WO2014159343A1 - Procédé de stimulation de la migration de cellules immunitaires - Google Patents

Procédé de stimulation de la migration de cellules immunitaires Download PDF

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WO2014159343A1
WO2014159343A1 PCT/US2014/023120 US2014023120W WO2014159343A1 WO 2014159343 A1 WO2014159343 A1 WO 2014159343A1 US 2014023120 W US2014023120 W US 2014023120W WO 2014159343 A1 WO2014159343 A1 WO 2014159343A1
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optionally substituted
group
cycloalkyl
cycloalkenyl
alkyl
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Eric B. SPRINGMAN
Lopa Bhatt
Margaret McCrann PUGH
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Celtaxsys Inc
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Celtaxsys Inc
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the migration of immune cells to a target site is a major step in eliciting an immune response.
  • Cell migration therefore plays an important role in the ability of immune cells to respond to infection, allergy, inflammation and other conditions that elicit an immune response.
  • the migration of cells is dependent on a number of factors including, for example, chemotactic factors, cell adhesion, as well as mechanical properties of the cells, such as the ability to deform or elongate in order to pass through the microvasculature (Lautenschlager, et al, The regulatory role of cell mechanics for migration of differentiating myeloid cells, PNAS, 106 (37): 15696-15701 ; Saito, et al. (2005) Journal of Leukocyte Biology, 78: 777- 784).
  • the present invention provides methods of stimulating the migration of an immune cell, methods of stimulating an immune response and methods of increasing immune cell deformability comprising administering an effective amount of a compound having the Formula (I) shown below.
  • the invention is directed to a method of stimulating the migration of an immune cell comprising exposing said immune cell to an effective amount of a compound having the Formula (I):
  • A is optionally substituted aryl or optionally substituted heteroaryl
  • each of Ri, R2, R 3 and R4 is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, OR c , NO2, S(0) n R c , S(0) n NR c R c , C(0)R c , C(0)OR c , C(0)NR c R c , NR c C(0)NR c R c , NR C R C , and NR c C(0)R c ;
  • Ri and R 3 and R2 and R4 are each independently taken together with the carbon atoms to which they are attached to form a fused optionally substituted cyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
  • each R e is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
  • R5 is selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; and each n is 0, 1 or 2.
  • the immune cell is selected from the group consisting of lymphocytes, monocytes, neutrophils, eosinophils, basophils, and mast cells.
  • the migration of the immune cell is stimulated in a subject in need thereof, wherein the subject is suffering from a condition that can be ameliorated by stimulation of an immune cell.
  • the invention also encompasses a method of stimulating an immune response in a patient in need thereof comprising administering to said patient an effective amount of a compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug of any of thereof.
  • the compound is co-administered with a vaccine.
  • the patient is suffering from cancer or an infection.
  • the infection is selected from the group consisting of a viral infection, a bacterial infection, a fungal infection, and a protozoal infection.
  • the invention also encompasses a method of increasing immune cell deformability in a patient in need thereof comprising administering to said patient an effective amount of a compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug of any of thereof.
  • the patient is suffering from an inflammatory condition.
  • the patient is suffering from a condition selected from the group consisting of disseminated intravascular coagulation, sepsis, septic shock, adult respiratory distress syndrome, cystic fibrosis, idiopathic pulmonary fibrosis, systemic sclerosis, gout, disseminated intravascular coagulopathy, and granuloma.
  • the figure is a plot of the number of cells (neutrophils and PBMCs) per well of chemoattraction (CA; left side) and chemorepulsion (CR; right side) of 0.03, 0.30, 3 and 30 uM of Compound 2 using transmigration assay.
  • the two plots at the bottom represent cells per well of chemokinesis for 0.015, 0.15, 1.5 and 15 uM (half the amount used for of CA and CR described above).
  • Chemoattraction is a measure of immune cell migration response toward an agent
  • Chemorepulsion is a measure of immune cell migration response away from an agent.
  • Chemokinesis measure assesses if an increase in random migration is the cause for what otherwise would be a chemoattractive or chemorepulsive response.
  • the present invention is based on the discovery that certain dihydropyridine compounds can stimulate the migration of immune cells.
  • Various dihydropyridine compounds have been described in the literature as calcium channel blockers.
  • the present invention is based on the discovery of a class of dihydropyridine compounds that stimulate immune cell migration. It has been found that this activity (to stimulate immune cell migration) does not correlate with calcium channel activity.
