EP1009405A1 - Modulateurs de pyrrolidine et de piperidine de l'activite du recepteur de chemokine - Google Patents

Modulateurs de pyrrolidine et de piperidine de l'activite du recepteur de chemokine

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Publication number
EP1009405A1
EP1009405A1 EP98944548A EP98944548A EP1009405A1 EP 1009405 A1 EP1009405 A1 EP 1009405A1 EP 98944548 A EP98944548 A EP 98944548A EP 98944548 A EP98944548 A EP 98944548A EP 1009405 A1 EP1009405 A1 EP 1009405A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
alkyl
substituted
trifluoromethyl
phenylpyrrolidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98944548A
Other languages
German (de)
English (en)
Other versions
EP1009405A4 (fr
Inventor
Richard J. Budhu
Jeffrey J. Hale
Edward Holson
Christopher Lynch
Malcolm Maccoss
Sander G. Mills
Scott C. Berk
Christopher A. Willoughby
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9801009.3A external-priority patent/GB9801009D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1009405A1 publication Critical patent/EP1009405A1/fr
Publication of EP1009405A4 publication Critical patent/EP1009405A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cvtokine. 3, 165-183 (1991) and Murphy, Rev. Immun.. 12, 593-633 (1994)).
  • ⁇ -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
  • ⁇ -chemokines such as RANTES, MlP-l ⁇ , MlP-l ⁇ , monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature. 381. 661-666 (1996)).
  • chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane- domain proteins (reviewed in Horuk, Trends Pharm. Sci.. 15, 159-165 (1994)) which are termed "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-l" [MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.. 270. 22123-22128 (1995); Beote, et al, Cell.
  • CCR- 2A and CCR-2B (or "CKR-2A7"CKR-2A” or “CC-CKR-2ATCC-CKR- 2A") [MCP-1, MCP-3, MCP-4]; CCR-3 (or “CKR-3” or "CC-CKR-3") [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem.. 270. 16491-16494 (1995); CCR-4 (or "CKR-4" or "CC-CKR-4") [MlP-l ⁇ , RANTES, MCP-1] (Power, et al., J. Biol. Chem.. 270.
  • ⁇ -chemokines include eotaxin, MIP ("macrophage inflammatory protein”), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted").
  • Chemokine receptors such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases.
  • HIV-1 human immunodeficiency virus
  • LAV human immunodeficiency virus
  • HTLV-III human immunodeficiency virus
  • Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Patent No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gpl20, the coat protein of HIV, to its target, the CD4 gyycoprotein of the cell.
  • the principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the ⁇ - chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ (Deng, et al., Nature. 381. 661-666 (1996)). HIV attaches to the CD4 molecule on cells through a region of its envelope protein, gpl20. It is believed that the CD-4 binding site on the gpl20 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4.
  • drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HIV-1 (Zhang, et al., Nature. 383, 768 (1996)). Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients. By focusing on the host's cellular immune response to HIV infection, better therapies towards all subtypes of HIV may be provided. These results indicate that inhibition of chemokine receptors presents a viable method for the prevention or treatment of infection by HIV and the prevention or treatment of AIDS.
  • peptides eotaxin, RANTES, MlP-l ⁇ , MlP-l ⁇ , MCP-1, and MCP-3 are known to bind to chemokine receptors.
  • the inhibitors of HIV-1 replication present in supernatants of CD8+ T cells have been characterized as the ⁇ -chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ .
  • PCT Patent Publication WO 97/10211 and EPO Patent Publication EP 0,673,928 disclose certain piperidines as tachykinin antagonists.
  • the present invention is 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, including asthma and allergic diseases, 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 further concerned with compounds which inhibit the entry of human immunodeficiency virus (HIV) into target cells and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS).
  • HIV human immunodeficiency virus
  • the present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV.
