WO2017106312A1 - Méthodes de modulation de niveaux d'il-6 et de pd-l1 - Google Patents

Méthodes de modulation de niveaux d'il-6 et de pd-l1 Download PDF

Info

Publication number
WO2017106312A1
WO2017106312A1 PCT/US2016/066610 US2016066610W WO2017106312A1 WO 2017106312 A1 WO2017106312 A1 WO 2017106312A1 US 2016066610 W US2016066610 W US 2016066610W WO 2017106312 A1 WO2017106312 A1 WO 2017106312A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
alkyl
cancer
heteroalkyl
Prior art date
Application number
PCT/US2016/066610
Other languages
English (en)
Inventor
Felix Kim
Halley OYER
Christina MAHER
Original Assignee
Drexel University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Drexel University filed Critical Drexel University
Publication of WO2017106312A1 publication Critical patent/WO2017106312A1/fr

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/155Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/4045Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4465Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • Interleukin 6 is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine.
  • IL-6 is secreted by T cells and macrophages to stimulate immune response, normally for infections and tissue damage such as burns.
  • IL-6 meditated signaling also stimulates inflammatory and auto-immune processes in many diseases, such as diabetes, atherosclerosis, depression, lupus, rheumatoid arthritis, and/or a wide range of cancers. Secretion of IL-6 by cancer cells is believed to promote tumor growth.
  • the protein complex associates with the transmembrane protein glycoprotein 130 (gp130 or IL- 6 ⁇ ) to induce cellular signaling.
  • Programmed death ligand 1 is a transmembrane protein that is involved with suppressing the immune system. Normally, the human immune system reacts to antigens by upregulating the proliferation of CD8+ T cells specific to those antigens. When PD-L1 binds to the PD-1 receptor on activated T and B cells, an inhibitory signal is produced, which both reduces the proliferation of the antigen specific CD8+ T cells and also induces apoptosis in currently activated cells.
  • PD-L1 signaling is involved in disease states, such as cancer (where upregulation of PD-L1 by tumors may allow the tumor to evade the host immune system and enjoy aggressive growth) and infection (where pathogen-induced up-regulation of PD-L1 may allow pathogens to sequester host immune response during both acute and chronic infection).
  • cancer where upregulation of PD-L1 by tumors may allow the tumor to evade the host immune system and enjoy aggressive growth
  • infection where pathogen-induced up-regulation of PD-L1 may allow pathogens to sequester host immune response during both acute and chronic infection.
  • IL-6 and PD-L1 have been implicated in a variety of disorders, several therapeutic strategies have been designed to inhibit IL-6 and/or PD-L1 activity.
  • Murine, chimeric, and other non-human anti-IL-6, anti-PD-1, and/or anti-PD-L1 antibodies have been developed. However, they may be limited in their potency, effectiveness, may often trigger an unacceptable immune response (i.e., immunogenicity) and/or require a high dosage (See, Trikha et al., 2003, Clin. Can. Res.9:4653-4665, herein incorporated by reference in its entirety). For example, antibodies containing non-human portions often give rise to an immune response in humans.
  • the present invention provides, in certain aspects, methods of treating conditions related to IL-6-, PD-1-, and/or PD-L1-mediated signaling by administering Sigma1 modulators.
  • the present disclosure provides methods of preventing, treating, or ameliorating at least one disorder or disease that is mediated via IL-6 and/or pg130 signaling in a subject, the method comprising administering to the subject at least one compound of the invention.
  • the present disclosure further provides methods of enhancing an IL-6-mediated immune response in a subject, the method comprising administering to the subject at least one compound of the invention:
  • the present disclosure provides methods of decreasing IL-6 and/or gp130-mediated signaling in a subject, the method comprising administering to the subject at least one compound of the invention.
  • the present disclosure provides methods of preventing, treating, or ameliorating at least one disorder or disease that is mediated via PD-L1 signaling in a subject, the method comprising administering to the subject at least one compound of the invention. In certain embodiments, the present disclosure provides methods of decreasing PD-L1- mediated signaling in a subject, the method comprising administering to the subject at least one compound of the invention.
  • the present disclosure provides methods of treating cancer in a subject, the methods comprising administering to a subject, in a cancer sample of whom at least one selected from the group consisting of PD-1 and PD-L1 is detected, at least one compound of the invention.
  • the methods further comprise detecting whether PD-1 or PD-L1 is present in a cancer sample from the subject.
  • the methods comprise counseling a subject, in a cancer sample of whom at least one selected from the group consisting of PD-1 and PD-L1 is detected, to be administered at least one compound of the invention.
  • the at least one disorder or disease is an autoimmune disease, inflammation, or cancer.
  • the at least one disorder or disease comprises an autoimmune disease.
  • the autoimmune disease is at least one selected from the group consisting of: asthma, Sjogren’s syndrome, multiple sclerosis, systemic lupus erythematosus, Graves’ disease, Hashimoto’s disease, Castleman’s disease, psoriasis, psoriatic arthropathy, ankylosing spondylitis, inflammatory bowel disease (IBD), polymyalgia rheumatica, giant cell arteritis, autoimmune vasculitis, graft versus host disease (GVHD), adult onset Still’s disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, obesity, diabetes, asthma, multiple sclerosis, Alzheimer’s disease, cerebrovascular disease, fever, acute phase response, allergies, chronic prostatitis, glomerulonephritis, pelvic inflammatory disease, reperfusion injury, and transplant rejection.
  • the at least one disorder or disease is inflammation.
  • the inflammation is acute and/or chronic inflammation.
  • the at least one disorder or disease comprises cancer.
  • the cancer is at least one selected from the group consisting of bladder cancer, brain cancer, bone cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, kidney cancer, large intestine cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, soft tissue cancer, and testicular cancer.
  • the at least one disorder or disease comprises a B-cell proliferative disorder.
  • the B-cell proliferative disorder is at least one selected from the group consisting of follicular lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, hairy cell leukemia, B cell lymphoma, T cell lymphoma, multiple myeloma, Waldenstrom’s macroglobulinemia, Wiskott-Aldrich syndrome, post-transplant lymphoproliferative disorder, and autoimmune lymphoproliferative syndrome.
  • At least one compound of the invention is selected from the group consisting of:
  • ring A is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl ring, and wherein the aryl or heteroaryl ring is optionally substituted with 0-4 R 1 groups;
  • each occurrence of R 2 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 - C 6 heteroalkyl, and–C 1 -C 3 alkyl-(C 3 -C 6 cycloalkyl), wherein the alkyl, heteroalkyl or cycloalkyl group is optionally substituted with 0-5 R 1 groups, or X 3 and R 2 combine to form a (C 3 -C 7 ) heterocycloalkyl group, optionally substituted with 0-2 R 1 groups;
  • each occurrence of R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 - C 6 heteroalkyl, aryl, and–C 1 -C 3 alkyl-(C 3 -C 6 cycloalkyl), wherein the alkyl, heteroalkyl, aryl, or cycloalkyl group is optionally substituted;
  • X 1 is–CH 2 –,–S–,–O– or–(NR 2 )–;
  • X 3 is–S–,–O–, or–NR 2 –;
  • R A is selected from the group consisting of and
  • R B is selected from the rou consistin of:
  • each occurrence of R 2 is independently selected from the group consisting of H, C 1 -C 3 alkyl, and C 1 -C 3 heteroalkyl, wherein the alkyl, heteroalkyl or cycloalkyl group is optionally substituted with 0-2 R 1 groups, or X 3 and R 2 combine to form a (C 3 -C 7 ) heterocycloalkyl group, optionally substituted with 0-2 R 1 groups; and
  • each occurrence of R 3 is independently selected from the group consisting of H, C 1 -C 2 alkyl, and C 1 -C 2 heteroalkyl, aryl, wherein the alkyl, heteroalkyl, aryl, or cycloalkyl group is optionally substituted with 0-2 groups.
