WO1998025617A1 - Arylpiperazines substituees utilisees comme modulateurs de l'activite du recepteur de la chemokine - Google Patents

Arylpiperazines substituees utilisees comme modulateurs de l'activite du recepteur de la chemokine Download PDF

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Publication number
WO1998025617A1
WO1998025617A1 PCT/US1997/022769 US9722769W WO9825617A1 WO 1998025617 A1 WO1998025617 A1 WO 1998025617A1 US 9722769 W US9722769 W US 9722769W WO 9825617 A1 WO9825617 A1 WO 9825617A1
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Prior art keywords
piperazine
phenyl
dichlorophenyl
butyl
methyl
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PCT/US1997/022769
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English (en)
Inventor
Sander G. Mills
Martin S. Springer
Malcolm Maccoss
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Merck & Co., Inc.
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Priority to AU55224/98A priority Critical patent/AU5522498A/en
Publication of WO1998025617A1 publication Critical patent/WO1998025617A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings

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, whereas ⁇ -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)).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • 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-1”
  • MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES a human chemokine receptor that bind or respond to ⁇ -chemokines with the following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1") [MlP-l ⁇ , MlP-l ⁇ , MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.. 270.
  • the ⁇ -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.
  • the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases.
  • HIV-1 human immunodeficiency virus
  • AIDS acute immune deficiency syndrome
  • Certain compounds have been demonstrated to inhibit the replication of HrV, 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 HTV-1 is CCR5, a receptor for the ⁇ - chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ (Deng, et al., Nature. 381. 661-666 (1996)).
  • Hr 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 Hr 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.
  • chemokine receptors may be used by some strains of HfV-1 or may be favored by non-sexual routes of transmission. Although most HIV-1 isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine. 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HTV-1 (Zhang, et al., Nature. 383. 768 (1996)).
  • the ⁇ -chemokine macrophage-derived chemokine has been shown to inhibit HrV-1 infection (Pal, et al., Science. 278 (5338), 695-698 (1997).
  • the chemokines RANTES, MlP-l ⁇ , MlP-l ⁇ , vMIP-I, vMIP-II, SDF-1 have also been shown to suppress H1TV.
  • a derivative of RANTES, (AOP)-RANTES is a subnanomolar antagonist of CCR-5 function in monocytes (Simmons, et al., Science. 276.276-279 (1997)).
  • Monoclonal antibodies to CCR-5 have been reported to block infection of cells by HPv 7 in vitro.
  • 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 (see Science. 275. 1261-1264 (1997)).
  • better therapies towards all subtypes of HrV may be provided.
  • peptides eotaxin, RANTES, MlP-l ⁇ , MlP-l ⁇ , MCP-1, and MCP-3 are known to bind to chemokine receptors.
  • inhibitors of HPV-l replication present in supematants of CD8+ T cells have been characterized as the ⁇ -chemokines RANTES, MlP-l ⁇ and MlP-l ⁇ .
  • PCT Patent Publications WO 94/17045 published August 4, 1994
  • WO 94/29309 published December 22, 1994
  • WO 96/10568 disclose certain azacycles 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 (HrV) into target cells and are of value in the prevention of infection by HrV, the treatment of infection by HPv 7 and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS).
  • HrV human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • 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 selected from a group consisting of: linear or branched Cl-8 alkyl, linear or branched C2-8 alkenyl, wherein the Cl-8 alkyl or C2-8 alkenyl is optionally mon( ), di, tri or tetra substituted, the substituents independently selected from:
  • halogen which is defined to include Br, Cl, I, and F,
  • heteroaryl wherein heteroaryl is selected from the group consisting of:
  • heteroaryl selected from the group consisting of:
  • Ci-6 alkyl branched or unbranched, unsubstituted or mono or di-substituted, the substituents being selected from hydrogen and hydroxy,
  • R7 is selected from:
  • R7 are joined together to form a 5-, 6-, or 7- membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or di-substituted, the substituents independently selected from:
  • R8 and R9 are each independently hydrogen or substituted Cl-4alkyl wherein the substitutent is selected from the group consisting of (1) hydroxy, (2) hydrogen,
  • Ar when Ar is phenyl, pyridyl or pyrimidyl, then Ar is mono di or tri-substituted; and further provided that when Ar is mono substituted phenyl, then the substituent is other than halo, hydroxy, -OCi_4alkyl, CF3 or Ci-4alkyl; and further provided that when Ar is di- or tri-substituted, at least one of the substituents is other than halo, hydroxy, -OCl-4alkyl, CF3 or Cl-4alkyl; and pharmaceutically acceptable salts thereof.
  • Preferred compounds for use in the present invention include those of Formula la: Ar
  • Rl is selected from a group consisting of:
  • CH2-heteroaryl, with the heteroaryl is selected from the group consisting of: (1*) imidazolyl,
  • Preferred compounds for use in the present invention include those of Formula I wherein:
  • Rl is selected from a group consisting of: C4, C5, C6, C7 or C ⁇ linear or branched alkyl, which is mono, di- or tri-substituted, where the substituents are independently selected from:
  • Preferred compounds for use in the present invention include those of Formula I wherein:
  • Ar is mono substituted or di-substituted phenyl, wherein the substituents are selected from the group consisting of:
  • Preferred compounds for use in the present invention include those of Formula la:
  • Rl is where B is selected from:
  • pyridyl and mono di or tri-substituted pyridyl wherein the substituents on pyridyl are independently selected from: chloro, methyl, phenyl, Ci-3alkoxy and CF3; and
  • thiophene and mono or disubstituted thiophene wherein the substituents on thiophene are independently selected from: chloro, methyl, phenyl, Cl-3alkoxy and CF3;
  • Ar is mono substituted phenyl wherein the substituent is selected from the group consisting of: (a) -CH2-tetrazolyl,
  • Rio is selected from: hydrogen, Ci-3alkyl, and phenyl
  • Rll and Ri2 are independently selected from: hydrogen, halogen, methyl, phenyl or CF3;
  • Still more preferred compounds for use in the present invention include those of Formula la wherein B is unsubstituted phenyl or unsubstituted thiophene.
  • halo as used herein are intended to include chloro, fluoro, bromo and iodo.
  • Cl-6, as in 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 or hexyl
  • 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-
  • the present invention is further directed to the use of compounds of this general structure which are disclosed as being antagonists of neurokinin receptors.
  • Such compounds are disclosed, for example, in: U.S. Patent No. 5,317,020; U.S. Patent No. 5,534,525; U.S. Patent No. 5,350,852; U.S. Patent No. 5,411,971; U.S. Patent No. 5,446,052; U.S. Patent No. 5,560,700; EP 0 559 538, Sep. 8, 1993; EP 0 591 040, Apr. 6, 1994; EP 0698601, Feb. 28, 1996; EP 0625 509, Nov. 23, 1994; EP 0 630 887, Dec. 28, 1994; EP 0 680962, Nov.
  • the present invention embraces the use of a compound disclosed in these publications as a modulator of chemokine receptor activity.
  • 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 Van 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 either the CCR-5 receptor or the CCR-3 receptor in the aforementioned assays. 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).
  • 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, Cysticercosis); visceral
  • 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,
  • 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.
