself can be converted to ethers (according to Scheme 3C).
  • the 5-aza-7-hydroxytetrahydroisoquinolines 3-14 and 3-16 in Scheme 3B can be converted to various ethers (see Scheme 3C).
  • Alkyl ethers can be generated from an alkyl halide and a base (such as K 2 CO 3 , NaOH, or NaH) giving compounds 3-19 and 3-22.
  • a trifluoromethyl ether can be prepared by initial methyl xanthate formation (NaH, CS 2 ; Mel), followed by sequential treatment with l,3-dibromo-5,5-dimethylhydantoin (or NBS) and HF/pyridine solution giving 3-20.
  • Aryl ethers can be prepared by a number of methods, including reaction of arylboronic acids in the presence of copper (II) acetate and triethylamine, to give compounds 3- 21.
  • fragments l-2c can be further modified so as to prepared 7-aryl-5-azotetrahydroisoquinoline containing analogs.
  • Heterocyclic 7-substituted tetrahydroisoquinolines could be obtained by utilizing commercially available tetrahydroisoquinoline.
  • tetrahydroisoquinoline (3-32) is nitrated by treatment with potassium nitrate in the presences of concentrated sulfuric acid.
  • the 7-nitro-tetrahydroisoquinoline 3-33 is treated with trifluoroacetic anhydride to protect the amine and the resulting amide then hydrogenated with 10% palladium on carbon under hydrogen at 50 psi pressure to afford the aniline derivative 3-34.
  • Base hydrolysis yields a 7-amino substituted tetrahydroisoquinoline (3-35) which could be used in the synthesis of further CCR2 antagonist or other tetrahydroisoquinoline derivatives. Protection of 3-35 with benzylchloroformate in the presence of an organic base such as triethylamine or diisopropylethyl amine affords the carbamate 3-37. This intermediate could be utilized to make the tetrazole and substituted tetrazoles such as l-2g.
  • N,N-dimethylforamide azine in the presences of a catalytic amount of an acid such as toluene sulfonic acid heated to reflux for 24 to 48 hours.
  • Basic hydrolysis of this intermediate gives amine component l-2f.
  • Amines 1-4 were obtained from various sources. Most were commercially available, some were known from the literature and could be prepared according to published procedures, and some were prepared as described herein. Since their structures and the methods for their preparation are diverse, only two schemes will be outlined in this section; individual syntheses of amines 1-4 can be found in the Experimental Section.
  • Scheme 4A shows one method for the synthesis of 4-aryl substituted piperidines. Enol triflate 4-1 (prepared according to Wustrow, D. J., Wise, L. D., Synthesis, (1991), 993-995.) could be coupled to boronic acids 4- 2 as described by Wustrow and Wise.
  • Hydrogenation of the olefin in 4-3 could be achieved using hydrogen in the presence of a catalyst such as Pd(OH) 2 /C. Removal of the Boc protecting group could be achieved using standard acidic conditions, such as HCl in dioxane or TFA/DCM to afford piperidine 1-4.1.
  • Scheme 5 Another principal route for the synthesis of chemokine receptor modulators is depicted in Scheme 5.
  • intermediate 2-11 (described in Scheme 2C) is condensed with amine 1-2 (described in Scheme 1) using a peptide coupling reagent such as EDC to give 5-1.
  • the Boc protecting group is removed under standard conditions such as with HCl in a solvent such as dioxane followed by treatment of the resulting amine 5-2 with a dialdehyde 5-3 in the presence of a reducing agent such as sodium triacetoxyborohydride leads to a double reductive alkylation sequence with concomitant cyclization to give 1-5.2.
  • further modifications, such as hydrolysis of an ester group present within 1-5.2 can be effected to give new chemokine receptor modulators 1-5.3.