  • the present invention is directed to compounds of formula I:
  • Rl is -X-R8, wherein X is selected from the group consisting of:
  • R ⁇ is a selected from: phenyl, naphthyl, biphenyl, fluorenyl, dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, Cl-6 alkyl, C5-8 cycloalkyl, cyclohexenyl, adamantyl, and heteroaryl, which may be unsubstituted or substituted, where the substituents are independently selected from:
  • R2 is selected from the group consisting of:
  • R ⁇ is a selected from: (1) -NR 6 CO-O-R 7 , wherein R 6 is hydrogen, Cl-6 alkyl or
  • R 7 is Cl-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubsituted or substituted with halo, Ci-3alkyl, Ci_3alkoxy or trifluoromethyl, (2) -phenyl, which is unsubsituted or substituted with halo,
  • Ci-3alkyl, Ci-3alkoxy or trifluoromethyl (3) -Cl-6alkyl-phenyl, which is unsubsituted or substituted with halo, Ci_3alkyl, Ci_3alkoxy or trifluoromethyl,
  • R3 is selected from the group consisting of: phenyl, naphthyl, biphenyl, fluorenyl, dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, Ci-6 alkyl, C5-8 cycloalkyl, cyclohexenyl, adamantyl, and heteroaryl, which may be unsubstituted or substituted, where the substituents are independently selected from: (a) hydroxy,
  • R4a, R4b ⁇ R4 C> R4d ? R 4e ? R 4f R4 ⁇ an d R 4h are independently selected from the group consisting of:
  • x is an integer selected from 0, 1, 2 and 3; y is an integer selected from 0, 1 and 2; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
  • Preferred compounds of the present invention include those of formula la:
  • Rl, R2 and R ⁇ are defined above; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • Preferred compounds of the present invention include those of formula lb:
  • Rl is -X-R8, wherein X is selected from the group consisting of:
  • R ⁇ is a selected from: phenyl, naphthyl, biphenyl, fluorenyl, dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, Cl-6 alkyl, C5-8 cycloalkyl, cyclohexenyl, adamantyl, and heteroaryl, which may be unsubstituted or substituted, where the substituents are independently selected from: (a) hydroxy,
  • R2 is selected from the group consisting of:
  • R ⁇ is a selected from: (1) -NR 6 CO-O-R 7 , wherein R ⁇ is hydrogen, Cl-6 alkyl or Ci-6 alkyl-C ⁇ -6 cycloalkyl, and R 7 is Ci-6 alkyl,
  • R ⁇ is selected from the group consisting of: phenyl, naphthyl, biphenyl, fluorenyl, dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, Cl-6 alkyl, C5-8 cycloalkyl, cyclohexenyl, adamantyl, and heteroaryl, which may be unsubstituted or substituted, where the substituents are independently selected from:
  • Rl is -X-R8, wherein X is selected from the group consisting of:
  • R ⁇ is a selected from cyclohexyl, cyclopentyl, naphthyl, unsubstituted phenyl or substituted phenyl , where the substituents on phenyl are independently selected from halogen and methyl;
  • R5 is a selected from:
  • ⁇ is a selected from:
  • Rl is -X-R8, wherein X is selected from the group consisting of: (1) -CH2-,
  • R ⁇ is a selected from: phenyl, naphthyl, biphenyl, fluorenyl, dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, Cl-6 alkyl, C5-8 cycloalkyl, cyclohexenyl, adamantyl, and heteroaryl, which may be unsubstituted or substituted, where the substituents are independently selected from:
  • Rl is -X-R8, wherein X is selected from the group consisting of: (1) -CH2-, and (2) -CO-, and wherein R ⁇ is a selected from: phenyl, naphthyl, Cl-6 alkyl, cyclohexyl, cyclopentyl, pyridyl, quinolyl, thiophenyl, indolyl, benzoxazolyl and benzthiazolyl, which may be unsubstituted or substituted, where the substituents are independently selected from:
  • Rl is selected from the group consisting of:
  • Rl is selected from the group consisting of: (1) -CH2-cyclopentyl,
  • R2 is selected from the group consisting of:
  • R ⁇ is a selected from:
  • R 6 is hydrogen, Ci-6 alkyl or Cl-6 alkyl-C ⁇ -6 cycloalkyl
  • R 7 is Cl-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubsituted or substituted with halo, CF3,
  • Ci-3alkyl, C ⁇ -3alkoxy or trifluoromethyl
  • R2 is:
  • R ⁇ is selected from:
  • R 6 is hydrogen, Cl-6 alkyl or Cl-6 alkyl-C ⁇ -6 cycloalkyl
  • R 7 is Cl-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubsituted or substituted with halo, CF3,
  • R ⁇ is selected from: (1) -phenyl, which is unsubsituted or substituted with halo,
  • CF3, Cl-3alkyl, Ci-3alkoxy or trifluoromethyl and (2) -Cl-6alkyl-phenyl, which is unsubsituted or substituted with halo, CF3, Ci-3alkyl, Ci-3alkoxy or trifluoromethyl.
  • R2 is:
  • R is a selected from:
  • R2 is:
  • R3 is selected from the group consisting of: phenyl, naphthyl, biphenyl, fluorenyl, dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, Cl-6 alkyl,
  • R3 is phenyl or thienyl, which may be unsubstituted or substituted, where the substituents are independently selected from: (a) chloro, (b) fluoro,
  • R3 is phenyl or thienyl.