  • HIV human immunodeficiency virus
  • Treating AIDS or preventing or treating infection by HrV is defined as including, but not limited to, treating a wide range of states of H ⁇ V infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HFV
  • the compounds of this invention are useful in treating infection by HTV after suspected past exposure to HrV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • a compound of the present invention may be used for the prevention of infection by HIV and the prevention of AIDS, such as in post-coital prophylaxis or in the prevention of maternal transmission of the H1TV virus to a fetus or a child upon birth.
  • 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
  • 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 pressent 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 preferred.
  • 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, WO97/03094, WO97/02289, WO96/40781, W096/22966, WO96/20216, WO96/01644, WO96/06108, W095/15973 and WO96/31206; (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 (Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine
  • the weight ratio of the compound 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 NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably 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 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.
  • Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, ARC (RT inhibitor)
  • Roussel AIDS Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)
  • Interferon Beta (Almeda, CA) sarcoma, ARC
  • Lamivudine 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT
  • Ribavirin (Costa Mesa, CA) positive, LAS, ARC
  • Tumor Necrosis Genentech ARC in combination Factor; TNF w/gamma Interferon
  • 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 Hr reverse transcriptase.
  • An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl.
  • HrV 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-butylcarboxamido)- piperazinyl))-pentaneamide 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 protease inhibitors are nelfinavir and ritonavir.
  • HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid.
  • Preferred non- nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
  • 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 include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
  • 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.
  • the pharmaceutical 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; 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.
  • 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 mono
  • 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.
  • compositions and methods 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 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
  • the 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 aldehyde needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention the preparation of a representative aldehyde is described in Examples 1 Step A by Hale, J.J.; Finke, P.E.; MacCoss, M. Bioorganic and Medicinal Chemistry Letters 1993 3, 319- 322.
  • the alkyl halide or alkyl sulfonate needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention an aldehyde, prepared as described above, can be reduced to an alcohol with sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride, and the product alcohol converted to either the alkyl halide using methods described in March J., Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, New York, pp. 382-384 (1985), or alkyl sulfonate ester using methods described in March J., Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, New York, p. 444 (1985).
  • acylating agent e.g. diborane including borane dimethylsulfide; and, lithium aluminum hydride
  • the acylating agent needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention an aldehyde, prepared as described above, can be oxidized using such commonly used reagents as permanganate in acid or silver oxide, and the resulting acid activated as an acid chloride or mixed anhydride which can be used to acylate I.
  • the product amide can be reduced with a strong reducing agent, such as diborane or lithium aluminum hydride, to give the tertiary amine.
  • Compound 1 formed in the alkylation step may be further modified in subsequent reactions.
  • 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 Meurer, US 5,057,517; US 4,242,344; J. Org. Chem, 1974, 39, 2143 and J.C.S. Perkin I, 1980, 506; J. Org. Chem. 1963, 28, 1753; J. Heterocyclic Chem., 1982 ,19, 1207; Arch. Int. Pharmacodyn.
  • Substituted 4-arylpiperazines can be prepared from appropriate fluorobenzene derivative as shown in Scheme 2.
  • reaction of 2-fluorobenzonitrile with 1-t-butoxycarbonylpiperazine in the presence of a base such as K2CO3 gives l-t-butoxycarbonyl-4-(2- cyanophenyD-piperazine.
  • Reduction of the cyano group by hydrogenation in the presence of Raney nickel or by other known methods gives a benzyl amine which can be acylated (Example 1, Step D).
  • the t-butoxycarbonyl protecting group is removed by treatment with trifluoroacetic acid or anhydrous HCl to give a piperazine which can be used in the reductive amination step (Example 1, Step E).
  • a piperazine which can be used in the reductive amination step (Example 1, Step E).
  • Similar reactions using 2-chloro-nitrobenzene in the place of 2-fluorobenzonitrile can provide compounds containing a substituted aniline.
  • Analogs containing a benzoic acid or its derivatives can be prepared by substituting 2-fluorobenzoic acid in this sequence.
  • Arylpiperazine derivatives containing heterocyclic substituents can be synthesized as shown in Scheme 3. Reaction between 2-fluorobenzaldehyde and 1-t-butoxycarbonylpiperazine as described above gives l-t-butoxycarbonyl-4-(2-formylphenyl)-piperazine (Example 9, Step A). Reduction of the aldehyde and treatment of the resulting alcohol with methanesulfonyl chloride gives a mesylate, while treatment of the alcohol with triphenylphosphine and carbon tetrabromide gives the bromide.
  • oxazolidinone imide is made from the indicated acid, by formation of the corresponding acid chloride (by treatment with oxalyl chloride or thionyl chloride) and addition of N- lithio 2(S)-benzyl oxazolidinone.
  • the enolate azidation can be accomplished by a variety of methods, such as the procedure of Evans, D. A.; et. al. J. Am. Chem. Soc. 1990, 112, 4011-4030.
  • Reduction of the oxazolidinone moiety can be carried out by a variety of metal hydride reagents (e.g.
  • the azide is then reduced by treatment with PPI13/H2O or NaBH4.
  • Formation of the cyclic carbamate is accomplished by literature methods; i.e. phosgene, triphosgene or carbonyl diimidazole.
  • the target compounds are prepared by oxidative cleavage of the olefin to the aldehyde followed by reductive amination with an amine salt as described for Scheme 1.
  • the aldehyde is reductively aminated with a heteroaryl substituted aryl piperazine to afford the target precursors.
  • Conversion to the corresponding benzylic amine 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 the primary amine 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 provide the primary amine.
  • the benzylic amine 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.
  • electrophilic reagents such as alkyl or aryl sulfonyl chlorides, carboxylic acid chlorides, carboxylic acid anhydrides, alkyl chloroformates, carbamyl chlorides or alkyl or aryl isocyanates.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • Step A 3-((S)-(3,4-Dichlorophenyl))-4-((3,5-dimethylbenzoyl)methyl- amino)-butanal
  • Step B l-t-Butoxycarbonyl-4-(2-cyano)phenyl-piperazine
  • Step C l-t-Butoxycarbonyl-4-(2-aminomethyl)phenyl-pi ⁇ erazine l-t-Butoxycarbonyl-4-(2-cyano)phenyl-piperazine 3g (10.4mmol) was dissolved in EtOH (65ml) and liq. NH3 (13ml), and was hydrogenated in a bomb (H2 lOOOpsi, 80° C, 36hr). The solvent was then removed under reduced pressure to give the title compound. This material was used in step D below without further purification.
  • Step D 4-(2-(Acetylaminomethyl)phenyl)-piperazine
  • a solution of 0.258 g (0.89 mmol) of 4-(2-aminomethyl)- phenyl-1-t-butoxycarbonylpiperazine (from Step C above) in 3 mL of CH2CI2 was treated with 0.075 mL (1.06 mmol) of acetyl chloride and 0.15 mL (1.07 mmol) of Et3N. After stirring for 20 min the reaction mixture was diluted with CH2CI2 and washed with water, saturated NaHC ⁇ 3, brine and dried over Na2S ⁇ 4. The filtrate was concentrated and the residue was treated with 10 drops of anisole and 2 mL of cold TFA.