  • dialdehydes 5-3 One way of preparing dialdehydes 5-3 is outlined in Scheme 6. According to this route, a cycloalkene 6-1 is oxidatively cleaved with, for example, ozone followed by dimethylsulfide, to give the dialdehyde. Alternatively, in place of the dialdehydes 5-3 the intermediate ozonides 6-2 can themselves be used directly in the double reductive amination reaction leading to 1-5.2.
  • Step C A flame dried 500 mL round bottom flask was charged with 100 mL of dry THF, and then, set under nitrogen and cooled to -78°C using an acetone/dry ice bath. Diisopropylamine (7.9 mL, 56 mmol) was added to the cooled solvent via syringe followed by the slow addition of 2.5 M n- butyllithium in hexane (22.6 mL, 56.45 mmol). After 5 minutes stirring, the acetal (described in Step B, Intermediate 6 ,10.0 g, 43.4 mmol) in 50 mL of THF was added dropwise via syringe and the resulting mixture stirred at -78°C for 2 hours.
  • Step B To a solution of the trifluoroacetamide formed in Step B (8.3 g , 26 mmol) in ethanol (200 mL) was added a solution of potassium carbonate (20 g , 150 mmol) in water (50 mL), and the resulting mixture was stirred at reflux for 1 h. The ethanol was removed under reduced pressure and water (150 mL) was added to the residue and extracted with CH 2 C1 2 (3 x 100 mL).
  • a 3-neck round bottomed flask equipped with an addition funnel and condenser and containing zinc dust (2.45 g, 37.4 mmol) was flame dried. After cooling, and purging the system with nitrogen gas, 6 mL of THF was added, followed by 1,2-dibromoethane (0.298 mL, 3.46 mmol). The mixture was warmed to a vigorous reflux using a heat gun and stirred at reflux for -30 seconds (gas evolution was observed), then cooled to room temperature. The warming and cooling was repeated two more times. Then chlorotrimethylsilane (0.402 mL, 3.17 mmol) was added and the mixture was stirred at room temperature for 20 minutes.
  • N-t-butoxycarbonyl-4- iodo-piperidine (known: Billotte, S. Synlett (1998), 379., 8.97 g, 28.8 mmol) in 15 mL of THF was added over a period of about 1 minutes.
  • the reaction mixture was stirred at 50 °C for 1.5 h, then was cooled to room temperature.
  • the reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate.
  • the filtrate was diluted further with ethyl acetate, and washed with saturated NaHCO 3 solution.
  • the aqueous layer was back extracted with ethyl acetate, the organic layers were combined and washed twice with water and once with brine.
  • the organic phase was dried over anhydrous MgSO 4 , filtered, and concentrated.
  • Step B tert-butyl 4-[(methylsulfonyl)oxy]piperidine-l-carboxylate
  • the aqueous layer was back-extracted with more ethyl acetate and the combined organic layers were washed four times with water and once with brine.
  • the organic layer was dried over anhydrous MgSO 4 , filtered, and concentrated to give 3.51 g of product.
  • the Boc intermediate (139 mg, 0.487 mmol) was dissolved in 4 N HCl in dioxane (5 mL) and stirred at room temperature for 1.5 h. The reaction mixture was concentrated to give 94.3 mg of piperidine hydrochloride product.
  • StepB l-benzyl-4 : (lH-pyrazol-3-yl)-l,2,3,6-tetrahydropyridine
  • reaction mixture was stirred at -78 °C for a further 15 minutes, then triethylamine (69 mL, 500 mmol) was added and the resulting mixture was allowed to rise to room temperature over 2 h.
  • the reaction mixture was washed with water (500 mL), saturated NaCl (150 mL), dried over MgSO , filtered and concentrated in vacuo, to give 18 g of product which was used in the next step without further purification.
  • Step F l-isopropyl-3-(4-(4-fluorophenyl)piperidin-l-yl)cyclopentanecarboxylic acid
  • 2,5-Dimethyl-3-pyrroline (3.128 g, 32.19 mmol) was dissolved in triethylamine (8.97 mL, 64.4 mmol) and cooled to 0 °C.