  • the present invention provides methods of stimulating the migration of an immune cell, methods of stimulating an immune response and methods of increasing immune cell deformability comprising the use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug of any of thereof.
  • the compound has the Formula (I), wherein A is optionally substituted aryl. In additional embodiments, A is optionally substituted phenyl. In further embodiments, A is phenyl substituted with O2 and further optionally substituted.
  • the compound has the Formula (I), wherein A is heteroaryl. In other embodiments, the compound has the Formula (I), wherein A is:
  • R 8 is selected from the group consisting of optionally substituted optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, ORc, N0 2 , S(0) n Rc, S(0) n NR c R c , C(0)R c , C(0)ORc, C(0)NR c R c , NR c C(0)NR c Rc, RcRc, and NR c C(0)R c ; and each of R 9 , Rio, R11 and R i2 is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl,
  • R 8 is selected from the group consisting of halo, haloalkyl, CN, ORc, NR c Rc, NR c C(0)R c , C(0)OR c , C(0)Rc, and NO2.
  • Rs is NO2.
  • each of R ⁇ Rio, R11 and R12 is independently selected from the group consisting of hydrogen, and optionally substituted C 1 -C 4 alkyl.
  • each of Rg, Rio, R11 and R12 is hydrogen.
  • the compound has the Formula (I) or is a compound described herein, wherein Rx and R2 are selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, ORc, N0 2 , S(0) n Rc, S(0) n NR c R c , C(0)R c , C(0)OR c , C(0)NR c R c , NR c C(0)NR c Rc, RcRc, and NR c C(0)R c .
  • Ri and R 2 are each independently selected from the group consisting of CN, C(0)ORc, C(0)R c , C(0)C(0)Rc, and C(0)NRcR c .
  • Ri and R2 are each independently selected from the group consisting of CN, C(0)OR c , and C(0)R. In some embodiments, Ri and R2 are each independently selected from C(0)OR c .
  • the compound has the Formula (I) or is a compound described herein wherein Ri and R3 are taken together with the carbon atoms to which they are attached to form a fused optionally substituted cyclic group selected from the group consisting of optionally substituted C 3 -C12 cycloalkyl, optionally substituted C 3 -C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.
  • the fused optionally substituted cyclic group is substituted with an oxo group.
  • the compound has the Formula (I) or is a compound described herein, wherein R2 and R4 are taken together with the carbon atoms to which they are attached to form a fused optionally substituted cyclic group selected from the group consisting of optionally substituted C 3 -C12 cycloalkyl, optionally substituted C 3 -C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.
  • the fused optionally substituted cyclic group is substituted with an oxo group.
  • the compound has the Formula (I) or is a compound described herein, wherein R 3 and R4 are each independently optionally substituted C1-C1 0 alkyl. In some embodiments, R3 and R4 are each independently methyl or ethyl.
  • the compound has the Formula (I) or is a compound described herein, wherein R 5 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkyl.
  • alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "Ci-Cio alkyl” denotes alkyl having 1 to 10 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, sec -butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3- methylpentyl, and 4-methylpentyl.
  • alkenyl refers to both straight and branched-chain moieties having the specified number of carbon atoms and having at least one carbon-carbon double bond.
  • alkynyl refers to both straight and branched-chain moieties having the specified number or carbon atoms and having at least one carbon-carbon triple bond.
  • cycloalkyl refers to cyclic alkyl moieties having 3 or more carbon atoms.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
  • cycloalkenyl refers to cyclic alkenyl moieties having 3 or more carbon atoms.
  • cycloalkynyl refers to cyclic alkynyl moieties having 5 or more carbon atoms.
  • heterocyclic encompasses heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, heteropolycycloalkenyl and the like.
  • Heterocycloalkyl refers to cycloalkyl groups containing one or more heteroatoms (O, S, or N) within the ring.
  • Heterocycloalkenyl as used herein refers to cycloalkenyl groups containing one or more heteroatoms (O, S or N) within the ring.
  • Heterobicycloalkyl refers to bicycloalkyl groups containing one or more heteroatoms (O, S or N) within a ring.
  • Heterobicycloalkenyl refers to bicycloalkenyl groups containing one or more heteroatoms (O, S or N) within a ring.