  • Step E l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-dimethylbenzoyl)- (methyl-amino))butyl)-4-(2-(acetylaminomethyl)phenyl)- piperazine
  • Step B l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5- dichlorobenzoyl)-(methylamino))butyl)-4-(2- acetylaminomethylphenyP-piperazine
  • the compounds in Examples 3-8 were prepared by reacting the requisite piperazine with either 3-((S)-(3,4-dichlorophenyl))-4-((3,5- dimethylbenzoyl)methylamino)butanal (Example 1, Step A) or 3-((S)-(3,4- dichlorophenyl))-4-((3,5-dichlorobenzoyl)methylamino) butanal (Example 2, Step A) according to the procedure of Example 1, Step E.
  • the piperazine substrates were synthesized by the method of Example 1, Step D by substituting the appropriate acylation reagent.
  • Step A l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-dimethylbenz amino))butyl)-4-(2-((l'-imidazolyl)methyl)phenyl)-piperazine
  • Step A l-t-Butoxycarbonyl-4-(2-formylphenyl)-piperazine
  • 2-fluorobenzaldehyde in 14 mL of DMF was added 2.25 g (12.1 mmol) of t-butyl 1-piperazine- carboxylate.
  • Step B l-t-Butoxycarbonyl-4-(2-hydroxymethylphenyl)-piperazine A solution of 1.15 g (3.96 mmol) of l-t-butoxycarbonyl-4-(2- formyl-phenyD-piperazine in 10 mL of MeOH was treated with 0.15 g (3.96 mmol) of NaBH4. After 2 h the reaction was quenched by adding
  • Step C l-t-Butoxycarbonyl-4-(2-((l'-imidazolyl)methyl)phenyl)- piperazine
  • Step D 4-(2-((l'-Imidazolyl)methyl)phenyl)-piperazine Cold TFA (1 mL) and 0.1 mL of anisole were added to 0.096 g
  • Step E l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-dimethyl benzoyl(methylamino))butyl)-4-(2-((l'-imidazolyl)-methyl)- phenyPpiperazine
  • Example 10-14 The compounds in Examples 10-14 were prepared by the procedure of Example 9 substituting the requisite heterocycle for imidazole in Step C and carrying out Step E with either 3-((S)-(3,4- dichlorophenyl))-4-((3,5-dimethylbenzoyl)methyl-amino)-butanal (from Example 1, Step A) or 3-((S)-(3,4-dichlorophenyl))-4-((3,5- dichlorobenzoyl)methyl-amino)-butanal (from Example 2, Step A).
  • Step A 3-(S)-(3,4-Dichlorophenyl)-4-(N-(3,5-dimethylbenzoyl) methylamino)butanol
  • Step B 4-Bromo-2-(S)-(3,4-dichlorophenyl)-l-(N-(3,5-dimethyl- benzoyl)methylamino)butane
  • Step C (3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)- (methyl-amino))butyl)-4-(2-methylphenyl)piperazine
  • Patent # 5,057,557 in 0.5 mL of acetonitrile was heated in a tightly capped vial at 50°C for four days. The solvent was evaporated and the residue was purified on a 1000 um silica gel prep plate (93:5:2 ethyl acetate :methanol:triethylamine) to furnish 32.5 mg of the title compound as a white foam.
  • Example 18-30 were (unless otherwise stated) prepared from 4-bromo-2-(S)-(3,4-dichlorophenyl)-l-(N-(3,5- dimethylbenzoyl)methylamino)butane (prepared in Example 15, Step B) and the appropiate piperazine derivatives by essentially the same procedure as in Example 17.
  • Step A 8-( l-(4-t-ButyloxycarbonyPpiperazinyP- 1 ,7-naphthyridine .
  • Step B 8-( 1-PiperazinyP- 1.7-naphthyridine dihydrochloride 8-(l-(4-t- Butyloxycarbonyl)piperazinyl)-l,7-naphthyridine, prepared as described above (1.02g, 3.24mmol), was dissolved in abs. EtOH (lOmL) and ethanolic HCl (8mL) was added. This solution was left at room temperature for lOmin and then was evaporated to dryness slowly under a nitrogen stream.
  • Step C l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylbenzoyl)- (methyl amino) )butyl)-4-( 1.7 -naphthyridin-8 -yPpiperazine .
  • Step A 8-(l-(4-t-Butyloxycarbonyl)piperazinyl)-(l,2,4)-triazolo(l,5- a)pyrazine
  • the reaction mixture was cooled and evaporated to dryness to give a yellow syrupy residue that was dissolved in CH2CI2 (60mL) and 10% aq. Na2C ⁇ 3 (60mL). After shaking, the layers were separated and the aqueous layer was washed with CH2CI2 (2 x 60mL) and the pooled organic layers were dried (over MgS ⁇ 4), filtered, and evaporated to dryness. The residue was dissolved in a little CH2CI2, absorbed onto silica gel 60, and chromatographed on a dry-packed silica gel 60 column (3 x 36 cm) developed with EtOAc : hexanes (1 : 3).
  • Step B 8-(l-Piperazinyl)-(l,2,4)-triazolo(l,5-a)pyrazine dihydrochloride
  • Step C l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5- dimethylbenzoyl)-(methylamino))butyl)-4-(l,2,4- triazolo(1.5-a)pyrazin-8-yPpiperazine.
  • Reaction of 4-bromo-2-(S)-(3,4-dichlorophenyl)-l-(N-(3,5- dimethylbenzoyl)methylamino)butane with 8-(l-piperazinyl)-(l,2,4)- triazolo(l,5-a)pyrazine dihydrochloride as described in example 17 gave the title compound.
  • Mass Spectrum (CI/NH3) M+H 566, 568 (35,37(31- isotope).
  • Step A 2-Amino-4-( 1 -piper azinyPpyrimidine dihydrochloride _
  • Step B l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethylben
  • Step A 7-( l-(4-t-ButyloxycarbonvPpiperazinyl)furo(2.3-c )pyridine _ 7-Chlorofuro(2,3-c)pyridine, prepared as described in J. Heterocyclic
  • Step B 7-(Piperazinyl)furo(2.3-c)pyridine trifluoroacetate
  • Step C l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5- dimethylbenzoyl)-(methylamino))butyl)-4-(furo(2,3- c)pyrid-4-yl))piperazine.
  • Step A 3-((S)-(3,4-Dichlorophenyl))-4-((N-3,5-bis- trifluoromethylbenzoyPmethylaminoVbutanal
  • Step B l-t-Butoxycarbonyl-4-(2-bromomethyPphenyP-piperazine
  • l-t-butoxycarbonyl-4-(2- hydroxymethyl)phenyl)-piperazine prepared in Example 9, Step B
  • 625 mg (2.38mmol) of triphenylphosphine and 698mg (2.1mmol) of carbon tetrabromide with cooling in an ice- water bath.
  • the solvent was removed under reduced pressure.
  • the resulting oil was dissolved in EtOAc and water was then added.