  • Carbobenzyloxychloride (10.11 mL, 70.83 mmol) in a minimal amount of dichloromethane was added dropwise.
  • the reaction mixture was slowly warmed to room temperature and stirred for 48 h.
  • the reaction was quenched with saturated sodium bicarbonate solution (150 mL), and the organic layer was then washed with saturated sodium bicarbonate solution (2 x 100 mL) and brine (1 x 100 mL), dried over MgSO , filtered, and concentrated.
  • the ether layer was further washed with aqueous NaHCO 3 solution (1 x 100 mL), brine (1x100 mL), dried over anhydrous Na 2 SO 4 , concentrated and purified by flash chromatography (15% ethyl acetate/hexanes) to afford the product (7.25 g, 85%).
  • bromo-tris-pyrrolidino-phosphoniu hexafluorophosphate (6.80 g, 14.3 mmol) was added, immediately followed by additional diisopropylethylamine (7.0 mL, 40 mmol).
  • the reaction mixture was stirred at room temperature overnight and then quenched with saturated NaHCO 3 .
  • the aqueous layer was back washed with dichloromethane (3 x 50 mL) and the organic layers were combined, dried over Na 2 SO , filtered, and evaporated in vacuo.
  • Procedure A Step A: o yCO 2 H H 2 S Q 4 , MgS Q 4 0 /. c ⁇ 2 -t-Bu t-BuOH, DCM
  • tert-Butyl l-isopropyl-3,3-dimethoxycyclopentanecarboxylate (8.32 g, 30.5 mmol) was dissolved in 4 N anhydrous HCl in dioxane (50 mL) and water (10 mL) was added. The reaction mixture was stirred at room temperature overnight, then was concentrated. The residue was dissolved in DCM, dried over anhydrous MgSO 4 , filtered, and concentrated to give 5.44 g of l-isopropyl-3- oxocyclopentanecarboxylic acid (used without purification).
  • Potassium bis(trimethylsilyl)amide 14 g, 71 mmol was mixed with 300 mL of THF in a 1000 mL flame-dried round bottomed flask and the resulting mixture was cooled to -78 °C.
  • tert-butyl 4-[3-(ethoxycarbonyl)phenyl]-2-oxopiperidine-l-carboxylate 22.5 g, 64.8 mmol
  • Example 7 A mixture of the product from Example 1 (185 mg, 0.349 mmol), 5 N NaOH (200 ⁇ L, 1.04 mmol), and MeOH (5 mL) was heated at 60 °C for 3 hours before adding a solution of 4N HCl in dioxane to neutralize the base. The reaction solution was concentrated and purified by reverse phase HPLC to yield Example 7 (115 mg, 65.7%). LC-MS for C 25 H 34 F 3 N 2 O 3 [M + H + ] calculated 467.24, found 467.35.
  • Examples 8-12 were prepared as detailed in Example 7 using Examples 2-6 as starting materials. These compounds are summarized in the table below.
  • Example 17 (30 mg, 43%) as a mixture of 4 diastereomers.
  • ESI-MS calculated MW: 527.28, found 528.25.
  • Example 29 The free base of the product prepared in Example 22 (55 mg) was resolved into its individual diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 25 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. 27 mg of the faster eluting diastereomer (Example 29) and 20 mg of the slower eluting diastereomer (Example 30) were recovered.
  • Example 29 ESI-MS calc. for C26H36F3N3O3: 495.27; found 496 (M+H).
  • Example 30 ESI-MS calc. for C26H36F3N3O3: 495.27; found 496 (M+H).
  • Example 29 (10 mg, 0.018 mmol), was dissolved in a mixture of methanol (1 mL) and THF (1 mL), and treated with a solution of lithium hydroxide monohydrate (5 mg, 0.12 mmol) in water (1 mL). The resulting solution was stirred for 18 h at room temperature before being concentrated under reduced pressure. The product was purified by reverse phase HPLC (C18, 20-100 % MeCN/H 2 O) and converted to its hydrochloride salt by addition of 2 N HCl in ethyl ether to give 6.8 mg of product (70 %).