  • the at least one compound is a compound of Formula (I-A), or a pharmaceutically acceptable salt or solvate thereof:
  • R A is selected from the group consisting of
  • X 4 is selected from the group consisting of OMe, F, Cl, Br, and I;
  • R B is selected from the group consisting of:
  • R A is X 4 is selected from the group consisting of F, Cl, Br, and I; and R B is selected from the group consisting of:
  • R A is X 4 is selected from the group consisting of F, Cl, Br, and I; and R B is selected from the group consisting of:
  • R A is X 4 is selected from the group consisting of F, Cl, Br, and I; and R B is selected from the group consisting of:
  • R A is ; and R B is selected from the group consisting of:
  • R A is and R B is selected from the group consisting of:
  • R A is ; and R B is selected from the group consisting of:
  • R A is ; and R B is selected from the group consisting of:
  • R A is and R B is selected from the group consisting of:
  • R A is ; and R B is selected from the group consisting of:
  • R 3 is selected from the group consisting of–C 1 -C 6 alkyl,–C 1 -C 6 fluoroalkyl,–C 1 -C 6 alkoxy, F, Cl, Br, and I;
  • R 4 is selected from the group consisting of–C 1 -C 6 alkyl,–C 1 -C 6 alkoxy, F, Cl, Br, and I;
  • each occurrence of R 5 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 - C 6 heteroalkyl, aryl, and–C 1 -C 3 alkyl-(C 3 -C 6 cycloalkyl), wherein the alkyl, heteroalkyl, aryl, or cycloalkyl group is optionally substituted;
  • n is an integer from 1-3;
  • x is an integer from 0-4;
  • y is an integer from 0-4.
  • the at least one compound is selected from the group consisting of: 1-(3-(4-fluorophenoxy )propyl)-3-(4-iodophenyl)guanidine (Compound A), 1-(3-(4- fluorophenoxy )propyl)-3-(4-methoxyphenyl)guanidine (Compound B), 1-(n-propyl)-3-(4- iodophenyl)guanidine (Compound C), 1-(n-propyl)-3-(4-methoxyphenyl)guanidine (Compound D), 1,3-bis(3-(4-fluorophenoxy)propyl)guanidine (Compound E), 1-(3-(4-fluorophenoxy) propyl)-3-(4-trifluoromethylphenyl)guanidine (Compound F), 1-(3-(4-fluorophenoxy)propyl)-3- (4-chlorophenyl)guanidine (Compound A), 1-(
  • the methods described herein further comprise administering to the subject an anti-PD-1 compound and/or an anti-PD-L1 compound.
  • the anti-PD-1 compound is an antibody.
  • the anti-PD-L1 compound is an antibody.
  • the methods described herein further comprise administering to the subject one or more anti-IL-6 and/or gp130 compounds.
  • the methods described herein further comprise administering to the subject an effective amount of at least one immune system modulator.
  • the methods described herein further comprise administering to the subject one or more compounds that block the activity of PD-1 and/or PD-L1.
  • the anti-IL-6 and/or gp130 compound(s) comprise(s) a IL-6 receptor antagonist. In other embodiments, the anti-IL-6 and/or gp130 compound(s) comprise(s) a IL-6 binding compound. In yet other embodiments, the anti-IL-6 and/or gp130 compound(s) comprise(s)s a gp130 antagonist.
  • the one or more anti-IL-6 compound(s) comprise(s) tocilizumab, siltuximab, sarilumab, olokizumab, elsilimomab, ALD518/BMS-94529, sirukumab, CPSI-2364, ARGX-109, FE301, or FM101, or any combination thereof.
  • the at least one immune system modulator modulates the interactions of T and/or B cells with Sigma1 modulators.
  • the at least one immune system modulator is at least one selected from the group consisting of blockers of ICOS-ICOS-L, IL-10, IL-24 IL-21, adenosine 2a, arginase, IDO1, CD40-CD40L, CD134- CD134L, CD137-CD137L, CTLA4, PD-1, PD-L1/PD-L2, TIM3, LAG3, TGF- ⁇ or activate toll- like receptors, IL-2, and STING.
  • the at least one compound that blocks the activity of PD-1 and/or PD-L1 is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab (CT- 011), BMS-936559, avelumab (MSB0010718C), durvalumab (MEDI4736), MEDI0680, B7-DC- Ig (AMP224,), atezolizumab (MPDL3280A), CX-072, REGN2810, TSR-042, STI-1014, STI- 1110, or any combinations thereof.
  • FIGs.1A and 1B depict reduced levels of IL-6 due to RNAi of Sigma1.
  • FIG.1A depicts an illustrative western blot of IL-6, beta-actin, and Sigma1 with and without the RNAi of Sigma1. Both Sigma1 and IL-6 expression levels were reduced with the RNAi of Sigma1.
  • FIG. 1B depicts the relative levels of the IL-6 protein shown in FIG.1A.
  • FIGs.2A, 2B, 2C depict reduced levels of PD-L1 due to exposure to the Sigma1 modulator IPAG.
  • FIG.2A depicts a western blot of PD-L1 and Vinculin with and without treatment with IPAG. PD-L1 expression levels were reduced with exposure to IPAG.
  • FIG.2B depicts the relative levels of the PD-L1 protein shown in FIG.2A.
  • FIG.2C depicts the fluorescence activity of Jurkat NFAT-luciferase cells, where disruption of the Sigma1 receptor- ligand interaction induces luciferase activity, when exposed to IPAG.
  • FIG.3A depicts protein levels of PD-L1, beta-actin, and Sigma1 under certain conditions as described elsewhere herein.
  • FIG.3B depicts a graph illustrating the protein levels of PD-L1 under the conditions used to generate the data illustrated in FIG.3A.
  • FIG.4A depicts the protein levels of PD-L1 under certain conditions as described elsewhere herein.
  • FIG.4B depicts a graph illustrating the protein levels of PD-L1 under certain conditions as described elsewhere herein.
  • FIG.5 depicts the effects of Compound G on tumor growth in immune competent animals (left panel) as compared to immune deficient animals (right panel).
  • abnormal when used in the context of organisms, tissues, cells or components thereof, refers to those organisms, tissues, cells or components thereof that differ in at least one observable or detectable characteristic (e.g., age, phenotype, treatment, time of day, etc.) from those organisms, tissues, cells or components thereof that display the“normal” (expected) respective characteristic. Characteristics that are normal or expected for one cell or tissue type might be abnormal for a different cell or tissue type.
  • a disease or disorder is“alleviated” if the severity of a symptom, phenotype, tumor size, and the like of the disease or disorder is reduced or the conditions is considered to be improved.