  • Step C l-t-Butoxycarbonyl-4-(2-(l'-(tetrazolyl)methyl)phenyl)- piperazine and l-t-Butoxycarbonyl-4-(2-(2'-(tetrazolyl)methyl)phenyl)- piperazine
  • Step D l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bis- (trifluoromethyl)benzoyl(methylamino))butyl)-4-(2-(2'-)
  • Step B l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bis-
  • Step A l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bis-(trifluoromethyl)benzoyl- (methylamino))butyl)-4-(2-(l'-(l', 2', 3'-triazolyl)-methyl)-phenyl)- piperazine
  • Step A l-t-Butoxycarbonyl-4-(2-(l'-(l ⁇ 2 * , 3'- triazolyPmethyPphenyP-piperazine
  • Step B l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bis- (trifl oromethyl)benzoyl(methylamino))butyl)-4-(2-(l'-(l , , 2X
  • Step A l-t-Butoxycarbonyl-4-(2-(methanesulfonylaminomethyl)- phenyP-piperazine
  • the piperazine synthesized in Example 1, Step C was subjected to the condition described in Example 1 Step D using methanesulfonyl chloride instead of acetyl chloride.
  • Step B l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bis- (trifluoromethyl)benzoyl(methylamino))butyl)-4-(2-
  • Example 40 to 44 were prepared by successively carrying out the procedures described in Example 9, Step D and Example 15, Step C, using the piperazines synthesized in Example 33, Step C for Example 40, Example 35, Step A for Examples 41 and 42, Example 37, Step A for Example 43, and Example 38, Step A for Example 44, which in each case are allowed to react with the bromide prepared in Example 30.
  • Step A 3-((S)-(3,4-Dichlorophenyl))-4-((3-fluoro-5- dimethylbenzoyl)methyl-amino)-butanal
  • the title compound was prepared following the procedure described in Example 1, Step A using 3-fluoro-5-trifluoromethylbenzoic acid instead of 3,5-dimethylbenzoic acid.
  • Step B 4-Bromo-2-((S)-(3,4-Dichlorophenyl))-4-((N-3-fluoro-5- trifluoromethylbenzovPmethylaminoVbutane
  • the aldehyde prepared in Step A was treated with the conditions described in Example 15, Steps A and B to give the title compound.
  • Step C l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3-fluoro-5- ( trifluoromethyl )benzoyl(methylamino))butyl)-4-(2-( -
  • Step A Diazomethyl-(2-(S)-(3.4-dichlorophenyP-pent-4-enyP-ketone
  • Step B 3-(R)-(3.4-DichlorophenyP-hex-4-enoic acid
  • Step D 2(S)-Azido-3(S -(3.4-dichlorophenyP-5-hexen-l-ol
  • Step D 2(S)-Azido-3(S -(3.4-dichlorophenyP-5-hexen-l-ol
  • Step E 2(S)-Amino-3(S)-(3.4-dichlorophenvP-5-hexen-l-ol
  • Step F 4(S)-(l(S)-(3.4-DichlorophenvP-3-butenvP-2-oxazolidinone
  • Step G 4(S)-(l(S)-(3,4-Dichlorophenyl)-3-butenyl)-3-methyl-2- oxazolidinone
  • a solution of 4(S)-(l(S)-(3,4-dichlorophenyl)-3-butenyl)-2- oxazolidinone (3.25 g, 11.4 mmol) in DMF (25 mL) at room temp was added NaH (573 mg, 95%, 22.7 mmol). The mixture was stirred for 20 min whereupon Mel (3.54 mL, 57.0 mmol) freshly filtered through basic alumina was added and the resultant reaction mixture was stirred at 70°C for 14 h.
  • Step H 4(S)-(l(S)-(3,4-Dichlorophenyl)-3-oxopropyl)-3-methyl-2- oxazolidinone
  • the title compound was prepared from 4(S)-(l(S)-(3,4- dichlorophenyl)-3-butenyl)-3-methyl-2-oxazolidinone (prepared in Step G above) as in Example 1, Step A to afford the aldehyde (98%).
  • 1-H NMR (CDCI3, 500 MHz) ⁇ 9.76 (s, IH), 7.45 (d, IH, J 8.4 Hz), 7.25-7.31 (m, IH),
  • Step I 4(S)-(l(S)-(3,4-Dichlorophenyl)-3-(4-(2-(l'-(tetrazolyl)- methyl)phenyl)-l-piperazinyl)-propyl)-3-methyl-2- oxazolidinone
  • Step J 2(S)-Amino-3(S)-(3,4-dichlorophenyl)-5-(4-(2-(l'-(tetrazolyl))- ethylphenvP-l-piperazinyP)-pentan-l-ol
  • Step K l-(3-((S)-(3,4-Dichlorophenyl))-4-((S)-(N-3,5-bis-(trifluoro- methyl)benzoyl(methylamino)))-5-hydroxy-pentyl)-4-(2-( -
  • Step A 4(S)-(l(S)-(3,4-Dichlorophenyl)-3-(4-(2-(l'-(l',2',4'- triazolyl)-methyl)phenyD-l-piperazinyl)-propyl)-3-methyl-2- oxazolidinone
  • Step B 2(S)-Amino-3(S)-(3,4-dichlorophenyl)-5-(4-(2-(l'- (l'.2'.4'-triazolyP)-methylphenyP-l-piperazinyP)-pentan-l-ol
  • Step C l-(3-((S)-(3,4-Dichlorophenyl))-4-((S)-(N-3,5-bis- (trifluoromethyl)benzoyl(methylamino)))-5-hydroxy- pentyl)-4-(2-(l'-(l',2',4'-triazolyl)-methyl)phenyl)- piperazine
  • Step A l-t-Butoxycarbonyl-4-(2-(methylthiomethyl)phenyl)- piperazine Potassium t-butoxide (159 mg, 1,42 mmol) in 15 mL of abs.
  • Step B l-(2-(MethylthiomethyPphenyl)-piperazine
  • Step C l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5- dimethyrbenzoyl)-(methylamino))butyl)-4-(2- (methylthiomethyPphen P-piperazine
  • Additional compounds for Formula I can be prepared from the piperazine starting materials given in the following Examples 59 or Example 60 or from the sources listed below by using the methods given in Example 1, Step E, Examplel ⁇ , Step C or Example 17: EXAMPLE 59
  • Step A 7-(l-(4-t-Butyloxycarbonyl)piperazinyl)triazolo(2,3- o pyrimidine
  • Step B 7-(l-PiperazinyPtriazolo(2.3- ⁇ )pyrimidine dihydrochloride
  • Step A 7-Chloro-triazolo(2.3- )pyrimidine
  • Step B 7-(l-(4-t-Butyloxycarbonyl)piperazinyPtriazolo(2.3- ⁇ )pyrimidine
  • Step C 7-( l-PiperazinyPtriazolo(2.3- ⁇ )pyrimidine dihydrochloride
  • 2-methoxy-6-(l-piperazinyl)-9-(l-(2-propenyl))purine dihydrochloride 9-cyclopropyl-2-ethyl-6-(l-piperazinyl)purine, 2-ethyl-9-(l-(2,2,2-trifluoroethylamino))-6-(l-piperazinyl)purine, 2-ethyl-9-methyl-6-(l-piperazinyl)purine dihydrochloride, 2-methoxy-6-(l-piperazinyl)-9-(2-propyl)purine dihydrochloride,
  • Step A l-t-butoxycarbonyl-4-(2-(l-(RS)-hydroxyethyl)phenyl)- piperazine
  • Step B l-t-butoxycarbonyl-4-(2-(l-(RS)-aminoethyl)phenyl)- iperazine
  • step A To a solution of lg of the alcohol obtained in step A (3.26mmol) in THF 10ml was added 1.03g (3.93mmol) of triphenyphosphine and 624mg (4.24m ol) of phthalimide , and finally 0.565ml (3.44mmol) of diethylazodicarboxylate with cooling in an ice- water bath. The cooling bath was then removed and the reaction mixture was stirred at rt overnight. THF was removed under reduced pressure. The remaining material was diluted with ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate.