  • Cycloalkyl, cycloalkenyl, heterocyclic, groups also include groups similar to those described above for each of these respective categories, but which are substituted with one or more oxo moieties.
  • aryl refers to mono- or polycyclic aromatic carbocyclic ring systems.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • aryl embraces aromatic radicals, such as, phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to aromatic carbocyclic groups containing one or more heteroatoms (O, S, or N) within a ring.
  • a heteroaryl group can be monocyclic or polycyclic.
  • a heteroaryl group may additionally be substituted or
  • heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindoly
  • heteroaryl groups may be C-attached or heteroatom-attached (where such is possible).
  • a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C- attached).
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -Ci- C ⁇ alkyl, -C2-C12 alkenyl, -C2-C12 alkynyl, -C 3 -C 5 cycloalkyl, -C 3 -Ci 5 cycloalkenyl, C 3 -C 5 cycloalkynyl, -heterocyclic, -F, -CI, -Br, -I, -OH, -N0 2 , -N 3 , -CN, -NH 2 , oxo, thioxo, -NHR X , -NR X R X , dialkylamino, -diarylamino, -diheteroarylamino, -OR x , -C(0)OR y , -C(0)R y
  • the invention encompasses a method of stimulating the migration of an immune cell.
  • the immune cell is selected from the group consisting of lymphocytes, monocytes, neutrophils, eosinophils, basophils, peripheral blood mononuclear cells (PBMCs) and mast cells.
  • PBMCs peripheral blood mononuclear cells
  • the immune cell is a lymphocyte, neutrophil or a monocyte.
  • the immune cell is a neutrophil or monocyte.
  • the invention is directed to a method of stimulating migration of an immune cell in a patient in need thereof.
  • a patient in need of immune cell migration is a patient suffering from a condition that can be ameliorated (for example, the symptoms for which can be improved or alleviated or for example, the progression of the disease can be delayed, and the like) by migration of an immune cell.
  • Non-limiting examples of such conditions are gout, granuloma, and disseminated intravascular coagulation.
  • the invention also encompasses a method of stimulating an immune response in a patient in need thereof comprising administering to said patient an effective amount of a compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug of any of thereof.
  • the compound is co-administered with a vaccine.
  • the patient is suffering from cancer or an infection.
  • the infection is selected from the group consisting of a viral infection, a bacterial infection, a fungal infection, and a protozoal infection.
  • Patients in need of immune stimulation include those that are suffering from or are likely to suffer from an infection or from a tumor or cancer. Patients in need of immune stimulation also include patients suffering from conditions associated with
  • the invention is a method of stimulating an immune response in a patient comprising administering to said patient an effective amount a compound described herein wherein the patient is suffering from a condition selected from the group consisting of an infection, ataxia-telangiectasia, Chediak-Higashi syndrome, leukocyte adhesion defects, Wiscott-Aldrich syndrome and complement deficiencies.
  • the invention is a method of treating cancer in a patient suffering therefrom comprising inducing migration of an immune cell toward a cancer cell, said method comprising administering a compound described herein in an effective amount.
  • the invention is a method of treating a bacterial infection in a patient suffering therefrom comprising inducing migration of an immune cell toward a bacterial cell or protein, said method comprising administering a compound described herein in an effective amount.
  • the invention is a method of treating a viral infection in a patient suffering therefrom comprising promoting the migration of an immune cell toward a virus or viral protein, said method comprising administering a compound described herein in an effective amount.
  • the invention is a method of treating a patient suffering from a condition characterized by decreased cell migration.
  • Disorders characterized by lack of immune cell chemotaxis include, but are not limited to, genetic conditions, infections and therapeutic methods associated with immunosuppression.
  • Exemplary conditions are bacterial infections, granulomatous diseases (e. g., tuberculosis), Gaucher disease (Aker et al. (1993), Br. J. Haematol, 83(2): 187-91), chronic obstructive pulmonary disease (Yoshikawa et al. (2007), Am J Resp Critical Care Medicine, 175: 473-79) and Crohn's disease (Harbord et al. (2006), Alimentary Pharmacology and Therapeutics 24(4):651-660).
  • the cancer is a solid tumor.
  • the solid tumor is selected from the group consisting of colon, prostate, breast, lung, skin, liver, bone, pancreas, ovary, testis, bladder, kidney, brain, head and neck cancer.