  • BD1047 refers to N’-[2-(3,4-dichlorophenyl)ethyl]-N,N,N’- trimethylethane-1,2-diamine, or a pharmaceutically acceptable salt or solvate thereof.
  • BD1063 refers to 1-[2-(3,4-dichlorophenyl)ethyl]-4-methyl piperazine, or a pharmaceutically acceptable salt or solvate thereof.
  • composition or“pharmaceutical composition” refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, sublingual, pulmonary and topical administration.
  • the compounds can also be a pharmaceutically acceptable salt of the compounds described herein.
  • E64d refers to (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3- methylbutane ethyl ester, or a pharmaceutically acceptable salt or solvate thereof.
  • the terms“effective amount,”“pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result.
  • the phrase“effective amount” or “therapeutically effective amount,” as used herein refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or condition associated with the Sigma1 receptor, including alleviating symptoms of such diseases. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • haloperidol refers to 4-[4-(4-chlorophenyl)-4-hydroxy-1- piperidyl]-1-(4-fluorophenyl)-butan-1-one, or a pharmaceutically acceptable salt or solvate thereof.
  • the phrase“in need thereof” means that the subject has been identified or suspected as having a need for the particular method or treatment. In certain embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the subject can be in need thereof.
  • IPAG refers to 1-(4-iodophenyl)-3-(2-adamantyl)guanidine, or a pharmaceutically acceptable salt or solvate thereof.
  • patient “subject,”“individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • patient, subject or individual is a human.
  • subject is a dog, cat, or horse.
  • PB28 refers to 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetra- hydronaphthalen-1-yl)propyl]piperazine, or a pharmaceutically acceptable salt or solvate thereof.
  • methyladenine refers to 3-methyladenine, or a
  • NE100 refers to 4-methoxy-3-(2-phenylethoxy)-N,N- dipropylbenzeneethanamine, or a pharmaceutically acceptable salt or solvate thereof.
  • the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • (+)-pentazocine refers to (+)-[2S-(2,6,11R*)]-1,2,3,4,5,6- hexahydro-6,1-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol, or a pharmaceutically acceptable salt or solvate thereof.
  • the term“pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • compositions physiologically acceptable to the patient.
  • Supplementary active compounds may also be incorporated into the compositions.
  • The“pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.
  • the language“pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic.
  • organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para- toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.
  • pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salt
  • PRE084 refers to 2-morpholin-4-ylethyl 1-phenyl
  • rimcazole refers to 9- ⁇ 3-[(3R,5S)-3,5-dimethylpiperazin-1- yl]propyl ⁇ -9H-carbazole, or a pharmaceutically acceptable salt or solvate thereof.
  • Sigma1 refers to the Sigma1 receptor (Sigma1), Sigma1 receptor gene (SIGMAR1), Sigma1 receptor protein, and any splice variant thereof or any isoform thereof.
  • a“Sigma1 modulator” refers to a compound, or solvate or salt thereof, that binds to the Sigma1 receptor and modifies the activity or biological function of the receptor as compared to the activity or biological function of the receptor in the absence of the modulator.
  • the modulator may be a receptor agonist, which is able to activate the receptor and cause a biological response that is enhanced over the baseline activity of the unbound receptor.
  • the modulator may be a partial agonist, which does not activate the receptor thoroughly and causes a biological response that is smaller in magnitude compared to those of full agonists.
  • the modulator may be an antagonist, which binds to the receptor but does not activate it, resulting in receptor blockage and inhibiting the binding of other agonists.
  • the modulator may be an inverse agonistic, which reduces the activity of the receptor by inhibiting its constitutive activity.
  • the modulator is a specific modulator to Sigma1.
  • the Sigma1 modulator possesses a binding affinity (K d ) for Sigma1 of less than about 100 nM and has an in vivo effect of restoring a normal immune system profile.
  • the term“(+)-SKF10047” refers to [2S-(2a,6a,11R*]-1,2,3,4,5,6- hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol, or a pharmaceutically acceptable salt or solvate thereof.
  • tamoxifen refers to (Z)-2-[4-(1,2-diphenylbut-1- enyl)phenoxy]-N,N-dimethylethanamine, or a pharmaceutically acceptable salt or solvate thereof.
  • A“therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.
  • treatment or“treating” is defined as the application or administration of a therapeutic agent or mixture of agents, e.g., a compound disclosed herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent or mixture of agents to a tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein, a symptom of a condition contemplated herein or the potential to develop a condition
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. C 1-6 means one to six carbon atoms) and including straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.
  • a (C 1 -C 6 ) alkyl is ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.
  • substituted alkyls include, but are not limited to, 2,2- difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example,–CH 2 –NH–OCH 3 , or–CH 2 –CH 2 –S–S–CH 3
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • the alkoxy is C 1 -C 3 alkoxy, such as ethoxy and methoxy.
  • halo or“halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • cycloalkyl refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • the cycloalkyl group is saturated or partially unsaturated.
  • the cycloalkyl group is fused with an aromatic ring.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene.
  • Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes“unsaturated nonaromatic
  • carbocyclyl or“nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon carbon double bond or one carbon carbon triple bond.
  • heterocycloalkyl or“heterocyclyl” refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, Sand N.
  • each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the heterocycloalkyl group is fused with an aromatic ring.
  • the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
  • a heterocycle may be aromatic or non- aromatic in nature. In one embodiment, the heterocycle is a heteroaryl.
  • An example of a 3-membered heterocycloalkyl group includes, and is not limited to, aziridine.
  • 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam.
  • 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.
  • 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine.
  • Other non-limiting examples of heterocycloalkyl groups are:
  • non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2) delocalized a (pi) electrons, where n is an integer.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (such as one, two or three rings), wherein such rings may also be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene.
  • aryl groups include phenyl, anthracyl, and naphthyl. Preferred examples are phenyl and naphthyl, most preferred is phenyl.
  • aryl-(C 1 -C 3 )alkyl means a functional group wherein a one- to three-carbon alkylene chain is attached to an aryl group, e.g.,–CH 2 CH 2 -phenyl. Preferred is aryl- CH 2 – and aryl-CH(CH 3 )–.
  • substituted aryl-(C 1 -C 3 )alkyl means an aryl-(C 1 -C 3 )alkyl functional group in which the aryl group is substituted. Preferred is substituted aryl(CH 2 )–.
  • heteroaryl-(C 1 -C 3 )alkyl means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g.,–CH 2 CH 2 -pyridyl. Preferred is heteroaryl-(CH 2 )–.
  • substituted heteroaryl-(C 1 -C 3 )alkyl means a heteroaryl-(C 1 - C 3 )alkyl functional group in which the heteroaryl group is substituted. Preferred is substituted heteroaryl-(CH 2 )–.
  • heteroaryl or“heteroaromatic” refers to a heterocycle having aromatic character.
  • a polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include the following moieties:
  • heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • polycyclic heterocycles and heteroaryls examples include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4- benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazoly
  • the term“substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • the term“substituted” further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.
  • the term“optionally substituted” means that the referenced group may be substituted or unsubstituted. In certain embodiments, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In other words, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In other words, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In other words
  • the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
  • an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine,–CN,–NH 2 ,–OH,–NH(CH 3 ),–N(CH 3 ) 2 ,–CH 3 ,–CH 2 CH 3 , etc
  • the substituents are independently selected from the group consisting of C 1 - 6 alkyl,–OH, C 1 - 6 alkoxy, halo, amino, acetamido, oxo and nitro.