  • Step C l-t-butoxycarbonyl-4-(2-(l-(RS)-(methanesulfonyl- amino)ethyPphenyl)-piperazine
  • Step D l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bis- (trifluoromethyl)benzoyl(methylamino))butyl)-4-(2-(l-(R)- (methanesulfonylamino)ethyl)phenyl)-piperazine and l-(3-((S)-(3,4-Dichlorophenyl))-4-(N-3,5-bis- (trifluoromethyl)benzoyl(methylamino))butyl)-4-(2-(l-(S)-

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Abstract

L'invention porte sur des arylpipérazines de formule (I) dans laquelle Ar, R1, R8 et R9 sont définis dans la description, et s'avérant utiles comme modulateurs de l'activité du récepteur de la chémokine, et en particulier comme modulateurs des récepteurs CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, et/ou CXCR-4 de la chémokine.
PCT/US1997/022769 1996-12-13 1997-12-12 Arylpiperazines substituees utilisees comme modulateurs de l'activite du recepteur de la chemokine WO1998025617A1 (fr)

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AU55224/98A AU5522498A (en) 1996-12-13 1997-12-12 Substituted aryl piperazines as modulators of chemokine receptor activity

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Cited By (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1013276A1 (fr) * 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalcanes comme modulateurs de CCR5
WO2000038680A1 (fr) * 1998-12-23 2000-07-06 Pfizer Limited Azabicycloalcanes modulateurs de ccr5
WO2000039125A1 (fr) * 1998-12-23 2000-07-06 Pfizer Limited Piperidines utilises comme modulateurs de ccr5
WO2000059873A1 (fr) * 1999-04-06 2000-10-12 Astrazeneca Ab N-(2-phenyl-4-amino-butyl)-1-naphthamides en tant qu'antagonistes du recepteur de la neurokinine-1
US6136827A (en) * 1997-07-25 2000-10-24 Merck & Co., Inc. Cyclic amine modulations of chemokine receptor activity
US6140349A (en) * 1998-02-02 2000-10-31 Merck & Co., Inc. Cyclic amine modulators of chemokine receptor activity
EP1050307A1 (fr) * 1999-05-06 2000-11-08 Applied Research Systems ARS Holding N.V. Antagonistes de CCR4 contre la septicémie
WO2000066141A2 (fr) * 1999-05-04 2000-11-09 Schering Corporation Pharmacotherapie anti-vih utilisant une combinaison d'un peg-interferon-alpha et d'un antagoniste ccr5
WO2000069815A1 (fr) * 1999-05-13 2000-11-23 Teijin Limited Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament
WO2000076972A1 (fr) * 1999-06-11 2000-12-21 Merck & Co., Inc. Modulateurs n-cyclopentyliques de l'activite du recepteur de la chimiokine
US6166037A (en) * 1997-08-28 2000-12-26 Merck & Co., Inc. Pyrrolidine and piperidine modulators of chemokine receptor activity
WO2001058907A1 (fr) * 2000-02-11 2001-08-16 Astrazeneca Ab Thiazolopyrimidines et leur utilisation comme modulateurs de l'activite du recepteur de chimiokine
WO2001058902A1 (fr) * 2000-02-11 2001-08-16 Astrazeneca Ab Composes de pyrimide et leur utilisation comme modulateurs de l'activite du recepteur de chimiokine
WO2001058906A1 (fr) * 2000-02-11 2001-08-16 Astrazeneca Ab Composes pyrimidiniques et leur utilisation comme modulateurs de l"activite des recepteurs de chimiokine
US6288084B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
EP1156801A1 (fr) * 1999-03-10 2001-11-28 Smithkline Beecham Corporation Compos s et m thodes
WO2001090106A2 (fr) * 2000-05-26 2001-11-29 Pfizer Limited Derives du tropane utiles en therapie
US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6331541B1 (en) 1998-12-18 2001-12-18 Soo S. Ko N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6331545B1 (en) 1998-12-18 2001-12-18 Soo S. Ko Heterocycyclic piperidines as modulators of chemokine receptor activity
US6358979B1 (en) 1999-06-11 2002-03-19 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6362177B1 (en) 2000-05-16 2002-03-26 Teijin Limited Cyclic amine derivatives and their use as drugs
US6432981B1 (en) 1999-06-11 2002-08-13 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6441001B1 (en) 1998-12-18 2002-08-27 Bristol-Myers Squibb Pharma Company 2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity
US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6451842B1 (en) 1997-11-18 2002-09-17 Dupont Pharmaceuticals Company Cyclic amine derivatives and their use as drugs
US6472410B1 (en) 1999-06-11 2002-10-29 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6486180B1 (en) 1998-12-18 2002-11-26 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6492400B1 (en) 1998-12-18 2002-12-10 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6500844B1 (en) 1999-06-11 2002-12-31 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6503926B2 (en) 1998-09-04 2003-01-07 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6506777B1 (en) 1999-06-11 2003-01-14 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6511826B2 (en) 1995-06-06 2003-01-28 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor (CCR5) HDGNR10
US6525069B1 (en) 1998-12-18 2003-02-25 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6538002B1 (en) 1999-06-11 2003-03-25 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6667314B2 (en) 2000-05-26 2003-12-23 Pfizer, Inc. Tropane derivatives useful in therapy
US6730671B2 (en) 1999-03-02 2004-05-04 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathespin S
US6743594B1 (en) 1995-06-06 2004-06-01 Human Genome Sciences, Inc. Methods of screening using human G-protein chemokine receptor HDGNR10 (CCR5)
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6770627B1 (en) 1998-09-12 2004-08-03 Astrazeneca Ab Piperizine-4-phenyl derivatives as inhibitors of the interaction between mdm2 and p 53
WO2004092136A1 (fr) * 2003-04-18 2004-10-28 Ono Pharmaceutical Co., Ltd. Compose heterocyclique azote et utilisation de celui-ci
US6897234B2 (en) 1999-12-17 2005-05-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6949643B2 (en) 2001-04-12 2005-09-27 Astrazeneca Ab Thiazolopytimidines and their use as modulators of chemokine receptor activity
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
WO2006028284A1 (fr) 2004-09-08 2006-03-16 Mitsubishi Pharma Corporation Dérivé de morpholine
WO2006059164A2 (fr) 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
US7071193B2 (en) 2000-10-20 2006-07-04 Astrazeneca Ab 7-amino-2-alkylthiopteridin-4-yl-amines for the treatment of chemokine-related diseases
US7115635B2 (en) 2001-04-27 2006-10-03 Mitsubishi Pharma Corporation Benzylpiperidine compound
US7157464B2 (en) 2002-06-12 2007-01-02 Chemocentryx, Inc. Substituted piperazines
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