  • R4a, R4b ? R4C ⁇ R4d ? R4e ? R4f R4g ; an d R 4 * 1 are independently selected from the group consisting of:
  • R a , R 4 , R 4c , R 4e , R 4f , R 4 S, and R h are each hydrogen and wherein R c * is selected from the group consisting of:
  • R 4a 5 R4b ? R4C ? R 4 e> R 4f R4g, an a R 4h are eac h hydrogen.
  • R 4 " is selected from the group consisting of: (1) hydrogen, and (2) CH 3 .
  • the compounds of the instant invention have at least two asymmetric centers at the ring junction of the substitutents bearing R and R ⁇ . 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 relative configurations of the most preferred compounds of this invention are of the trans orientation, i.e. as depicted:
  • Ci-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5, or 6 carbons, such that Ci-6alkyl specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and cyclohexyl.
  • heteroaryl as used herein is intended to include the following groups: benzimidazolyl, benzofuranyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isooxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.
  • Specific compounds within the present invention include a compound which selected from the group consisting of:
  • 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 spiro-substituted azacycles as modulators of chemokine receptor activity.
  • these compounds are useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR- 3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
  • 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 CCR-1 and/or CCR-5 binding as disclosed by Nan Riper, et al., J. Exp. Med..
  • Cell lines for expressing the receptor of interest include those naturally expressing the receptor, such as EOL-3 or THP-1, or a cell engineered to express a recombinant receptor, such as CHO, RBL-2H3, HEK-293.
  • a CCR3 transfected AML14.3D10 cell line has been placed on restricted deposit with American Type Culture Collection in Rockville, Maryland as ATCC No. CRL-12079, on April 5, 1996.
  • the compounds of the following examples had activity in binding to the CCR-5 receptor or to the CCR-3 receptor in the aforementioned assays, generally with an IC50 of less than about 10 ⁇ 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, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, 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.
  • eosinophilic infiltration to inflammatory sites e.g., in asthma
  • inflammatory sites e.g., in asthma
  • an instant compound which promotes one or more functions of a mammalian chemokine receptor is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes.
  • a mammalian chemokine receptor e.g., a human chemokine
  • an inflammatory response such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes.
  • eosinophils can be recruited to combat parasitic infections.
  • 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 method of the present invention.
  • the disease or condition is one in which the actions of eosinophils and/or 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, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (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 rheumatoid arthritis
  • 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.
  • Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due congenital deficiency in receptor function or other causes; and infectious 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,
  • immunosuppression such as that in individuals
  • Cysticercosis visceral worms, visceral larva migrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum).
  • the compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases.
  • the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4.
  • the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which 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.
  • 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-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4.
  • putative specific modulators of the chemokine receptors including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4.
  • 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 these compounds in the prevention or treatment of infection by a retrovirus, in particular, the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS.
  • Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to Hr .
  • the compounds of this invention are useful in treating infection by HITV after suspected past exposure to Hr 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 human immunodeficiency virus to a chemokine receptor, such as CCR-5 and/or CXCR-4, 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 virus to the chemokine receptor.
  • a chemokine receptor such as CCR-5 and/or CXCR-4
  • the subject treated in the methods above is a mammal, preferably 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 and/or partial agonism.
  • 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 or a prodrug of a compound of the invention to the individual in need of treatment.
  • Combined therapy to modulate chemokine receptor activity and thereby prevent and treat 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, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.
  • 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
  • the present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
  • Drug Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)
  • Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
  • HIV positive also in combination with
  • Ribavirin (Costa Mesa, CA) positive, LAS, ARC
  • Isethionate (IM & IV) (Rosemont, IL)
  • Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HrV protease and or a non-nucleoside inhibitor of HIV reverse transcriptase.
  • An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl.
  • Preferred agents for combination therapy include: Zidovudine, Lamivudine, Stavudine, Efavirenz, Ritonavir, Nelfinavir, Abacavir, Indinavir, 141-W94 (4-amino-N-((2 syn,3S)-2-hydroxy-4-phenyl- 3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl- benzenesulfonamide), N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl- 4-(S)-hydroxy-5-(l-(4-(2-benzo[b]furanylmethyl)-2(S)-N'(t-butylcarbox- amido)-piperazinyl))-pentaneamide, and Delavirdine.
  • a preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N- (2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(l-(4-(3- pyridyl-methyl)-2(S)-N'-(t-butylcarbo-xamido)-piperazinyl))-pentane- amide ethanolate, and is synthesized according to U.S. 5,413,999.