  • the substituents are independently selected from the group consisting of C 1 - 6 alkyl, C 1 - 6 alkoxy, halo, acetamido, and nitro.
  • the carbon chain may be branched, straight or cyclic. In certain embodiments, the chain is straight.
  • Ranges various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub- ranges as well as individual numerical values within that range and also the endpoints of the range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. DETAILED DESCRIPTION OF THE INVENTION
  • the present disclosure provides, in certain aspects, compounds that are useful in the treatment of Sigma receptor-related diseases and disorders, either alone or in combination with at least one additional therapeutic agent.
  • the present disclosure further provides, in certain aspects, methods of preventing, treating, and/or ameliorating disorders or diseases in a subject that are mediated by IL-6 and/or gp130 using compounds that bind to and modulate the activity of the Sigma receptor.
  • the method comprising administering one or more compounds contemplated herein, alone or in combination with an additional therapeutic agent to the subject.
  • the Sigma modulator is a Sigma antagonist, inverse agonist or agonist.
  • the Sigma modulator is a Sigma antagonist.
  • the Sigma receptor is a Sigma1 receptor.
  • the method comprises administering therapeutically effective amount(s) of one or more compounds described herein, alone or in combination with an additional therapeutic agent, to the subject.
  • the IL-6- and/or gp130-mediated disease or disorder comprises at least one selected from the group consisting of cancer, autoimmune disease, and infection, such as, but not limited to leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), acute myelogenous leukemia, chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin’s disease, a malignant lymphoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, Kaposi’s sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paran
  • orchitis/vasectomy reversal procedures allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn’s pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitivity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, end
  • hypersensitivity reactions Graves disease, Raynaud’s disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type III hypersensitivity reactions, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison’s disease, diabetes mellitus, chronic active hepatitis, primary biliary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson’s disease, hemachromatosis, alpha
  • Mycobacterium tuberculosis Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis/epidydimitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral-associated hemaphagocytic syndrome, viral
  • the present disclosure further provides, in certain aspects, methods of preventing, treating, and/or ameliorating disorders or diseases mediated by PD-L1 using compounds that bind to and modulate the activity of the Sigma receptor.
  • the method comprises administering one or more compounds contemplated herein, alone or in combination with an additional therapeutic agent, to the subject.
  • the Sigma modulator of the invention is a Sigma antagonist, inverse agonist or agonist.
  • the Sigma modulator of the invention is a Sigma antagonist.
  • the Sigma1 receptor is a Sigma1 receptor (also known as Sigma1).
  • the method comprises administering therapeutically effective amount(s) of one or more compounds described herein, alone or in combination with an additional therapeutic agent, to the subject.
  • the PD-L1-mediated disease or disorder comprises at least one selected from the group consisting of cancer, autoimmune disease and infection, such as, but not limited to, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), acute myelogenous leukemia, chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin’s disease, a malignant lymphoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, Kaposi’s sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome/
  • ALL acute
  • thrombocytopenic purpura malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, Mycobacterium tuberculosis,
  • Mycobacterium avium intracellulare Pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis/epidydimitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral- associated hemaphagocytic syndrome, viral encephalitis/aseptic meningitis, and the like.
  • the invention provides methods of treating cancer in a subject.
  • the methods comprise detecting whether PD-1 or PD-L1 is present in a cancer sample from the subject.
  • the methods comprise administering to the subject in which cancer sample PD-1 or PD-L1 is detected one or more compounds, compositions or therapeutic agents described herein, or any combination thereof.
  • the method comprising administering therapeutically effective amount(s) of one or more compounds described herein, alone or in combination with an additional therapeutic agent, to the subject.
  • PD-1 and/or PD-L1 can be detected using any method known in the art and/or described herein.
  • the detection can be based upon protein or mRNA levels of PD-L1.
  • the PD-L1 IHC 22C3 PHARMDXTM immunohistochemistry companion diagnostic test can be used to detect PD-L1.
  • This particular test is already used, for example, as a companion diagnostic in the use of pembrolizumab.
  • a tumor sample for a subject can be analyzed for the expression of PD-L1.
  • the subject can be treated with the compounds and compositions described herein. However, in certain embodiments, the subject is treated with any of the compounds described herein even if PD-L1 is not present. In certain embodiments, the subject is not treated with any of the compounds described herein if PD-L1 is not detected in the sample.
  • compounds that can be used in the methods described herein include the compounds, or pharmaceutically acceptable salts thereof, of Formula (I), Formula (I- A), Formula (I-B), and Formula (II) as described herein, and/or species thereof, as well as any compound known to be a Sigma1 antagonist, agonist or inverse agonist, such as but not limited to haloperidol, IPAG, PB28, rimcazole, BD1063, BD1047, PRE084, NE100, (+)-SKF10047, (+)- pentazocine, and any combinations thereof.
  • protein homeostasis /“proteostasis” i.e., maintenance of proper protein synthesis, processing, folding. transport, assembly, and degradation
  • modulating properties of the compounds of the invention allow them to be used in the treatment of any disease in which protein homeostasis is disrupted (e.g., neurodegenerative diseases) or in which this process plays an important role, which in some cases be a key or crucial role (e.g., cancer).
  • the compound of the invention crosses the blood-brain barrier. In certain embodiments, the compound of the invention does not cross the blood-brain barrier.
  • the invention provides compositions comprising at least one compound described herein.
  • the composition further comprises at least one additional therapeutic agent.
  • the composition is administered with or in timing proximity to an additional therapeutic agent.
  • compositions are provided comprising a Sigma1 receptor-modulating compound and at least one additional therapeutic agent.
  • the additional therapeutic agent targets the UPR and/or autophagic survival pathway.
  • the additional therapeutic agent binds to and modulates the Sigma1 receptor.
  • the additional therapeutic agent is a chemotherapeutic and/or hormone therapy agent.
  • the additional therapeutic binds to IL-6.
  • the additional therapeutic inhibits the activity of IL-6.
  • the additional therapeutic enhances the activity of IL-6.
  • IL-6 acts through its binding to IL-6R. Therefore, a composition provided herein can also comprise or be administered with an additional therapeutic agent that acts on IL-6R.
  • the additional therapeutic binds to IL-6R and blocks its activity.
  • the additional therapeutic binds to PD-L1 and blocks its activity.
  • the additional therapeutic inhibits the activity of PD-L1.
  • PD-L1 acts through its binding to PD-1. Therefore, a composition provided herein can also comprise or be administered with an additional therapeutic agent that acts on PD- 1.
  • the additional therapeutic binds to PD-1 and blocks its activity.
  • the additional therapeutic inhibits the activity of PD-1.
  • the additional therapeutic is an antibody.
  • the additional therapeutic is an anti-PD-1 antibody.
  • the additional therapeutic is an anti-PD-L1 antibody.
  • the additional therapeutic is an anti-IL-6 antibody.
  • the antibody can be any suitable therapeutic antibody for the subject.
  • the antibody is a chimeric antibody, a murine antibody, a human antibody, a humanized antibody, and the like.