  • a bacterial infection includes, but is not limited to, an Actinomyces infection, an anthrax infection, a Bacteriodes infection, a Borrelia infection, a Campylobacter infection, a Citrobacter infection, a Clostridium difficile infection, a Corynebacterium infection, an E. coli infection, an Enterobacter infection, a Gardnerella infection, a Haemophilus infection, an H.
  • pylori infection a Klebsiella infection, a Legionella infection, a Listeria infection, a Neisseria infection, a Nocardia infection, a Pasteurella infection, a Pneumococcus infection, a Proteus infection, a Pseudomonas infection, a Salmonella infection, a Shigella infection, a Spirillum infection, a Spirochaeta infection, a Staphylococcal infection, a Streptobacillus infection, a Streptococcal infection, and a Treponema infection.
  • a viral infection includes, but is not limited to, an adenovirus infection, a retrovirus infection, a rotavirus infection, etc.
  • Such infections also include cytomegalovirus infection, an Epstein Barr virus infection, a hepatitis A virus infection, a hepatitis B virus infection, a hepatitis C virus infection, a Herpes simplex virus 1 infection, a Herpes simplex virus 2 infection, an HIV infection, a human papilloma virus infection, an influenza A virus infection, a monkey pox infection, a respiratory syncytial virus infection, a SARS infection a small pox infection, a varicella-zoster virus infection.
  • the infection can also be a fungal infection.
  • Fungal infections include, but are not limited to, aspergillosis, blastomycosis, candidiasis, chromomycosis, crytococcosis, histoplasmosis, mycetoma infections, paracoccidioidomycosis, pseudallescheriasis, ringworm, and tinea versicolor infection.
  • Exemplary cancers and tumors that can be treated according to the methods of the invention include, for example, biliary tract cancer; brain cancer including glioblastomas and medulloblastomas; breast cancer; cervical cancer; choriocarcinoma; colon cancer;
  • endometrial cancer esophageal cancer, gastric cancer
  • hematological neoplasms including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms, including Bowen's disease and Paget's disease
  • liver cancer hepatocarcinoma
  • lung cancer lymphomas, including Hodgkin's disease and lymphocytic lymphomas
  • neuroblastomas oral cancer, including squamous cell carcinoma; ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreas cancer; prostate cancer; rectal cancer; sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma; skin cancer, including melanoma,
  • the compound described herein can be co-administered with a second agent (e.g., an anti-viral drug or a chemotherapeutic agent).
  • a second agent e.g., an anti-viral drug or a chemotherapeutic agent.
  • Co-administered agents need not be administered at exactly the same time. In certain embodiments, however, the compound is administered substantially simultaneously as the second agent.
  • Second agents include, for example, anti-cancer agents, anti-infective agents, chemoattractants, immunostimulants and other therapeutic compounds.
  • a second agent can be chosen based on the condition or disease to be treated. For example, in a method of treating cancer or a tumor, the compound described herein can be administered with another anti-cancer agent. Similarly, in a method of stimulating an immune response, the compound described herein can be administered with an immunostimulant.
  • the invention also encompasses administering a compound of the invention with an antibiotic, anti-viral or anti-fungal agent.
  • the compound can be administered in pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient.
  • the excipient can be chosen based on the expected route of administration of the composition in therapeutic applications.
  • the route of administration of the composition depends on the condition to be treated. For example, intravenous injection may be preferred for treatment of a systemic disorder and oral administration may be preferred to treat a gastrointestinal disorder.
  • compositions to be administered can be determined by the skilled artisan without undue experimentation in conjunction with standard dose-response studies. Relevant circumstances to be considered in making those determinations include the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • the vaccine can be administered to a person in need of immunostimulation (i.e., a person who would benefit by mounting or increasing an immune response to an antigen, a tumor cell or a tumor) in order to stimulate an immune response.
  • immunostimulation i.e., a person who would benefit by mounting or increasing an immune response to an antigen, a tumor cell or a tumor
  • vaccines include Hepatitis B Diptheria, Tetanus, Pertussis, Haemoplilus influenzae Type B,
  • the vaccine can further comprise an adjuvant.
  • an "adjuvant” is an immunologic reagent that increases an antigenic response.
  • adjuvants for use in pharmaceuticals include immunostimulatory oligonucleotides, imidazoquinolines (e.g., imiquimod), monophosphoryl lipid A, and detoxified lipopolysaccharide (LPS), as described, for example, by O'Hagan et al. (Biomol. Eng. 18:69-85, 2001)).