  • ESI-MS calc. for C24H32F3N3O3: 467.24; found 468 (M+H).
  • Example 30 (10 mg, 0.018 mmol), was dissolved in a mixture of methanol (1 mL) and THF (1 mL), and treated with a solution of lithium hydroxide monohydrate (5 mg, 0.12 mmol) in water (1 mL). The resulting solution was stirred for 18 h at room temperature before being concentrated under reduced pressure. The product was purified by reverse phase HPLC (C18, 20-100 % MeCN/H 2 O) and converted to its hydrochloride salt by addition of 2 N HCl in ethyl ether to give 3.8 mg of product (39 %). ESI-MS calc. for C24H32F3N3O3: 467.24; found 468 (M+H).
  • Example 30 To a solution of Example 30 (15 mg, 0.026 mmol), in THF (2 mL) was added lithium triethylborohydride (1.0 M solution in THF, 150 ⁇ L, 0.15 mmol). After 18 h at room temperature an additional portion of lithium triethylborohydride (100 ⁇ L) was added and the resulting mixture was stirred for 24 h before being concentrated under reduced pressure. The resulting residue was dissolved in DCM and washed with aqueous saturated sodium bicarbonate, 1 N aqueous HCl, and then brine.
  • Li triethylborohydride 1.0 M solution in THF, 150 ⁇ L, 0.15 mmol
  • Example 20 The free base of the product prepared in Example 20 (60 mg) was resolved into its individual diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 25 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. 26 mg of the faster eluting diastereomer (Example 34) and 17 mg of the slower eluting diastereomer (Example 35) were recovered.
  • Example 34 ESI-MS calc. for C25H35F3N4O2: 480.27; found 481 (M+H).
  • Example 35 ESI-MS calc. for C25H35F3N4O2: 480.27; found 481 (M+H).
  • Example 22 The free base of the product prepared in Example 22 (54 mg) was resolved into 2 mixtures of 2 diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 13 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. 33 mg of the faster eluting diastereomers (Example 36) and 10 mg of the slower eluting diastereomers (Example 37) were recovered.
  • Example 36 ESI-MS calc. for C26H36F3N3O3: 495.27; found 496 (M+H).
  • Example 37 ESI-MS calc. for C26H36F3N3O3: 495.27; found 496 (M+H).
  • Example 24 The free base of the product prepared in Example 24 (40 mg) was resolved into its individual diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 20 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. 15 mg of the fastest eluting diastereomer (Example 38), 1.5 mg of diastereomer 2 (Example 39), 7 mg of diastereomer 3 (Example 40), and 6 mg of the slowest eluting diastereomer (Example 41) were recovered.
  • Example 40 ESI-MS calc. for C24H34F3N3O: 437.27; found 438 (M+H).
  • Example 41 ESI-MS calc. for C24H34F3N3O: 437.27; found 438 (M+H).
  • Example 25 The free base of the product prepared in Example 25 (40 mg) was resolved into its individual diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 20 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. All 6 diastereomers were resolved, but peaks 2 and 6 were combined in overlapping runs to give 4 pure diatereomers and one mixture of 2.
  • Example 42 Peak 1: ESI-MS calc. for C25H36F3N3O: 451.28; found 452 (M+H).
  • Example 43 Peak 2/6: ESI-MS calc.
  • Example 44 Peak 3: ESI-MS calc. for C25H36F3N3O: 451.28; found 452 (M+H).
  • Example 45 Peak 4: ESI-MS calc. for C25H36F3N3O: 451.28; found 452 (M+H).
  • Example 46 Peak 5: ESI-MS calc. for C25H36F3N3O: 451.28; found 452 (M+H).