  • the antibody comprises nivolumab (OPDIVO ® ), pembrolizumab (KEYTRUDA ® ), pidilizumab (CT-011, Curetech Bio), avelumab (MSB0010718C, Merck KGaA), durvalumab (MEDI4736, Medimmune), MEDI0680 (Medimmune), B7-DC-Ig
  • AMP224 GlaxoSmithKline
  • BMS-936559 atezolizumab
  • CX-072 CytomX Therapeutics
  • REGN2810 REGN2810
  • TSR-042 Tesaro, Inc.
  • STI-1014 Sorrento Therapeutics
  • STI-1110 Sorrento Therapeutics
  • sirukumab CNTO 136, Janssen
  • siltuximab SYLVANT ®
  • olokizumab UMB
  • clazakizumab ALD518, Alder Biopharmaceuticals
  • gerilimzumab ARGX-109, RuiYi/arGEN-X
  • additional therapeutic agents contemplated within the invention also include, but are not limited to, growth factor receptor inhibitors, monoclonal antibodies against growth factor receptors (e.g., traztuzumab), hormone receptor antagonists (e.g., androgen receptor inhibitors), autophagy modulators (such as rapamycin and its analogs or“rapalogs”), ER stress response inhibitors, proteasome inhibitors, protein translation inhibitors (e.g., MAPK- interacting Ser/Thr kinase 1 (MNK1) inhibitors), p97/VCP inhibitors (e.g., DBeQ and derivatives thereof; Chou et al., 2011, PNAS U S A 108(12):4834-9), DNA repair inhibitors (e.g., olaparib), and combinations thereof.
  • growth factor receptor inhibitors e.g., monoclonal antibodies against growth factor receptors (e.g., traztuzumab), hormone receptor antagonists (e.g., androgen receptor inhibitor
  • Non-limiting examples of additional therapeutic agents contemplated within the disclosure include octapeptide, somatostatin, analoguem, lanreotide, angiopeptin, dermopeptin, octreotide, pegvisomant, 3-methyladenine, chloroquine, hydroxychloroquine, wortmannin, eeyarestatin I, salubrinal, versipelostatin, 2H-isoindole-2-carboxylic acid, 4-fluoro-1,3-dihydro- (2R,6S,12Z,13aS,14aR,16aS)-14a-[[(cyclopropyl-sulfonyl)amino]carbonyl]-6-[[(1,1-dimethyl ethoxy)carbonyl]amino]-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydr
  • the compounds described herein may be synthesized using techniques well-known in the art of organic synthesis.
  • the starting materials and intermediates required for the synthesis may be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as described herein.
  • the compound of the invention is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • ring A is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl ring, and wherein the aryl or heteroaryl ring is optionally substituted with 0-4 R 1 groups;
  • each occurrence of R 2 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, and–C 1 -C 3 alkyl-(C 3 -C 6 cycloalkyl), wherein the alkyl, heteroalkyl or cycloalkyl group is optionally substituted with 0-5 R 1 groups, or X 3 and R 2 combine to form a (C 3 -C 7 )heterocycloalkyl group, optionally substituted with 0-2 R 1 groups;
  • each occurrence of R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, aryl, and–C 1 -C 3 alkyl-(C 3 -C 6 cycloalkyl), wherein the alkyl, heteroalkyl, aryl, or cycloalkyl group is optionally substituted;
  • X 1 is–CH 2 –,–S–,–O– or–(NR 2 )–;
  • X 3 is–S–,–O–, or–NR 2 –.
  • ring A is a monocyclic aryl or monocyclic heteroaryl ring optionally substituted with 0-4 R 1 groups. In certain embodiments, ring A is unsubstituted. In certain embodiments, ring A is phenyl or substituted phenyl.
  • X 1 and X 3 are both–NH–, and X 2 is NH.
  • the compound of the invention is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof:
  • R A is selected from the group consisting of , and
  • R B is selected from the group consisting of:
  • the compound of the invention is a compound of formula (I-A), or a pharmaceutically acceptable salt or solvate thereof:
  • R A is selected from the group consisting of ;
  • X 4 is selected from the group consisting of OMe, F, Cl, Br, and I;
  • R B is selected from the group consisting of:
  • the compound of the invention is a compound of formula (I-B), or a pharmaceutically acceptable salt or solvate thereof:
  • R 3 is selected from the group consisting of–C 1 -C 6 alkyl,–C 1 -C 6 fluoroalkyl,–C 1 - C 6 alkoxy, F, Cl, Br, and I;
  • R 4 is selected from the group consisting of–C 1 -C 6 alkyl,–C 1 -C 6 alkoxy, F, Cl, Br, and I;
  • each occurrence of R 5 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, aryl, and–C 1 -C 3 alkyl-(C 3 -C 6 cycloalkyl), wherein the alkyl, heteroalkyl, aryl, or cycloalkyl group is optionally substituted;
  • n is an integer from 1-3;
  • x is an integer from 0-4;
  • y is an integer from 0-4.
  • the compound is selected from the group consisting of: 1-(3-(4- fluorophenoxy)propyl)-3-(4-iodophenyl)guanidine (Compound A); 1-(3-(4-fluorophenoxy) propyl)-3-(4-methoxyphenyl)guanidine (Compound B); 1-(n-propyl)-3-(4-iodophenyl)guanidine (Compound C); 1-(n-propyl)-3-(4-methoxyphenyl)guanidine (Compound D); 1,3-bis(3-(4- fluorophenoxy)propyl)guanidine (Compound E); 1-(3-(4-fluorophenoxy)propyl)-3-(4- trifluoromethylphenyl)guanidine (Compound F); 1-(3-(4-fluorophenoxy)propyl)-3-(4- chlorophenyl)guanidine (Compound G); 1-(3-(4-flu
  • the compound, or any pharmaceutically acceptable salt thereof can include any of those described in U.S. Patent Application Publication No.2015/0166472, which is hereby incorporated by reference in its entirety.
  • the compounds can be prepared according to any method known in the art. Methods of synthesis are, for example, described in U.S. Patent Application Publication No.2015/0166472, which is hereby incorporated by reference in its entirety. The methods of synthesis described therein are non-limiting.
  • the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S)-configuration.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity.
  • Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents, such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated form.
  • the compounds may exist as tautomers. All tautomers are included within the scope of the compounds described herein.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the active moiety in vivo.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Compounds described herein also include isotopically labeled compounds, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • isotopically labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as 1 1C, 18 F, 15 O and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non- labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the invention further provides methods of treating, ameliorating and/or preventing a IL-6 and/or PD-L1 related disorder or disease in a subject.
  • the method comprises administering to the subject a therapeutic (pharmaceutical) composition comprising one or more compounds, or pharmaceutically acceptable salts or solvents thereof, as described herein.
  • the disease or disorder comprises at least one selected from the group consisting of cancer, immune related disorders, infection, neuropathic pain, depression, substance abuse, epilepsy, psychosis, Alzheimer’s disease, Parkinson’s disease, and
  • the cancer is at least one selected from the group consisting of prostate cancer, breast cancer, renal cancer, pancreas cancer, colon cancer, skin cancer, lung cancer, bone cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, non-Hodgkin’s lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia
  • the invention further provides methods of treating, ameliorating and/or preventing a IL-6 and/or PD-L1 related disorder or disease in a subject.