  • An example of an immunostimulatory oligonucleotide is an oligonucleotide having ummethylated CpG sequences.
  • the invention is additionally directed to a method of increasing immune cell deformability in a patient in need thereof comprising administering to said patient an effective amount of a compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug of any of thereof.
  • a compound having the Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug of any of thereof.
  • inflammatory diseases are associated with the sequestration of immune cells in the microvasculature of various organs, including, for example, the lungs (Saito et al).
  • the present invention encompasses a method of increasing the deformability of an immune cell in a patient in need thereof comprising administering an effective amount of a compound described herein.
  • the patient is suffering from an inflammatory condition.
  • the patient is suffering from a condition selected from the group consisting of disseminated intravascular coagulation, sepsis, septic shock, adult respiratory distress syndrome, cystic fibrosis, idiopathic pulmonary fibrosis, systemic sclerosis, gout, disseminated intravascular coagulopathy, bacterial pneumonia, and granuloma.
  • the compound described herein can be co-administered with a second agent.
  • second agents include, for example, an anti-infective agent, and an anticancer agent.
  • An anti-infective agent is an agent which reduces the activity of or kills a
  • microorganism and include, but are not limited to: Aztreonam; Chlorhexidine Gluconate; Imidurea; Lycetamine; Nibroxane; Pirazmonam Sodium; Propionic Acid; Pyrithione Sodium; Sanguinarium Chloride; Tigemonam Dicholine; Acedapsone; Acetosulfone Sodium;
  • Carbenicillin Potassium Carumonam Sodium; Cefaclor; Cefadroxil; Cefamandole;
  • Cefamandole Nafate Cefamandole Sodium
  • Cefaparole Cefatrizine
  • Cefaparole Cefatrizine
  • Cefaparole Cefatrizine
  • Cefaparole Cefatrizine
  • Cefazaflur Sodium Cefazaflur Sodium
  • Cefazolin Cefazolin Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride;
  • Cefetecol Cefixime; Cefinenoxime Hydrochloride; Cefmetazole; Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Ceforanide; Cefotaxime
  • Ceftibuten Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin
  • Cephradine Cetocycline Hydrochloride
  • Cetophenicol Chloramphenicol
  • Chloramphenicol Chloramphenicol
  • Erythromycin Erythromycin; Erythromycin Acistrate; Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin Gluceptate; Erythromycin Lactobionate; Erythromycin Propionate;
  • Gloximonam Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium; Hexedine;
  • Ibafloxacin Imipenem; Isoconazole; Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate;
  • Kitasamycin Levofuraltadone; Levopropylcillin Potassium; Lexithromycin; Lincomycin;
  • Lincomycin Hydrochloride Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin
  • Methenamine Methenamine Hippurate; Methenamine Mandelate; Methicillin Sodium;
  • Netilmicin Sulfate Neutramycin; Nifuradene; Nifuraldezone; Nifuratel; Nifuratrone;
  • Nifurdazil Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole; Nitrocycline;
  • Nitrofurantoin Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim;
  • Oxytetracycline Calcium Oxytetracycline Hydrochloride; Paldimycin; Parachlorophenol;
  • Penicillin G Potassium; Penicillin G Procaine; Penicillin G Sodium; Penicillin V; Penicillin V
  • Repromicin Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin; Rifapentine; Rifaximin;
  • Rolitetracycline Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate; Rosaramicin Stearate; Rosoxacil; Roxarsone;
  • Sisomicin Sisomicin Sulfate; Sparfloxacin; Spectinomycin Hydrochloride; Spiramycin;
  • Stallimycin Hydrochloride Steffimycin; Streptomycin Sulfate; Streptonicozid; Sulfabenz:
  • Sulfabenzamide Sulfacetamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine Sodium; Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter: Sulfamethazine; Sulfamethizole; Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfanilate Zinc; Sulfanitran; Sulfasalazine; Sulfasomizole; Sulfathiazole; Sulfazamet; Sulfisoxazole;
  • Trisulfapyrimi dines Trisulfapyrimi dines; Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Virginiamycin; Zorbamycin; Difloxacin Hydrochloride; Lauryl Isoquinolinium Bromide; Moxalactam Disodium; Ornidazole; Pentisomicin; and Sarafloxacin Hydrochloride.