US7247631B2 (en) 1999-05-04 2007-07-24 Schering Corporation Pegylated interferon alfa-CCR5 antagonist combination HIV therapy
US7271176B2 (en) 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US7279481B2 (en) 2003-07-18 2007-10-09 Glaxo Group Limited Quinoline and quinazoline derivatives having affinity for 5HT1-type receptors
US7390830B1 (en) 1999-05-18 2008-06-24 Teijin Limited Remedies or prophylactics for diseases in association with chemokines
US7393934B2 (en) 2001-12-21 2008-07-01 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
US7405210B2 (en) 2003-05-21 2008-07-29 Osi Pharmaceuticals, Inc. Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US7435830B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7501123B2 (en) 2004-03-12 2009-03-10 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
US7541365B2 (en) 2001-11-21 2009-06-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
US7579342B2 (en) 2000-02-23 2009-08-25 Astrazeneca Pteridine compounds for the treatment of psoriasis
US7585867B2 (en) 2002-09-20 2009-09-08 Astrazeneca Ab Substituted thiazolo[4,5-d]pyrimidin-2(3H)-one
US7589199B2 (en) 2002-06-12 2009-09-15 Chemocentryx, Inc. Substituted piperazines
US7618959B2 (en) 2002-11-05 2009-11-17 Smithklinebeecham Corp Antibacterial agents
US7732459B2 (en) 2002-11-13 2010-06-08 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US7790883B2 (en) 2003-12-05 2010-09-07 Astrazeneca Ab Process for the preparation of thiazolopyrimidines
US7842693B2 (en) 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
WO2011121558A1 (fr) 2010-04-02 2011-10-06 Phivco-1 Llc Traitement d'association comprenant un antagoniste du récepteur ccr5, un inhibiteur de la protéase du vih-1 et un accélérateur pharmacocinétique
US8143261B2 (en) 1999-10-01 2012-03-27 Astrazeneca Ab Thiazolo (4,5-D) pyrimidine compounds
US8247576B2 (en) 2003-12-23 2012-08-21 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8343953B2 (en) 2005-06-22 2013-01-01 Astex Therapeutics Limited Pharmaceutical compounds
US8497294B2 (en) 2007-03-14 2013-07-30 Astex Therapeutics Limited Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
US9353086B2 (en) 2010-10-14 2016-05-31 Proximagen Limited CXCR4 receptor antagonists
CN106117242A (zh) * 2016-06-27 2016-11-16 山东大学 四氢噻喃并嘧啶类衍生物及其制备方法与应用
WO2018112264A1 (fr) 2016-12-14 2018-06-21 Progenity Inc. Traitement d'une maladie du tractus gastro-intestinal avec une chimoikine/un inhibiteur du récepteur de chimiokine
WO2019133901A1 (fr) * 2017-12-28 2019-07-04 Reviva Pharmaceuticals, Inc. Procédé de traitement de la fibrose pulmonaire
WO2020106704A2 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Dispositif ingestible pour administrer un agent therapeutique dans le tractus digestif
WO2021119482A1 (fr) 2019-12-13 2021-06-17 Progenity, Inc. Dispositif ingérable pour administrer un agent thérapeutique dans le tractus gastro-intestinal
US11311552B2 (en) 2015-04-02 2022-04-26 Proximagen, Llc Therapies for cancer
EP4252629A2 (fr) 2016-12-07 2023-10-04 Biora Therapeutics, Inc. Procédés, dispositifs et systèmes de détection du tractus gastro-intestinal

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5231082A (en) * 1976-09-17 1977-03-09 Ajinomoto Co Inc Preparation of 2- piperazinophenylpropionic acid
WO1981003172A1 (fr) * 1980-05-07 1981-11-12 Cerm Cent Europ Rech Mauvernay Nouvelles benzo(1,4)dioxines, leurs procedes de preparation et leur utilisation dans des compositions pharmaceutiques
GB2076395A (en) * 1980-04-23 1981-12-02 Nisshin Flour Milling Co Nonaprenylamine derivatives
EP0187618A1 (fr) * 1984-11-30 1986-07-16 Sandoz Ag Dérivés de pipérazine, procédé de leur préparation et leur application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5231082A (en) * 1976-09-17 1977-03-09 Ajinomoto Co Inc Preparation of 2- piperazinophenylpropionic acid
GB2076395A (en) * 1980-04-23 1981-12-02 Nisshin Flour Milling Co Nonaprenylamine derivatives
WO1981003172A1 (fr) * 1980-05-07 1981-11-12 Cerm Cent Europ Rech Mauvernay Nouvelles benzo(1,4)dioxines, leurs procedes de preparation et leur utilisation dans des compositions pharmaceutiques
EP0187618A1 (fr) * 1984-11-30 1986-07-16 Sandoz Ag Dérivés de pipérazine, procédé de leur préparation et leur application

Cited By (149)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6743594B1 (en) 1995-06-06 2004-06-01 Human Genome Sciences, Inc. Methods of screening using human G-protein chemokine receptor HDGNR10 (CCR5)
US7160546B2 (en) 1995-06-06 2007-01-09 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
US6800729B2 (en) 1995-06-06 2004-10-05 Human Genome Sciences, Inc. Human G-Protein chemokine receptor HDGNR10 (CCR5 receptor)
US6759519B2 (en) 1995-06-06 2004-07-06 Human Genome Sciences, Inc. Antibodies to human G-protein chemokine receptor HDGNR10 (CCR5receptor)
US6511826B2 (en) 1995-06-06 2003-01-28 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor (CCR5) HDGNR10
US6136827A (en) * 1997-07-25 2000-10-24 Merck & Co., Inc. Cyclic amine modulations of chemokine receptor activity
US6166037A (en) * 1997-08-28 2000-12-26 Merck & Co., Inc. Pyrrolidine and piperidine modulators of chemokine receptor activity
US6451842B1 (en) 1997-11-18 2002-09-17 Dupont Pharmaceuticals Company Cyclic amine derivatives and their use as drugs
US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6140349A (en) * 1998-02-02 2000-10-31 Merck & Co., Inc. Cyclic amine modulators of chemokine receptor activity
US6476054B1 (en) 1998-02-02 2002-11-05 Merck & Co., Inc. Cyclic amine modulators of chemokine receptor activity
US7271176B2 (en) 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US6288084B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6288083B1 (en) 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6503926B2 (en) 1998-09-04 2003-01-07 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6770627B1 (en) 1998-09-12 2004-08-03 Astrazeneca Ab Piperizine-4-phenyl derivatives as inhibitors of the interaction between mdm2 and p 53
US6759411B2 (en) 1998-12-18 2004-07-06 Bristol-Myers Squibb Pharma Company Heterocyclic piperidines as modulators of chemokine receptor activity
US7312222B2 (en) 1998-12-18 2007-12-25 Bristol-Myers Squibb Pharma Company Heterocyclic piperidines as modulators of chemokine receptor activity
US6331541B1 (en) 1998-12-18 2001-12-18 Soo S. Ko N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6331545B1 (en) 1998-12-18 2001-12-18 Soo S. Ko Heterocycyclic piperidines as modulators of chemokine receptor activity