  • the method comprises administering to the subject a therapeutic composition comprising a Sigma1 modulating compound, or a pharmaceutically acceptable salt thereof, such as those described herein, and further administering to the subject a therapeutic agent that inhibits the ubiquitin proteasome system (UPS) and/or autophagic survival pathways.
  • the Sigma1 modulating compound is a compound of the invention.
  • administering the Sigma1 modulating compound to the subject allows for administering a lower dose of the therapeutic agent that inhibits the ubiquitin proteasome system (UPS) and/or autophagic survival pathways, as compared to the dose of the therapeutic agent alone that is required to achieve similar results in treating, ameliorating or preventing the IL-6 and/or PD-L1 related disorder or disease in the subject.
  • UPS ubiquitin proteasome system
  • the Sigma1 modulating compound and the therapeutic agent are co-administered to the subject.
  • the Sigma1 modulating compound and the therapeutic agent are co-formulated and/or co-administered to the subject.
  • the subject is a mammal. In certain embodiments, the mammal is a human. In certain embodiments, the subject is a subject in need thereof.
  • the compounds described herein can also be used in combination with one or more additional compounds or therapeutic agents.
  • additional compounds may comprise compounds of the present disclosure and/or therapeutic agents known to treat, prevent, or reduce the symptoms or effects of IL-6, PD-1, and/or PD-L1 related disorder or disease.
  • additional compounds include, but are not limited to, hormone receptor antagonists, autophagy inhibitors, ER stress response inhibitors, protein translation inhibitors, DNA repair inhibitors, anti-IL-6 and/or gp130 compounds, PD-1 inhibitors, PD-L1 inhibitors, immune system modulators, and proteasome inhibitors. Non-limiting examples of these are described herein.
  • the compounds, or pharmaceutically acceptable salts thereof may be used in combination with one or more therapeutic agents (or a salt, solvate or prodrug thereof) selected from the group consisting of hormone receptor antagonists, including but are not limited to octapeptide, somatostatin, analoguem, lanreotide, angiopeptin, dermopeptin, octreotide, pegvisomant, tamoxifen, lasofoxifene, raloxifene, RAD1901, enzalutamide, ARN- 509, ARN-810, galeterone, ODM-201, ORM-15341, and ARV-330; autophagy inhibitors, including but are not limited to 3-methyladenine, chloroquine, hydroxychloroquine, and wortmannin; ER stress response inhibitors, including but are not limited to eeyarestatin I, salubrinal, and versipelostatin;
  • hormone receptor antagonists
  • the additional therapeutic is nivolumab, pembrolizumab, pidilizumab, avelumab, durvalumab, MEDI0680, AMP224, atezolizumab, CX-072, REGN2810, TSR-042, STI-1014, STI-1110, sirukumab, siltuximab, olokizumab, clazakizumab, gerilimzumab, sarilumab, PF-04236921,ALX-0061, and tocilizumab.
  • the compounds described herein can be administered with one or more than one additional therapeutic.
  • the additional therapeutic can be administered simultaneously or sequentially with a compound, or
  • the additional therapeutic is administered before or after a compound described herein.
  • the combination can be provided a synergistic effect.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either prior to or after the onset of a IL-6 and/or PD-L1 related disorder or disease. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • compositions of the present disclosure may be carried out using known procedures, at dosages and for periods of time effective to treat Sigma1 receptor-related disorders or diseases in the patient.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat Sigma1 receptor- related disorders or diseases in the patient.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique
  • compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, may be included in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • compositions can include effective amounts of one or more compound(s) described herein together with, for example, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers.
  • Such compositions may include diluents of various buffer content (e.g., TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc.
  • additives such as detergents and solubilizing agents (e.g., surfactants such as Pluronics, Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol, parabens, etc.) and bulking substances (e.g., sugars such as sucrose, lactose, mannitol, polymers such as polyvinylpyrrolidones or dextran, etc.); and/or incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc.
  • surfactants such as Pluronics, Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.
  • compositions can be employed to influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a compound described herein. See, e.g., Remington’s
  • compositions can, for example, be prepared in liquid form, or can be in dried powder, such as lyophilized form. Particular methods of administering such compositions are described elsewhere herein.
  • the buffer can be selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)-aminomethane, or mixtures thereof.
  • the buffer can also be glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate or mixtures thereof.
  • the preservative can be selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2- phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof.
  • the preservative can also be phenol or m-cresol.
  • the preservative is present in a concentration from about 0.1 mg/ml to about 50 mg/ml, in a concentration from about 0.1 mg/ml to about 25 mg/ml, or in a concentration from about 0.1 mg/ml to about 10 mg/ml.
  • the use of a preservative in pharmaceutical compositions is well- known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
  • the formulation may further comprise a chelating agent where the chelating agent may be selected from the group consisting of salts of ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof.
  • the chelating agent can be present in a concentration from 0.1 mg/ml to 5 mg/ml, from 0.1 mg/ml to 2 mg/ml or from 2 mg/ml to 5 mg/ml.
  • the use of a chelating agent in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
  • the formulation of the compounds described herein may further comprise a stabilizer selected from the group consisting of high molecular weight polymers and low molecular compounds where such stabilizers include, but are not limited to, polyethylene glycol (e.g. PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g. sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, and threonine or any mixture thereof.
  • the stabilizer can also be L-histidine, imidazole or arginine.
  • the high molecular weight polymer can be present in a concentration from 0.1 mg/ml to 50 mg/m, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.
  • the low molecular weight compound can be present in a concentration from 0.1 mg/ml to 50 mg/ml, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.
  • the use of a stabilizer in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
  • the formulation of the compounds described herein may further include a surfactant.
  • the surfactant may be selected from the group consisting of a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters,
  • polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween- 20, or Tween-80), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and
  • sphingoglycolipids ceramides, gangliosides
  • DSS docusate sodium, docusate calcium, docusate potassium
  • SDS sodium dodecyl sulfate or sodium lauryl sulfate
  • dipalmitoyl phosphatidic acid sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates
  • ursodeoxycholic acid sodium cholate, sodium deoxycholate, sodium taurocholate
  • sodium glycocholate N-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate
  • anionic (alkyl-aryl-sulphonates) monovalent surfactants palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g.1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threon
  • lysophosphatidylthreonine e.g. N-alkyl-N,N-dimethylammonio-1- propanesulfonates, 3-cholamido-1-propyldimethylammonio-1-propanesulfonate,
  • dodecylphosphocholine myristoyl lysophosphatidylcholine, hen egg lysolecithin
  • cationic surfactants quarternary ammonium bases
  • cetyl-trimethylammonium bromide e.g. cetyl-trimethylammonium bromide
  • cetylpyridinium chloride non-ionic surfactants
  • polyethyleneoxide/polypropyleneoxide block copolymers Pluronics/Tetronics, Triton X-100, Dodecyl ⁇ -D-glucopyranoside
  • polymeric surfactants Tween-40, Tween-80, Brij-35
  • fusidic acid derivatives e.g. sodium tauro- dihydrofusidate etc.
  • long-chain fatty acids and salts thereof C6-C12 e.g.
  • acylcarnitines and derivatives N ⁇ -acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N ⁇ -acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N ⁇ -acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof.
  • a surfactant in pharmaceutical compositions is well- known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
  • Pharmaceutically acceptable sweeteners can be part of the formulation of the compounds described herein.