  • Indinavir is generally administered at a dosage of 800 mg three times a day.
  • Other preferred inhibitors of HIV protease include nelfinavir and ritonavir.
  • Preferred non-nucleoside inhibitors of HIV reverse transcriptase include (-) 6-chloro-4(S)-cyclopropylethynyl-4(S)- trifluoromethyl-l,4-dihydro-2H-3,l-benzoxazin-2-one, which may be prepared by methods disclosed in EP 0,582,455.
  • the preparation of ddC, ddl and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV.
  • Preferred combinations with the compounds of the present invention include the following: (1) Zidovudine and Lamivudine; (2) Stavudine and Lamivudine; (3) Efavirenz; (4) Ritoavir; (5) Nelfinavir; (6) Abacavir; (7) Indinavir; (8) 141-W94; and (9)
  • Preferred combinations with the compounds of the present invention further include the following (1) indinavir, with efavirenz or (-) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-l,4-dihydro-2H-3,l- benzoxazin-2-one, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and or ddl and/or ddC.
  • 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.
  • the compounds of the invention are effective for use in humans.
  • 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 absorption 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;
  • 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.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • 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 or 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 heptadecaethyleneoxycetanol, 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 monoo
  • 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.
  • 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.
  • 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.
  • topical application For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of The present invention are employed. (For purposes of this application, topical application shall include mouth washes 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; more preferably 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 are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 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.
  • the compounds of the present invention are prepared by alkylating heterocycle I (wherein X is a leaving group such as, for example, bromide, iodide, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate) with cyclic amine II under appropriate conditions to provide compound III (Scheme 1).
  • X is a leaving group such as, for example, bromide, iodide, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate
  • Cyclic amine II is available commercially or can be prepared using the methods given below.
  • heterocycle IV bearing a carbonyl group
  • heterocycle IV bearing a carbonyl group
  • the intermediate imine or iminium species is reduced to tertiary amine III under homogenous conditions (e.g. using sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride) or in the presence of hydrogen and a heterogeneous catalyst (e.g. palladium on carbon or Raney nickel).
  • a heterogeneous catalyst e.g. palladium on carbon or Raney nickel
  • heterocycle V bearing an activated acyl side chain (wherein X', for example, is a chloride or bromide atom, or is a hydroxybenzotriazole residue from activation of the corresponding carboxylic acid with HOBt in the presence of a suitable carbodiimide) is allowed to react with cyclic amine II to provide the corresponding tertiary amide VI (Scheme 1).
  • Compound VI can then be treated with a suitable reducing agent (e.g. diborane; borane in THF; borane dimethylsulfide, or lithium aluminum hydride) to provide the desired product VII.
  • a suitable reducing agent e.g. diborane; borane in THF; borane dimethylsulfide, or lithium aluminum hydride
  • ester XVII for example, with diisobutylaluminum hydride, lithium aluminium hydride, or sodium bis(2-methoxyethoxy)aluminum hydride, provides the primary alcohol XVIII.
  • Oxidation to the aldehyde XIX can be carried out under numerous conditions, such as with the Dess-Martin periodinane, with DMSO and oxalyl chloride at low temperature, followed by triethylamine (Swern oxidation), or with various chromium trioxide-based reagents (see March J.
  • N-benzyl group is cleaved in a hydrogen atmosphere in the presence of 20% palladium on carbon to provide the secondary amine XXI.
  • the 1 -unsubstituted pyrrolidine XXI may be further functionalized as shown in Scheme 4. Reductive amination with suitable aldehydes under standard conditions provides the tertiary amine XXII. For subunits with a primary or secondary aliphatic carbon linked to nitrogen, alkylation with a suitable halide, methanesulfonate, p-toluene-sulfonate, etc. is carried out under standard conditions to provide N-alkylated pyrrolidine XXIII.
  • secondary amine XXI are acylated with, for example, acid chlorides or bromides, or activated esters such as HOBt esters (prepared by treating the precursor carboxylic acid with a suitable carbodiimide in the presence of HOBt) or a symmetrical or mixed anhydride, to give amide XXIV.
  • the sulfonamide XXV is prepared under standard conditions by exposing XXI to an alkyl or aryl sulfonyl chloride in the presence of a suitable base to neutralize the formed hydrogen chloride.
  • cyclic amine II employed in the preceding Schemes can be obtained commercially in many cases or is prepared by a number of procedures.