  • Example 27 The free base of the product prepared in Example 27 (20 mg) was resolved into its individual diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 25 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. 7 mg of the faster eluting diastereomer (Example 47) and 6 mg of the slower eluting diastereomer (Example 48) were recovered.
  • Example 47 ESI-MS calc. for C23H32F3N3O2: 439.24; found 440 (M+H).
  • Example 48 ESI-MS calc. for C23H32F3N3O2: 439.24; found 440 (M+H).
  • Example 53 The free base of the product prepared in Example 50 (60 mg) was resolved into its individual diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 20 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. 26 mg of the faster eluting diastereomer (Example 53) and 27 mg of the slower eluting diastereomer (Example 54) were recovered.
  • Example 54 ESI-MS calc. for C24H34F3N3O2: 453.26; found 454 (M+H).
  • Example 52 The free base of the product prepared in Example 52 (48 mg) was resolved into its individual diastereomers using an HPLC equipped with a ChiralCel OD column, eluting with 25 % ethanol/hexanes. Each compound was converted to its hydrochloride salt by the addition of 2 N HCl in ethyl ether. 18 mg of the faster eluting diastereomer (Example 53) and 23 mg of the slower eluting diastereomer (Example 54) were recovered.
  • Example 57 Several other examples were made according to the procedure described in Example 57 except that various substituted pyrollidines where used as the amine component in place of pyrrolidine. The examples are compiled in Table 6.
  • step H The product from step H (510 mg, 1.0 mmol) was mixed with TFA (10 mL) for 30 min. TFA was removed and the residue was purified on preparative TLC (10%[aq. NH4OH/MeOH l/9]/DCM) to yield the desired product as a white solid (223 mg, 55%).
  • LC-MS calc. for C20H19F3N2O2S: 408; Found: 409 (M+H).
  • the diastereoisomers were separated into one mixture of 2 cis diastereoisomers and two single diastereomers using HPLC (AD column, 5% EtOH/hexane).
  • Example 68 was prepared starting from Intermediate 3 and (lS,4S)-(+)-2-aza-5- oxabiclclo[2.2.1]heptane hydrochloride as detailed in Example 66. The cis and trans isomers were resolved on preparative TLC (4/95.6/0.4, MeOH/DCM/NHUOH). Top spot: ESI-MS calc. for C24H31F3N2O2: 436.23; Found: 437 (M+H). Bottom spot: ESI-MS calc. for C24H31F3N2O2: 436.23; Found: 437 (M+H).
  • Example 68 was prepared starting from piperidine and Intermediate 3 as detailed in Example 49. ESI-MS calc. for C24H33F3N2O: 422.25; Found: 423 (M+H).
  • Palladium catalyst on carbon top: 6 mg, middle: 18 mg, bottom: 20 mg was added to three flasks each containing one of the three diastereomers of Example 70 (top: 29.6 mg, middle: 89.9 mg, bottom: 102.3 mg).
  • the mixtures were dissolved in MeOH (3-6 mL), and the reaction vessels were flushed repeatedly with hydrogen gas.
  • the reaction was stirred at room temperature under a hydrogen atmosphere for 4.5 hours and then passed through an Acrodisc ® syringe filter with a 0.45 ⁇ m PTFE membrane.
  • Example 76 (middle stereoisomer on TLC, 11 mg, 0.024 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0°C. Ethylchloroformate (5 ⁇ L, 0.05 mmol), triethylamine (10 ⁇ L, 0.07 mmol), and a catalytic amount of DMAP (1-2 mg) was added to the reaction flask. The reaction was warmed to room temperature and stirred for two hours under a nitrogen atmosphere. Thereafter, the reaction was diluted with DCM and washed with saturated sodium bicarbonate solution (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated.