  • Pharmaceutically acceptable sweeteners include at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4,1’,6’- trichloro-4,1’,6’-trideoxygalactosucrose), saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey.
  • intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweet
  • Intense sweeteners are conveniently employed in low concentrations.
  • concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation, or is about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones.
  • the bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35%, or from about 10% to 15% (w/v).
  • formulations of the compounds described herein may be prepared by conventional techniques, e.g. as described in Remington’s Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where such conventional techniques of the pharmaceutical industry involve dissolving and mixing the ingredients as appropriate to give the desired end product.
  • phrases“pharmaceutically acceptable” or“therapeutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and preferably do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • the term“pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia (e.g., Remington’s Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit.1985)) for use in animals, and more particularly in humans.
  • compositions of the invention are administered to the patient in dosages that range from one to five times per day or more.
  • compositions of the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of
  • compositions of the invention varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors.
  • the disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account.
  • Compounds of the invention for administration may be in the range of from about 1 Pg to about 10,000 mg, about 20 Pg to about 9,500 mg, about 40 Pg to about 9,000 mg, about 75 Pg to about 8,500 mg, about 150 Pg to about 7,500 mg, about 200 Pg to about 7,000 mg, about 3050 Pg to about 6,000 mg, about 500 Pg to about 5,000 mg, about 750 Pg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.
  • the dose of a compound of the invention is from about 1 mg and about 2,500 mg. In certain embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the present disclosure provides packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of at least one compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the at least one compound to treat, prevent, or reduce one or more symptoms of Sigma receptor-related disorders or diseases in a patient.
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
  • compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the disclosure may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal),
  • intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration are examples of the following agents:
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethyl cellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • the tablets may be coated using suitable methods and coating materials such as OPADRY® film coating systems available from Colorcon, West Point, Pa.
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid
  • Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient.
  • the powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a“granulation.”
  • solvent-using“wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.
  • Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents.
  • the low melting solids when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium.
  • the liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together.
  • the resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form.
  • Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution.
  • U.S. Pat. No.5,169,645 discloses directly compressible wax-containing granules having improved flow properties.
  • the granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture.
  • certain flow improving additives such as sodium bicarbonate
  • the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.
  • the present disclosure also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of the disease or disorder.
  • a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.
  • the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • Additional dosage forms of this disclosure include dosage forms as described in U.S. Pat. Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this disclosure also include dosage forms as described in U.S. Patent Application Publications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this disclosure also include dosage forms as described in PCT Application Publications Nos.
  • the formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release that is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds.
  • the compounds for use the method of the invention may be administered in the form of
  • microparticles for example, by injection or in the form of wafers or discs by implantation.
  • the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • the therapeutically effective amount or dose of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of Sigma receptor-related disorders or diseases in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.
  • a suitable dose of a compound of the present disclosure may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.
  • the amount of compound dosed per day may be administered, in non- limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
  • a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the administration of a compound or composition is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”).
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose may be administered if necessary.
  • patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the compounds, or pharmaceutically acceptable salts thereof, may be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • the unit dosage form may also comprise one or more additional therapeutics, such as, but not limited to, those described herein.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD 50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • Example 1 Reduction in IL-6 protein levels by RNAi of Sigma1
  • RNA interference RNA interference
  • Protein lysates were prepared from MDA-468 cells.10 cm plates were seeded to 50-60% confluent the day before the transfection.32 ⁇ L of Sigma1 siRNA + 600 ⁇ L OPTIMEM were combined, mixed through pipetting and incubated 10 minutes at room temperature (RT). During the 10 minute incubation, media was replaced in plate with 10 mL fresh media. To that tube of siRNA and OPTIMEM, 35 ⁇ L of interferin were added, and the system was vortexed immediately for 20 seconds, and incubated for 20 minutes at RT. The entire volume was added to the plate. The system was incubated for 2 days. On third day, plates were split so that cells were 50-60% confluent. On the following day, the procedure was repeated with a second Sigma1 SiRNA transfection. After the next 2 days, the cells were harvested, lysed, and run on gel to confirm Sigma1 knockdown.
  • Cells were rinsed with Ca/Mg-free PBS and detached using 2 mM EDTA in Ca/Mg-free PBS. Cells were spun for 4 minutes at 14,000 rpm at 4 °C. PBS was aspirated and pellets were re-spun. Pellets were snap-frozen on dry ice. The pellets were lysed using RIPA + 10% glycerol + Protease inhibitor cocktail + Phosphatase inhibitor cocktail + EDTA. Lysis consisted of pipetting up and down 20 times, rotating the tubes at 4 °C for 30 minutes then centrifuged for 15 minutes at 14,000 rpm at 4 °C. The lysates were aliquoted into 30 ⁇ L volumes and stored at -80 °C.
  • Anti-Rabbit HRP was used as a secondary antibody (Cell Signaling 70741:2000 in 5% non-fat dry milk in TBST) and HRP-beta actin was used as a loading control (Cell Signaling 47778, 2:1000 in 5% non-fat dry milk in TBST). Protein levels were measured using ImageJ, IL-6 expression was normalized to beta actin.
  • RNAi of Sigma1 reduced levels of IL-6 but not the control beta-actin.
  • FIG.1A the protein bands for IL-6, beta-actin, and Sigma1 are illustrated. The left column is the control RNAi, while the right column used the Sigma1 RNAi construct.
  • both Sigma1 and IL-6 expression levels were reduced, while the beta-actin expression levels remained unchanged.
  • the decrease in levels of the IL-6 protein shown in FIG.1A is quantitated in FIG.1B.
  • the control expression levels of IL-6 were set to 1.0.
  • the RNAi of Sigma1 reduced IL-6 expression to about 0.45. This demonstrates that the modulation of Sigma1 can be used to control the expression of IL-6, which can be used to treat various disorders as described herein.
  • Example 2 Reduction in PD-L1 expression in prostate cancer cells by administration of Sigma1 modulator
  • PC3 (AR- PCa) cells were treated with 10 ⁇ M of IPAG for 16 hours.
  • PC3 (AR- PCa) cells were seeded 24h prior to treatment with dimethyl sulfoxide (DMSO) or 10 ⁇ M IPAG for 16h.
  • DMSO dimethyl sulfoxide
  • Cells were rinsed with Ca/Mg-free PBS and detached using 2 mM EDTA in Ca/Mg-free PBS. Cells were spun for 4 minutes at 14,000 rpm at 4 °C. PBS was aspirated and pellets were re-spun. Pellets were snap-frozen on dry ice. The pellets were lysed using RIPA + 10% glycerol + Protease inhibitor cocktail + Phosphatase inhibitor cocktail. Lysis consisted of pipetting up and down 20 times, rotating the tubes at 4 °C for 30 minutes then centrifuged for 15 minutes at 14,000 rpm at 4 °C. The lysates were aliquoted into 30 ⁇ L volumes and stored at -80 °C.
  • Anti-rabbit HRP was used as a secondary antibody (Cell Signaling 70741:2000 in 5% non-fat dry milk in TBST). Vinculin was used as a loading control (Sigma Aldrich V91311:1000 in 5% non-fat dry milk in TBST) with anti-mouse HRP as a secondary (Cell Signaling 70761:2000 in 5% non-fat dry milk in TBST). Protein levels were measured using ImageJ, PD-L1 expression was normalized to Vinculin.