  • compound XLII the N-t-butoxycarbonyl protected form of isonipecotic acid (4-piperidine- carboxylic acid) is activated under standard conditions, for example with a carbodiimide, and converted into ester XLIII or amide XLIV.
  • acid XLII is converted into the N-methyl-N-methoxy amide, XLV, which upon reaction with organomagnesium and organolithium reagents forms the ketone XLVI.
  • XLIII, XLrV and XLVI is removed under acidic conditions to provide secondary amines XL VII, XLVIII and XLIX, respectively.
  • CBZ-protected piperidine L is allowed to react with oxalyl chloride and then sodium azide, to provide the corresponding acyl azide, which can then be thermally rearranged to isocyanate LI (Scheme 9).
  • Compound LI is treated with an alcohol ROH or an amine RR'NH to form carbamate LII or urea LIII, respectively, each of which is deprotected with hydrogen in the presence of palladium on carbon to secondary amines LIV or LV.
  • R'X primary or secondary alkyl, allyl, propargyl or benzyl
  • X bromide, iodide, tosylate, mesylate or trifluoromethanesulfonate
  • a suitable base such as sodium hydride, lithium hexamethyldisilazide or potassium t
  • amine LXI is sulfonated with an alkyl or arylsulfonyl chloride, to give sulfonamide LXIII.
  • Compounds LXII and LXIII optionally is alkylated under the conditions given above for the preparation of LVII from LII. SCHEME 12
  • Substituted spiro(indoline-3,4'-piperidine) derivatives can be prepared as shown in Scheme 14 starting from the substituted phenylhydrazine LXIX and the aldyhyde LXX. Following the Fischer indole reaction and reduction of the intermediate imine with a mild reducing agent such as sodium borohydride, the indoline LXXI can be combined with an electrophile such as an acyl chloride or a sulfonyl chloride.
  • the protecting group on compound LXXII for example a benzyloxycarbonyl group, can be removed by treatment with hydrogen in the presence of palladium on carbon or by exposure to trimethylsilyl iodide, to give the deprotected substituted spiro(indoline-3,4'-piperidine) LXXIII.
  • Displacement of the chloride with the 2-bromothiophenol LXXVIII provides allylic sulfide LXXIX, which can be cyclized under radical conditions to give spiro(2,3- dihydrobenzothiophene-3,4'-piperidine) LXXX. Cleavage of the t- butoxy carbonyl group under standard conditions, such as trifluoroacetic acid, then provides the desired spirocycle LXXXI.
  • deprotection of the piperidine nitrogen is carried out by treatment with acid, for example trifluoroacetic acid, to provide ketone LXXXIX.
  • acid for example trifluoroacetic acid
  • the product is exposed to hydrazoic acid in the presence of sulfuric acid. Heating of this mixture effects a Schmidt rearrangement, to provide both tetrahydroquinoline XC and the tetrahydroisoquinoline XCI.
  • Cyclic amines (compound II) which are 4-arylpiperazines functionality are prepared using methods described in the following Schemes. Starting materials are made from known procedures or as illustrated. Substituted purines are prepared as disclosed in US
  • the piperazine fragment may contain a nitro group, which is reduced to the amine after the coupling step.
  • the resulting amine is further modified by acylation to provide the desired compounds.
  • the piperazine fragment may also contain a protecting group such as a benzyl ester or a t-butyl ester. After reductive amination the protecting group is removed and the resulting acid is further reacted to provide additional analogs.
  • the aldehyde portion may also contain a protecting group such as a t-butoxycarbonyl for an amino function.
  • the t-butoxycarbonyl group is removed by treatment with a strong acid such as trifluoroacetic acid, formic acid or hydrochloric acid and the resulting amine may be acylated to provide other analogs.
  • a strong acid such as trifluoroacetic acid, formic acid or hydrochloric acid
  • the piperazine starting materials used in the coupling reaction are prepared using methods described in the literature; more specifically as described in US Patent No. 5,057,517; US Patent No. 4,242,344; J. Org. Chem, 1974, 39, 2143 and J.C.S. Perkin 1, 1980, 506; J. Org. Chem. 1963, 28, 1753; J. Heterocyclic Chem., 1982 ,19, 1207; Arch. Int. Pharmacodyn.
  • Substituted 4-arylpiperazines are prepared from appropriate fluorobenzene derivative as shown in Scheme 18.
  • reaction of 2-fluorobenzonitrile with 1-t-butoxycarbonylpiperazine in the presence of a base such as K2CO3 gives l-t-butoxycarbonyl-4-(2- cyanophenyl)-piperazine (compound XCII).