US6486180B1 (en) 1998-12-18 2002-11-26 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6706735B2 (en) 1998-12-18 2004-03-16 Bristol-Myers Squibb Pharma Company 2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity
US6919368B2 (en) 1998-12-18 2005-07-19 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6780857B2 (en) 1998-12-18 2004-08-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6525069B1 (en) 1998-12-18 2003-02-25 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6521592B2 (en) 1998-12-18 2003-02-18 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6441001B1 (en) 1998-12-18 2002-08-27 Bristol-Myers Squibb Pharma Company 2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity
US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6875776B2 (en) 1998-12-18 2005-04-05 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6492400B1 (en) 1998-12-18 2002-12-10 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US7217714B1 (en) 1998-12-23 2007-05-15 Agouron Pharmaceuticals, Inc. CCR5 modulators
WO2000039125A1 (fr) * 1998-12-23 2000-07-06 Pfizer Limited Piperidines utilises comme modulateurs de ccr5
EP1013276A1 (fr) * 1998-12-23 2000-06-28 Pfizer Inc. Aminoazacycloalcanes comme modulateurs de CCR5
US6586430B1 (en) 1998-12-23 2003-07-01 Pfizer Inc. CCR5 modulators
CZ300926B6 (cs) * 1998-12-23 2009-09-09 Pfizer Inc. Azabicykloalkan jako modulátor CCR5 a farmaceutická kompozice s jeho obsahem
US7041667B1 (en) 1998-12-23 2006-05-09 Pfizer, Inc. CCR5 modulators
HRP20010468B1 (en) * 1998-12-23 2012-06-30 Pfizer Inc. Azabicycloalkanes as ccr5 modulators
WO2000038680A1 (fr) * 1998-12-23 2000-07-06 Pfizer Limited Azabicycloalcanes modulateurs de ccr5
US6730671B2 (en) 1999-03-02 2004-05-04 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathespin S
EP1156801A4 (fr) * 1999-03-10 2003-05-14 Smithkline Beecham Corp Compos s et m thodes
EP1156801A1 (fr) * 1999-03-10 2001-11-28 Smithkline Beecham Corporation Compos s et m thodes
US6821973B2 (en) 1999-04-06 2004-11-23 Astrazeneca Ab Compounds
WO2000059873A1 (fr) * 1999-04-06 2000-10-12 Astrazeneca Ab N-(2-phenyl-4-amino-butyl)-1-naphthamides en tant qu'antagonistes du recepteur de la neurokinine-1
US6586432B2 (en) 1999-04-06 2003-07-01 Astrazenela Ab Neurokinin-1 receptor antagonists
US6476077B1 (en) 1999-04-06 2002-11-05 Astrazeneca Ab N-(2-phenyl-4-amino-butyl)-1-naphthamides as neurokinin-1 receptor antagonists
WO2000066141A3 (fr) * 1999-05-04 2001-02-08 Schering Corp Pharmacotherapie anti-vih utilisant une combinaison d'un peg-interferon-alpha et d'un antagoniste ccr5
WO2000066141A2 (fr) * 1999-05-04 2000-11-09 Schering Corporation Pharmacotherapie anti-vih utilisant une combinaison d'un peg-interferon-alpha et d'un antagoniste ccr5
US7247631B2 (en) 1999-05-04 2007-07-24 Schering Corporation Pegylated interferon alfa-CCR5 antagonist combination HIV therapy
WO2000067791A1 (fr) * 1999-05-06 2000-11-16 Glaxo Group Limited Antagonistes du ccr4 dans la septicemie
EP1050307A1 (fr) * 1999-05-06 2000-11-08 Applied Research Systems ARS Holding N.V. Antagonistes de CCR4 contre la septicémie
WO2000069815A1 (fr) * 1999-05-13 2000-11-23 Teijin Limited Derives d'amines cycliques ureido-substituees et leur utilisation en tant que medicament
US7390830B1 (en) 1999-05-18 2008-06-24 Teijin Limited Remedies or prophylactics for diseases in association with chemokines
JP2003502315A (ja) * 1999-06-11 2003-01-21 メルク エンド カムパニー インコーポレーテッド ケモカインレセプター活性のｎ−シクロペンチルモジュレーター
WO2000076972A1 (fr) * 1999-06-11 2000-12-21 Merck & Co., Inc. Modulateurs n-cyclopentyliques de l'activite du recepteur de la chimiokine
US6472410B1 (en) 1999-06-11 2002-10-29 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6538002B1 (en) 1999-06-11 2003-03-25 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6358979B1 (en) 1999-06-11 2002-03-19 Merck & Co., Inc. N-cyclopentyl modulators of chemokine receptor activity
US6500844B1 (en) 1999-06-11 2002-12-31 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6432981B1 (en) 1999-06-11 2002-08-13 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
US6593346B2 (en) 1999-06-11 2003-07-15 Merck & Co. Inc. N-cyclopentyl modulators of chemokine receptor activity
US6506777B1 (en) 1999-06-11 2003-01-14 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
JP4688381B2 (ja) * 1999-06-11 2011-05-25 メルク・シャープ・エンド・ドーム・コーポレイション ケモカインレセプター活性のｎ−シクロペンチルモジュレーター
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US8143261B2 (en) 1999-10-01 2012-03-27 Astrazeneca Ab Thiazolo (4,5-D) pyrimidine compounds
US6897234B2 (en) 1999-12-17 2005-05-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6958344B2 (en) 2000-02-11 2005-10-25 Astrazeneca Ab Pyrimidine compounds and their use as modulators of chemokine receptor activity
JP2003522191A (ja) * 2000-02-11 2003-07-22 アストラゼネカ・アクチエボラーグ ケモカイン受容体活性のモジュレーターとしてのピリミジン化合物およびそれらの使用
WO2001058907A1 (fr) * 2000-02-11 2001-08-16 Astrazeneca Ab Thiazolopyrimidines et leur utilisation comme modulateurs de l'activite du recepteur de chimiokine
WO2001058902A1 (fr) * 2000-02-11 2001-08-16 Astrazeneca Ab Composes de pyrimide et leur utilisation comme modulateurs de l'activite du recepteur de chimiokine
US6958343B2 (en) 2000-02-11 2005-10-25 Astrazeneca, Ab Thiazolopyrimidines and their use as modulators of chemokine receptor activity
WO2001058906A1 (fr) * 2000-02-11 2001-08-16 Astrazeneca Ab Composes pyrimidiniques et leur utilisation comme modulateurs de l"activite des recepteurs de chimiokine
US7579342B2 (en) 2000-02-23 2009-08-25 Astrazeneca Pteridine compounds for the treatment of psoriasis
US6362177B1 (en) 2000-05-16 2002-03-26 Teijin Limited Cyclic amine derivatives and their use as drugs
US6410566B1 (en) 2000-05-16 2002-06-25 Teijin Limited Cyclic amine derivatives and their use as drugs
WO2001090106A2 (fr) * 2000-05-26 2001-11-29 Pfizer Limited Derives du tropane utiles en therapie
EP1990341A1 (fr) 2000-05-26 2008-11-12 Pfizer Inc. Derives de triazolyltropane comme modulateurs de CCR5
HRP20020938B1 (en) * 2000-05-26 2011-05-31 Pfizer Inc. Tropane derivatives useful in therapy
EP1526134A2 (fr) * 2000-05-26 2005-04-27 Pfizer Limited Derives de triazolyltropane comme modulateurs de ccr5
EP1526134A3 (fr) * 2000-05-26 2006-11-29 Pfizer Limited Derives de triazolyltropane comme modulateurs de ccr5
JP2005194283A (ja) * 2000-05-26 2005-07-21 Pfizer Inc 療法において有用なトロパン誘導体
US7576097B2 (en) 2000-05-26 2009-08-18 Pfizer, Inc. Tropane derivatives useful in therapy
US6667314B2 (en) 2000-05-26 2003-12-23 Pfizer, Inc. Tropane derivatives useful in therapy
AP1965A (en) * 2000-05-26 2009-03-04 Pfizer Tropane derivatives useful in therapy.