  • anti-cancer agents include, but are not limited to, Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin;
  • Ametantrone Acetate Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin;
  • Chlorambucil Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide;
  • Cytarabine dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine;
  • Dexormaplatin Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin;
  • Doxorubicin Hydrochloride Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexatc; Eflorithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate;
  • Epipropidine Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride;
  • Gemcitabine Gemcitabine Hydrochloride; Hydroxyurea; Idarubicin Hydrochloride;
  • Tubulozole Hydrochloride Uracil Mustard; Uredepa; Vapreotide; Verteporlin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleursine Sulfate; Vinorelbine Tartrate Virlrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and Zorubicin Hydrochloride.
  • Treating” or “treatment” includes preventing or delaying the onset of the symptoms, complications, or biochemical indicia of a disease, alleviating or ameliorating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder.
  • a "subject' is a mammal in need of treatment.
  • a “patient” refers to a human subject in need of treatment.
  • a “therapeutically effective amount” or an “effective amount” is amount of a compound or composition that, when administered to a subject, for example a human patient, is sufficient to effect treatment, of a disease or condition and/or that is sufficient to achieve the indicated effect (for example, increasing immune cell migration, increasing immune cell deformability).
  • the compounds described herein can be administered in pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient.
  • the excipient can be chosen based on the expected route of administration of the composition in therapeutic applications.
  • the route of administration of the composition depends on the condition to be treated. For example, intravenous injection may be preferred for treatment of a systemic disorder and oral administration may be preferred to treat a gastrointestinal disorder.
  • the route of administration and the dosage of the composition to be administered can be determined by the skilled artisan without undue experimentation in conjunction with standard dose-response studies. Relevant circumstances to be considered in making those determinations include the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • compositions comprising the compounds described herein can be administered by a variety of routes including, but not limited to, parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural, topical, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intralymphatic, intraarticular, intrathecal and intraperitoneal.
  • the compound is administered using a drug eluting device.
  • the pharmaceutical composition can be administered orally.
  • the pharmaceutical compositions can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • Tablets, pills, capsules, troches and the like may also contain binders, excipients, disintegrating agent, lubricants, glidants, sweetening agents, and flavoring agents.
  • binders include microcrystalline cellulose, gum tragacanth or gelatin.
  • excipients include starch or lactose.
  • disintegrating agents include alginic acid, corn starch and the like.
  • lubricants examples include magnesium stearate or potassium stearate.
  • An example of a glidant is colloidal silicon dioxide.
  • sweetening agents include sucrose, saccharin and the like.
  • flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. In another embodiment, the composition is administered as a tablet or a capsule.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like.
  • a pharmaceutical composition may be presented as pessaries, tampons, creams, gels, pastes, foams or spray.
  • nasally administering or nasal administration includes administering the composition to the mucus membranes of the nasal passage or nasal cavity of the patient.
  • pharmaceutical compositions for nasal administration of a composition include effective amounts of the compounds described herein prepared by well-known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the composition may also take place using a nasal tampon or nasal sponge.
  • suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers. Such formulations may be
  • compositions can be administered parenterally such as, for example, by intravenous, intramuscular, intrathecal or subcutaneous injection. Parenteral administration can be accomplished by incorporating a composition into a solution or suspension. Such solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
  • Parenteral formulations may also include antibacterial agents such as, for example, benzyl alcohol or methyl parabens, antioxidants such as, for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA. Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added.
  • antibacterial agents such as, for example, benzyl alcohol or methyl parabens
  • antioxidants such as, for example, ascorbic acid or sodium bisulfite
  • chelating agents such as EDTA.
  • Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions comprising a compound described herein can also be administered using a drug-eluting medical device.
  • a "drug eluting medical device” is a device which is capable of being inserted into a human or animal body, internally or subcutaneous ly, which is intended to remain in said human or animal body for a period of time, and which is capable of eluting one or more pharmaceutical compositions for a portion of the time during which the device resides in the human or animal body.
  • Drug-eluting implantable medical devices include, for example, stents, stent grafts, anastomosis devices, vascular grafts, vascular patches, AV shunts, catheters, guide wires, balloons, and filters.
  • Various drug-eluting coating materials can be applied to the surface of traditional implantable medical devices to impart desired pharmacological effects to the otherwise inert devices, in addition to the basic, mechanical functions performed by the traditional, uncoated devices.