  • Reduction of the cyano group by hydrogenation in the presence of Raney nickel or by other known methods gives benzyl amine XCIII, which is acylated or sulfonylated, to provide piperazine XCIV.
  • the t-butoxycarbonyl protecting group is removed under acidic conditions, for example by treatment with trifluoroacetic acid or anhydrous HCI to give 1- unsubstituted piperazine XCV which can be used in the reductive amination or alkylation steps described in Scheme 1.
  • 2-chloro-nitrobenzene in the place of 2-fluorobenzonitrile provides compounds containing a substituted aniline.
  • Analogs containing a benzoic acid or its derivatives are prepared by substituting 2- fluorobenzoic acid in this sequence.
  • Conversion to CIV can also be carried out by activation of the hydroxyl group with a alkyl- or arylsulfonyl chloride, such as p-toluenesulfonyl chloride, to give a benzylic sulfonate ester.
  • the sulfonate ester is then displaced with ammonia or a primary or secondary amine.
  • the sulfonate ester can be displaced with a suitable salt of the azide anion, such as sodium azide, zinc azide, or tetrabutylammonium azide, and the resulting alkyl azide can be reduced to primary amine CIV with hydrogen gas in the presence of a suitable catalyst, such as 5% palladium on carbon.
  • a suitable catalyst such as 5% palladium on carbon.
  • the alkyl azide can be reduced by treatment with triphenyl phosphine followed by hydrolysis to afford CIV.
  • Benzylic amine CIV can then be derivatized with a number of electrophilic reagents, such as alkyl or aryl sulfonyl chlorides, carboxylic acid chlorides, carboxylic acid anhydrides, alkyl chloroformates, carbamyl chlorides or alkyl or aryl isocyanates to provide sulfonamides, carboxamides, ureas, or carbamates CV. These intermediates can then be deprotected under acidic conditions to remove the Boc group to provide free piperazine CVl for use in the coupling reactions described in Scheme I.
  • electrophilic reagents such as alkyl or aryl sulfonyl chlorides, carboxylic acid chlorides, carboxylic acid anhydrides, alkyl chloroformates, carbamyl chlorides or alkyl or aryl isocyanates to provide sulfonamides, carboxamides, ureas, or carbamates CV.
  • This intermediate is then coupled with sulfonyl chlorides or carbonyl chlorides in the presence of a suitable amine, preferably a hindered tertiary amine such as diisopropylethylamine (DIEA), lutidine, DBU, etc., to provide the N- functionalized pyrrolidine D.
  • a suitable amine preferably a hindered tertiary amine such as diisopropylethylamine (DIEA), lutidine, DBU, etc.
  • DIEA diisopropylethylamine
  • Alkylation of the acyl sulfonamide nitrogen can be carried out with trimethylsilyldiazomethane, diazomethane, with bromoacetonitrile in the presence of DBU and DMF, or under Mitsunobu conditions with a phenol such as pentafluorophenol.
  • Cyclic amines (compound II) from Scheme 1 which are spirocyclic piperidines are prepared using azacyclic starting materials prepared using methods described in the literature; more specifically, as described in Claremon, D.A. et al. European Patent Publication 0431 943, Evans, B.E. et al, U.S. Patent 5,091,387, Davis, L. et al, U.S. Patent 4,420,485, and Parham et al, Journal of Organic Chemistry. 41, 2628 (1976). None of the compounds in the foregoing references are alleged to be chemokine receptor modulators.
  • Step A l-Phenylmethyl-3-(SR)-carbomethoxy-4-(SR)- phenylpyrrolidine
  • Step B l-Phenylmethyl-3-(SR)-hydroxymethyl-4-(SR)- phenylpyrrolidine
  • Step D l-(Benzenesulfonyl)-3-(SR)-benzenesulfonyloxymethyl-4-
  • Step E l-(Benzenesulfonyl)-3-(SR)-iodomethyl-4-(SR)- phenylpyrrolidine
  • Step F l-Benzenesulfonyl-3-(RS)-(spiro[2,3-dihydrobenzo- thiophene-3,4'-piperidin-l'-yl])methyl-4-(SR)- phenylpyrrolidine
  • Step B 1-Phenylmethyl -3-(SR)-((4-phenyl) piperidin-l-yl)methyl-
  • Example 10-29 The compounds in Examples 10-29 were prepared using procedures analogous to those described in Example 9 substituting the appropriate secondary amine for (4-phenyl)piperidine in Example 9, Step B.