WO2001090106A3 (fr) * 2000-05-26 2002-03-28 Pfizer Ltd Derives du tropane utiles en therapie
US7368460B2 (en) 2000-05-26 2008-05-06 Pfizer, Inc. Tropane derivatives useful in therapy
CN100355753C (zh) * 2000-05-26 2007-12-19 辉瑞大药厂 用于制备具有治疗作用的莨菪烷衍生物的中间体
EA005382B1 (ru) * 2000-05-26 2005-02-24 Пфайзер Инк. Производные тропана, полезные для терапии
CZ299102B6 (cs) * 2000-05-26 2008-04-23 Pfizer Inc. Tropanový derivát, zpusoby a meziprodukty pro jeho výrobu, léciva a lécivové kombinace s jeho obsahem
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US7071193B2 (en) 2000-10-20 2006-07-04 Astrazeneca Ab 7-amino-2-alkylthiopteridin-4-yl-amines for the treatment of chemokine-related diseases
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
US6949643B2 (en) 2001-04-12 2005-09-27 Astrazeneca Ab Thiazolopytimidines and their use as modulators of chemokine receptor activity
US7115635B2 (en) 2001-04-27 2006-10-03 Mitsubishi Pharma Corporation Benzylpiperidine compound
US7514430B2 (en) 2001-09-18 2009-04-07 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use
US7541365B2 (en) 2001-11-21 2009-06-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US7393934B2 (en) 2001-12-21 2008-07-01 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
US7157464B2 (en) 2002-06-12 2007-01-02 Chemocentryx, Inc. Substituted piperazines
US8324216B2 (en) 2002-06-12 2012-12-04 Chemocentryx, Inc. Substituted piperazines
US7589199B2 (en) 2002-06-12 2009-09-15 Chemocentryx, Inc. Substituted piperazines
US7449576B1 (en) 2002-06-12 2008-11-11 Chemocentryx, Inc. Substituted piperazines
US7842693B2 (en) 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines
US7585867B2 (en) 2002-09-20 2009-09-08 Astrazeneca Ab Substituted thiazolo[4,5-d]pyrimidin-2(3H)-one
US7618959B2 (en) 2002-11-05 2009-11-17 Smithklinebeecham Corp Antibacterial agents
US7732459B2 (en) 2002-11-13 2010-06-08 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US7977350B2 (en) 2002-11-13 2011-07-12 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US9334283B2 (en) 2002-11-13 2016-05-10 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use thereof
WO2004092136A1 (fr) * 2003-04-18 2004-10-28 Ono Pharmaceutical Co., Ltd. Compose heterocyclique azote et utilisation de celui-ci
US7405210B2 (en) 2003-05-21 2008-07-29 Osi Pharmaceuticals, Inc. Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US8158622B2 (en) 2003-05-21 2012-04-17 Prosidion Limited Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US7732600B2 (en) 2003-07-18 2010-06-08 Glaxo Group Limited Quinoline and quinazoline derivatives having affinity for 5HT1-type receptors
US7592346B2 (en) 2003-07-18 2009-09-22 Glaxo Group Limited Quinoline and quinazoline derivatives having affinity for 5HT1-type receptors
US7279481B2 (en) 2003-07-18 2007-10-09 Glaxo Group Limited Quinoline and quinazoline derivatives having affinity for 5HT1-type receptors
US7459456B2 (en) 2003-07-18 2008-12-02 Glaxo Group Limited Quinoline and quinazoline derivatives having affinity for 5HT1-type receptors
US7790883B2 (en) 2003-12-05 2010-09-07 Astrazeneca Ab Process for the preparation of thiazolopyrimidines
US9283226B2 (en) 2003-12-23 2016-03-15 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8691806B2 (en) 2003-12-23 2014-04-08 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US8247576B2 (en) 2003-12-23 2012-08-21 Astex Therapeutics Limited Pyrazole derivatives as protein kinase modulators
US7435830B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
US7501123B2 (en) 2004-03-12 2009-03-10 Human Genome Sciences, Inc. Human G-protein chemokine receptor (CCR5) HDGNR10
WO2006028284A1 (fr) 2004-09-08 2006-03-16 Mitsubishi Pharma Corporation Dérivé de morpholine
WO2006059164A2 (fr) 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
US8343953B2 (en) 2005-06-22 2013-01-01 Astex Therapeutics Limited Pharmaceutical compounds
US8541461B2 (en) 2005-06-23 2013-09-24 Astex Therapeutics Limited Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
US8497294B2 (en) 2007-03-14 2013-07-30 Astex Therapeutics Limited Compositions comprising (S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases
WO2011121558A1 (fr) 2010-04-02 2011-10-06 Phivco-1 Llc Traitement d'association comprenant un antagoniste du récepteur ccr5, un inhibiteur de la protéase du vih-1 et un accélérateur pharmacocinétique
US10995091B2 (en) 2010-10-14 2021-05-04 Proximagen Llc CXCR4 receptor antagonists
US9353086B2 (en) 2010-10-14 2016-05-31 Proximagen Limited CXCR4 receptor antagonists
US10155761B2 (en) 2010-10-14 2018-12-18 Proximagen, Llc CXCR4 receptor antagonists
US11311552B2 (en) 2015-04-02 2022-04-26 Proximagen, Llc Therapies for cancer
CN106117242A (zh) * 2016-06-27 2016-11-16 山东大学 四氢噻喃并嘧啶类衍生物及其制备方法与应用
EP4252629A2 (fr) 2016-12-07 2023-10-04 Biora Therapeutics, Inc. Procédés, dispositifs et systèmes de détection du tractus gastro-intestinal
US10980739B2 (en) 2016-12-14 2021-04-20 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a chemokine/chemokine receptor inhibitor
WO2018112264A1 (fr) 2016-12-14 2018-06-21 Progenity Inc. Traitement d'une maladie du tractus gastro-intestinal avec une chimoikine/un inhibiteur du récepteur de chimiokine
WO2019133901A1 (fr) * 2017-12-28 2019-07-04 Reviva Pharmaceuticals, Inc. Procédé de traitement de la fibrose pulmonaire
WO2020106704A2 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Dispositif ingestible pour administrer un agent therapeutique dans le tractus digestif
WO2020106757A1 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Dispositif ingérable pour administrer un agent thérapeutique au tube digestif
WO2020106750A1 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Méthodes et dispositifs pour traiter une maladie au moyen d'une biothérapie
WO2020106754A1 (fr) 2018-11-19 2020-05-28 Progenity, Inc. Méthodes et dispositifs pour traiter une maladie à l'aide d'agents biothérapeutiques
WO2021119482A1 (fr) 2019-12-13 2021-06-17 Progenity, Inc. Dispositif ingérable pour administrer un agent thérapeutique dans le tractus gastro-intestinal
EP4309722A2 (fr) 2019-12-13 2024-01-24 Biora Therapeutics, Inc. Dispositif ingérable pour l'administration d'un agent thérapeutique au tractus gastro-intestinal

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