  • Example 77 (4.2 mg, 0.0080 mmol, 33% yield) was purified through preparatory TLC using a 2% NTL ⁇ OH/MeOH (1:9) in dichloromethane solvent system. ESI-MS calculated for C 27 H 39 F 3 N 4 O 3 : 524.62, found: 525 (M+H).
  • Example 76 (middle stereoisomer on TLC, 11 mg, 0.024 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0 °C. Acetic anhydride (11 ⁇ L, 0.12 mmol), triethylamine (23 ⁇ L, 0.17 mmol), and a catalytic amount of DMAP (1-2 mg) was added to the reaction flask. The reaction was warmed to room temperature and stirred for 2.5 hrs. under a nitrogen atmosphere. The reaction was then diluted with DCM and washed with saturated sodium bicarbonate solution (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgSO , filtered, and concentrated.
  • Example 78 (5.3 mg, 0.011 mmol, 45% yield) was purified through preparatory TLC using a 2% NELOH/MeOH (1:9) in dichloromethane solvent system. ESI-MS calculated for C 26 H 37 F 3 N 4 O 2 : 494.59, found: 495 (M+H).
  • Example 79 top isomer: 12.8 mg, 0.0251 mmol, 72% yield; middle isomer: 10.4 mg, 0.0204 mmol, 89% yield; bottom isomer: 11.1 mg, 0.0218 mmol, 70% yield) by preparatory TLC using a 2% NH t OH/MeOH (1:9) in dichloromethane solvent system.
  • ESI-MS calculated for C 2 H 38 F 3 N 5 O : 509.61, found: 510 (M+H).
  • Example 92 This product was prepared in an analogous fashion to that of Example 81, except Intermediate 21 was replaced with commercially available 4-cyano-4-phenylpiperidine.
  • the crude product was purified by preparative TLC (eluant: 5 % methanol: 94.5 % DCM: 0.5 % NHtOH) to yield Example 92 as a mixture of four isomers.
  • Example 93 This product was prepared in an analogous fashion to that of Example 81, except Intermediate 21 was replaced with commercially available 4-phenylpiperidine.
  • the crude product was purified by preparative TLC (eluant: 10 % methanol: 89.5 % DCM: 0.5 % NIL H) to yield Example 93 as a mixture of four isomers.
  • LC-MS for C 30 H 37 F 3 N 2 O calculated 498.29, found [M+H] + 499.
  • Example 105 To a solution of Example 105 (100 mg, 0.210 mmol), phenylboronic acid (30 mg, 0.23 mmol), toluene (1.4 mL), and MeOH (0.6 mL) was added a solution of Na 2 CO 3 (80 mg, 0.74 mmol) and Pd(PPh 3 ) 2 Cl 2 (8 mg, 0.01 mmol) in H 2 O (0.4 mL). The reaction mixture was heated at 80 °C in a high pressure tube for 12 h before filtered through celite and concentrated to dryness. The concentrate was diluted with DCM, washed with 1 N NaOH solution (3 x), dried over Na SO , and concentrated in vacuo.
  • Example 106 (63.3 mg, 63.3 %) a mixture of 2 cis isomers.
  • LC-MS for C 35 H 1 FN 2 O calculated 524.29, found [M+H] + 525.4.
  • Example 107 This product was prepared in an analogous fashion to that of Example 106, except phenylboronic acid was replaced with 4-pyridylboronic acid.
  • the crude product was purified by preparative TLC (eluent: 10/89/1.0, MeOH/DCM/NTLOH) to yield Example 107 as a mixture of two cis isomers.
  • LC-MS for C 34 H4 0 FN 3 O calculated 525.26, found [M+H] + 526.3.
  • Example 108 This product was prepared in an analogous fashion to that of Example 106, except phenylboronic acid was replaced with 3-pyridylboronic acid.
  • the crude product was purified by preparative TLC (eluent: 10/89/1.0, MeOH/DCM/NHjOH) to yield Example 108 as a mixture of two cis isomers.