  • the title compound was prepared from 103 mg of l-Benzyl-3- (SR)-formyl-4-(SR)-phenylpyrrolidine, 105 mg of l,2-diphenyl-3-(SR)- methyl-4-methylamino-2-(SR)-butanol-hydrochloride and 120 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 76 mg of the title compound.
  • RF 0.53 (50% Acetone in hexanes).
  • the title compound was prepared from 400 mg of l-Benzyl-3- (SR)-formyl-4-(SR)-phenylpyrrolidine, 0.24 mL of ethyl isonipecotate and 480 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 363 mg of the title compound.
  • RF 0.31 (50% EtOAc in hexanes).
  • Step A 3-(SR)-((4-Phenyl)piperidin-l-yl)methyl-4-(SR)- phenylpyrrolidine
  • Step B l-(4-Chloro)benzenesulfonyl-3-(SR)-((4-phenyl) piperidin-1- yl)methyl-4-(SR)-phenylpyrrolidine
  • Example 31-35 The compounds in Examples 31-35 were prepared using procedures analogous to those described in Example 30 substituting the appropriate aryl sulfonyl chloride for (4-chloro)benzenesulfonyl chloride in Example 30, Step B.
  • Examples 36-62 were prepared using procedures analogous to those described in Example 30, 59, or 63 substituting the appropriate aromatic or aliphatic acid chloride for (4- chloro)benzenesulfonyl chloride in Example 30, Step B, the appropriate aromatic or aliphatic carboxylic acid for 1-fluorene carboxylic acid in Example 59 or the appropriate aromatic or aliphatic acid chloride for nicotinoyl chloride • HCI in Example 63.
  • Examples 72-76 were prepared from 1- phenylmethyl -3-(RS)-((4-(N-methoxycarbonyl-N-cyclohexyl- methyl)amino)piperidin-l-yl)methyl-4-(SR)-phenylpyrrolidine (from
  • Example 12 using procedures analogous to those described in Example 30 substituting the appropriate acid chloride for (4-chloro)benzene- sulfonyl chloride in Example 30, Step B.
  • Carbon monoxide gas was bubbled through a mixture of 42 mg (0.08 mmol) of l-phenylmethyl-3-(SR)-((4-phenyl)piperidin-l- yl)methyl-4-(SR)-(3-bromo)phenylpyrrolidine (from Example 70), 24 ⁇ L (0.17 mmol) of TEA and 40 mg (0.03 mmol) of tetrakis(triphenyl- phosphine)palladium(O) in 2.5 mL of 4:1 v/v DMF/MeOH and the resulting mixture was stirred under an atmosphere of CO at 70 °C for 12 h. The reaction mixture was cooled, filtered and the filtrate was concentrated in vacuo.
  • Step A l-(2-Chloro)benzoyl-3-(RS ) -hydroxymethyl-4-(SR)- phenylpyrrolidine
  • Step B l-(2-Chloro)benzoyl-3-(RS)-formyl -4-(SR)- phenylpyrrolidine
  • the title compound was prepared from l-(2-chloro)benzoyl- 3-(RS)-hydroxymethyl-4-(SR)-phenylpyrrolidine (from Example 80, Step A) using a procedure analogous to that descibed in Example 9, Step A.
  • Step C l-(2-Chlorobenzoyl) -3-(RS)-((4-(N-phenylmethoxy- carbonyl-N-ethyl)amino)piperidin-l-yl)methyl-4-(SR)- phenylpyrrolidine
  • Example 81-84 The compounds described in Examples 81-84 were prepared using procedures analogous to those described in Example 80 substituting the appropriate acid chloride for (2-chloro)benzoyl chloride in Example 80, Step A.
  • the title compound was prepared from 35 mg of l-benzyl-3- (SR)-(4-carboethoxy-piperidin-l-ylmethyl)-4-(SR)-phenylpyrrolidine (from Example 29), 0.015 mL of N-methylaniline and 0.070 mL of isopropylmagnesium chloride (2M in THF) using a procedure analogous to that described in Example 93 to provide 12 mg of the title compound.
  • RF 0.30 (5% MeOH in CH2CI2).
  • the title compound was prepared from 35 mg of l-benzyl-3- (SR)-(4-carboethoxy-piperidin-l-ylmethyl)-4-(SR)-phenylpyrrolidine (from Example 29), 0.017 mL of N-benzyl-N-methylamine and 0.070 mL of isopropylmagnesium chloride (2M in THF) using a procedure analogous to that described in Example 93 to provide 7.5 mg of the title compound.
  • RF 0.25 (5% MeOH in CH2CI2).