  • Rectal administration includes administering the pharmaceutical compositions into the rectum or large intestine. This can be accomplished using suppositories or enemas.
  • Suppository formulations can easily be made by methods known in the art.
  • suppository formulations can be prepared by heating glycerin to about 120°C, dissolving the pharmaceutical composition in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
  • Transdermal administration includes percutaneous absorption of the composition through the skin.
  • Transdermal formulations include patches, ointments, creams, gels, salves and the like.
  • pulmonary will also mean to include a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses.
  • an aerosol formulation containing the active agent a manual pump spray, nebulizer or pressurized metered-dose inhaler as well as dry powder formulations are contemplated.
  • Suitable formulations of this type can also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.
  • a drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister.
  • the compound intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
  • FCS Fetal Calf Serum
  • IMDM Iscove's Modified Dulbecco's Medium
  • the assay plates are Neuroprobe ChemoTx plates, part number 206-3 (3um pore size) for neutrophils and 206-5 (5um pore size) for PBMCs.
  • Assay Medium For media controls and for chemorepulsion samples, Assay Medium was used. For chemoattraction samples, appropriate dilution of ligand at IX concentration was used. For chemokinesis samples, appropriate dilution of ligand at 0.5X concentration was used. The membrane was carefully placed onto the plate, starting at one side and then slowly lowering the other edge onto the plate.
  • Assay Medium For media controls and chemoattraction samples, use Assay Medium. For chemorepulsion samples, appropriate dilution of ligand at IX concentration was used. For chemokinesis samples, appropriate dilution if ligand at 0.5X concentration was used.
  • the plate was covered with the supplied lid and incubated for the desired time at 37°C in 5% C02. Unless otherwise indicated, the incubation time was 1 hour for neutrophils and 3 hours for T cells. For monocytes and B cells, the incubation time was 2 hours. After the desired assay time, the liquid was removed from the top of the plate using a Kimwipe. The membrane was carefully removed from the top of the plate and discarded. The plate was examined under a microscope to look for ligand crystallization, contamination and overall migration.
  • the plate was then incubated for 8 minutes in the dark at room temperature.
  • the Guava Easy Cyte Plus was used to read the plate and quantify the number of migrated cells.
  • the extent of cell migration was displayed as a bar graph with thick horizontal line showing the level of spontaneous unstimulated migration (media background).

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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des procédés de stimulation de la migration d'une cellule immunitaire, des procédés de stimulation d'une réponse immunitaire et des procédés d'augmentation de la capacité de déformation des cellules immunitaires comprenant l'administration d'une quantité efficace d'un composé de formule (I).
PCT/US2014/023120 2013-03-14 2014-03-11 Procédé de stimulation de la migration de cellules immunitaires Ceased WO2014159343A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105175326A (zh) * 2015-08-19 2015-12-23 四川国康药业有限公司 5-甲基-2(1h)吡啶酮衍生物及其制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6545028B2 (en) * 1997-11-14 2003-04-08 Neurosearch A/S Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
US20060165744A1 (en) * 2003-05-22 2006-07-27 Neopharm, Inc Combination liposomal formulations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6545028B2 (en) * 1997-11-14 2003-04-08 Neurosearch A/S Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
US20060165744A1 (en) * 2003-05-22 2006-07-27 Neopharm, Inc Combination liposomal formulations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BACON ET AL.: "Potent and Specific Inhibition of IL -S, IL -la and IL -Ib-induced In Vitro Human Lymphocyte Migration by Calcium Channel Antagonists", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 165, 1989, pages 349 - 354 *
SHWAB.: "Function and spatial distribution of ion channels and transporters in cell migration", AM J PHYSIOL RENAL PHYSIOL., vol. 280, 2001, pages F739 - F747 *
ZHOU ET AL.: "New 4-Aryl-1,4-Dihydropyridines and 4-Arylpyridines as P-Glycoprotein Inhibitors", DRUG METABOLISM AND DISPOSITION, vol. 33, 2005, pages 321 - 328 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105175326A (zh) * 2015-08-19 2015-12-23 四川国康药业有限公司 5-甲基-2(1h)吡啶酮衍生物及其制备方法和用途
CN105175326B (zh) * 2015-08-19 2018-02-27 四川国康药业有限公司 5‑甲基‑2(1h)吡啶酮衍生物及其制备方法和用途

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