  • LC-MS for C 34 H ⁇ FN 3 O calculated 525.26, found [M+H] + 526.3.
  • Example 109 This product was prepared in an analogous fashion to that of Example 106, except phenylboronic acid was replaced with 2-pyridylboronic acid.
  • the crude product was purified by preparative TLC (eluent: 10/89/1.0, MeOH/DCM/NHiOH) to yield Example 109 as a mixture of two cis isomers..
  • LC-MS for C 34 H 40 FN 3 O calculated 525.26, found [M+H] + 526.3.
  • Example 30 This product was prepared in an analogous fashion to that of Example 81, except Intermediate 1 was replaced with the product described in Step E.
  • the crude product was purified by preparative TLC (eluant: 10 % methanol: 89.5 % DCM: 0.5 % NHUOH) to yield Example 30 as a mixture of two cis isomers.
  • LC-MS for C 3 ⁇ H 38 FN 5 O calculated 515.31, found [M+H] + 516.

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EP04750112A 2003-04-17 2004-04-14 Heterocyclische cyclopentyltetrahydroisochinolin- und -tetrahydropyridopyridinmodulatoren der chemokinrezeptoraktivität Withdrawn EP1622916A4 (de)

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TWI350168B (en) 2004-05-07 2011-10-11 Incyte Corp Amido compounds and their use as pharmaceuticals
WO2007053498A1 (en) 2005-11-01 2007-05-10 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of ccr2
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BRPI0710512A2 (pt) * 2006-04-20 2012-06-05 Hoffmann La Roche moduladores derivados de diazepan de receptores de quimiocinas
WO2008108445A1 (ja) 2007-03-07 2008-09-12 Takeda Pharmaceutical Company Limited ベンゾオキサゼピン誘導体およびその用途
AU2010276537B2 (en) 2009-07-27 2015-04-16 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
AR080375A1 (es) 2010-03-05 2012-04-04 Sanofi Aventis Procedimiento para la preparacion de 2-(cicloheximetil)-n-{2-[(2s)-1-metilpirrolidin-2-il] etil}-1,2,3,4-tetrahidroisoquinolina- 7-sulfonamida
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PL2707361T3 (pl) * 2011-05-10 2018-01-31 Gilead Sciences Inc Skondensowane związki heterocykliczne stosowane jako modulatory kanału sodowego
UY34171A (es) 2011-07-01 2013-01-31 Gilead Sciences Inc Compuestos heterocíclicos fusionados como moduladores del canal iónico
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JP2019527233A (ja) 2016-08-01 2019-09-26 アプティニックス インコーポレイテッド スピロ−ラクタムｎｍｄａ受容体修飾因子及びその使用
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US11304952B2 (en) 2017-09-25 2022-04-19 Chemocentryx, Inc. Combination therapy using a chemokine receptor 2 (CCR2) antagonist and a PD-1/PD-L1 inhibitor
EP3737367A4 (de) 2018-01-08 2022-11-09 ChemoCentryx, Inc. Verfahren zur behandlung von soliden tumoren mit ccr2-antagonisten
US20190269664A1 (en) 2018-01-08 2019-09-05 Chemocentryx, Inc. Methods of treating solid tumors with ccr2 antagonists
KR20200115611A (ko) 2018-01-31 2020-10-07 앱티닉스 인크. 스피로-락탐 nmda 수용체 조정제 및 그의 용도
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CN100384856C (zh) * 2003-04-17 2008-04-30 麦克公司 趋化因子受体活性调节剂杂环基环戊基四氢异喹啉和杂环基环戊基四氢吡啶并吡啶

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WO2004094371A3 (en) 2005-03-24
CN100384856C (zh) 2008-04-30
EP1622916A4 (de) 2008-11-05
JP2006523704A (ja) 2006-10-19
CN1805965A (zh) 2006-07-19
WO2004094371A2 (en) 2004-11-04
CA2521625A1 (en) 2004-11-04

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