  • the title compound was prepared from 30 mg of l-benzyl-3- (SR)-(4-carboethoxy-piperidin-l-ylmethyl)-4-(SR)-phenylpy ⁇ rolidine, 0.022 mL of N-benzyl-N-methylamine and 0.075 mL of isopropyl-magnesium chloride (2M in THF) using a procedure analogous to that described in Example 93 to provide 16 mg of the title compound.
  • RF 0.30 (5% MeOH in CH2CI2).
  • the title compound was prepared from 37.5 mg of 1-benzyl- 3-(SR)-(4-carboethoxy-piperidin-l-ylmethyl)-4-(SR)-phenylpyrrolidine, 0.020 mL of N-methyl-N-phenethylamine and 0.070 mL of isopropyl- magnesium chloride (2M in THF) using a procedure analogous to that described in Example 93 to provide 25.5 mg of the title compound.
  • RF 0.20 (5% MeOH in CH2CI2).
  • Step B l-Benzyl-(SR)-[3--methyl-3-((4-phenyl)piperidin-l- yl)methyl1-4-(SR)-phenylpyrrolidine
  • the title compound was prepared from l-benzyl-(RS)-[3- methyl-3-formyl]-4-(SR)-phenylpyrrolidine (from Example 98, Step A) and(4-phenyl)piperidine using a procedure analogous to that described in Example 9.
  • iH NMR 500 MHz, CDCI3: ⁇ 0.69 (s, 3H), 1.72-1.79 (4H),
  • Step A l-Benzyl-3-(RS)-acetyl-4-(SR)-phenylpyrrolidine
  • the title compound was prepared from (E)-4-phenyl-3- butan-2-one using a procedure analogous to that described in Example 1, Step A.
  • Step B l-Benzyl-3-(SR)-(l-(RS)-((hydroxy)ethyl)-4-(SR)- phenylpyrrolidine and l-Benzyl-3-(SR)-(l-(RS)- (hydroxy)ethyl)-4-(SR)-phenylpyrrolidine A solution of 750 mg (2.7 mmol) of l-benzyl-3-(RS)-acetyl-4-
  • Step C l-Benzyl-3-(SR)-(l-(RS)-((azido)ethyl)-4-(SR)-phenyl- pyrrolidine and l-Benzyl-3-(SR)-(l-(RS)- (azido)ethyl)-4-(SR)-phenylpyrrolidine
  • Step D l-Benzyl-3-(SR)-(l-(RS)-((4-phenyl)piperidin-lyl)ethyl)-4- (SR)-phenylpyrrolidine and l-Benzyl-3-(SR)-(l-(SR)-((4- phenyl)piperidin-l-yl)ethyl)-4-(SR)-phenylpyrrolidine
  • SR l-Benzyl-3-(SR)-(l-(RS)-((4-phenyl)piperidin-lyl)ethyl)-4- (SR)-phenylpyrrolidine
  • Step A N-Benzyl-4-trifluoromethanesulfonyl-l, 2, 5, 6- tetrahydropyridine
  • Step B N-Benzyl-4-carbomethoxy-l, 2, 5, 6-tetrahydro- pyridine
  • Step D N-Benzyl-4-(4-phenylpiperidinecarboxamide)-3-phenyl- piperidine To a solution 12 mg of methyl ester (from Example 101, Step D),
  • Step E N-Benzyl-3-(SR)-phenyl-4-(SR)-(4-phenylpiperidin-l- ylmethyP-piperidine

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Abstract

L'invention concerne des composés de pyrrolidine et de pipéridine représentés par la formule (I) (dans laquelle R?1, R2, R3, R4a, R4b, R4c, R4d, R4e, R4f, R4g, R4h¿, m, n, x et y sont tels qu'ils sont définis dans le descriptif) et présentant une utilité en tant que modulateurs de l'activité du récepteur de chemokine. En particulier, ces composés sont utiles en tant que modulateurs des récepteurs de chemokine CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, soit CXCR-3, soit CXCR-4.
EP98944548A 1997-08-28 1998-08-27 Modulateurs de pyrrolidine et de piperidine de l'activite du recepteur de chemokine Withdrawn EP1009405A4 (fr)

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US5774397P 1997-08-28 1997-08-28
US57743P 1997-08-28
GBGB9801009.3A GB9801009D0 (en) 1998-01-16 1998-01-16 Pyrrolidine and piperidine modulators of chemokine receptor activity
GB9801009 1998-01-16
PCT/US1998/017755 WO1999009984A1 (fr) 1997-08-28 1998-08-27 Modulateurs de pyrrolidine et de piperidine de l'activite du recepteur de chemokine

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