  • the Jurkat NFAT Luciferase Assay utilized the Promega PD1/PD-L1 Blockade Assay Kit (CS187111).10,000 PC3 cells/well were plated on Wallac B&W 96-well Isoplate (with white wells and bottom and black matrix) in complete culture medium, i.e., RPMI-1640 supplemented with 5% fetal bovine serum (FBS). The next day, PC3 cells were treated with 10 ⁇ M IPAG for 16 hours. After 16 hour treatment, the IPAG containing culture medium was removed and treated PC3 cells were washed with complete medium. Subsequently, 10,000 Jurkat (NFAT-luciferase) cells were added to wells in complete culture medium. Six hours later, Promega Bio-Glo reagent was added to each well. After 5 minutes, the plate was read with a GloMax plate reader.
  • IPAG reduced levels of PD-L1 but not control Vinculin.
  • FIG.2A the protein bands for PD-L1 and the control Vinculin are shown.
  • the left column is the control treatment (DMSO), while the right column is the 10 ⁇ M IPAG treatment.
  • IPAG greatly reduces expression of PD-L1, but not the control.
  • the decrease in expression of the PD-L1 protein is quantitated in FIG.2B.
  • the control expression levels of PD-L1 are set to 1.0.
  • the exposure to IPAG reduced PD-L1 expression to less than 0.1.
  • Protein lysates were prepared from MDA-231 cells.10 cm plates were seeded to 50-60% confluent the day before the transfection.32 ⁇ L of Sigma1 siRNA + 600 ⁇ L OPTIMEM were combined, mixed through pipetting and incubated 10 minutes at room temperature (RT). During the 10 minute incubation, media was replaced in plate with 10 mL fresh media. To that tube of siRNA and OPTIMEM, 35 ⁇ L of interferin were added, and the system was vortexed immediately for 20 seconds, and incubated for 20 minutes at RT. The entire volume was added to the plate. The system was incubated for 2 days. On third day, plates were split so that cells were 50-60% confluent. On the following day, the procedure was repeated with a second Sigma1 SiRNA transfection. After the next 2 days, the cells were harvested, lysed, and run on gel to confirm Sigma1 knockdown.
  • Cells were rinsed with Ca/Mg-free PBS and detached using 2 mM EDTA in Ca/Mg-free PBS. Cells were spun for 4 minutes at 14,000 rpm at 4 °C. PBS was aspirated and pellets were respun. Pellets were snap-frozen on dry ice. The pellets were lysed using RIPA + 10% glycerol + Protease inhibitor cocktail + Phosphatase inhibitor cocktail + EDTA. Lysis comprised pipetting up and down 20 times, rotating the tubes at 4 °C for 30 minutes then centrifuged for 15 minutes at 14,000 rpm at 4 °C. The lysates were aliquoted into 30 ⁇ L volumes and stored at -80 °C.
  • Anti-Rabbit HRP was used as a secondary antibody (Cell Signaling 70741:2000 in 5% non-fat dry milk in TBST) and HRP-beta actin was used as a loading control (Cell Signaling 47778, 2:1000 in 5% non-fat dry milk in TBST). Protein levels were measured using ImageJ, PD-L1 expression was normalized to beta actin.
  • RNAi of Sigma1 reduced levels of PD-L1 but not the control beta-actin.
  • FIG.3A the protein bands for PD-L1, beta-actin, and Sigma1 are illustrated. The left column is the control RNAi, while the right column used the Sigma1 RNAi construct.
  • both Sigma1 and PD-L1 expression levels were reduced, while the beta-actin expression levels remained unchanged.
  • the decrease in levels of the PD-L1 protein shown in FIG.3A is quantitated in FIG.3B.
  • the control expression levels of PD-L1 were set to 1.0.
  • the RNAi of Sigma1 reduced PD-L1 expression to about 0.36. This demonstrates that the modulation of Sigma1 can be used to control the expression of PD-L1, which can be used to treat various disorders as described herein.
  • Example 4 Reduction in PD-L1 expression in breast cancer cells by administration of Sigma1 modulator
  • Sigma1 protein was inhibited by the Sigma1 inhibitor 1-(4-iodo phenyl)-3-(2-adamantyl)guanidine (IPAG) or activated by the Sigma1 agonist 1-[2-(3,4- Dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)-piperazine dihydrochloride (SA4503), and then levels of PD-L1 were measured to determine if a lower expression levels of Sigma1 resulted in lower expression of PD-L1.
  • MDA231 triple negative breast cancer cells that are PD-L1 positive were treated with 10 ⁇ M of IPAG, 20 ⁇ M of SA4503, or the combination of both for 16 hours.
  • MDA231 cells were seeded 24h prior to treatment with dimethyl sulfoxide (DMSO) or 10 ⁇ M IPAG, 20 ⁇ M of SA4503, or the combination of both for 16h.
  • DMSO dimethyl sulfoxide
  • IPAG reduced levels of PD-L1 but not control Vinculin, and the Sigma1 agonist SA4503 reversed IPAG-mediated PD-L1 inhibition. Together, this indicates that IPAG inhibition of PD-L1 is Sigma1-dependent.
  • FIG.4A the protein bands for PD-L1 and the control Vinculin are shown. The left column is the control treatment (DMSO), while the right columns are the 10 ⁇ M IPAG treatment, followed by 20 ⁇ M of SA4503 or the combination of both. IPAG greatly reduces expression of PD-L1, but not the control. IPAG-mediated PD-L1 inhibition is reversed by the addition of SA4503. The decrease in expression of the PD-L1 protein is quantitated in FIG.4B.
  • the control expression levels of PD-L1 are set to 1.0.
  • the exposure to IPAG reduced PD-L1 expression to approximately 0.5.
  • the exposure to IPAG plus SA4503 increased PD-L1 expression to approximately 1.35, indicating that a Sigma1 agonist (SA4503) can reverse PD-L1 inhibition by a Sigma1 inhibitor (IPAG).
  • SA4503 a Sigma1 agonist
  • IPG Sigma1 inhibitor
  • Example 5 Reduction in tumor growth in PD-L1-dependent breast caner cells by administration of Sigma1 modulator.
  • Sigma1 protein was inhibited by the Sigma1 inhibitor, Compound G, and then tumor growth inhibition was measured to determine if Sigma1 inhibition delayed tumor growth in a PD-L1 positive triple negative breast cancer cell line (MDA231).
  • MDA-MB-231 human breast carcinoma cell lines were obtained from the American Type Culture Collection (Manassas, VA) and maintained according to the supplier’s instructions. Cells were harvested at the exponential phase of growth for injection into the mammary fat pads of mice. NOD scid (NOD/SCID) and BalBC mice were purchased from Jackson Laboratory. Eight week old female mice were injected unilaterally with 2.5 ⁇ 10 6 cells in 200 ⁇ L of 50:50
  • DMSO DMSO
  • Compound G drug
  • Compound G inhibited tumor growth in BalbC and not NOD/SCID mice, indicating that Sigma1 inhibition requires mice to have an intact immune system (BalbC) to stimulate an anti-tumor response through PD-L1 downregulation.
  • FIG.5 tumor growth inhibition in immune-competent mice (BalbC) are shown on the left while tumor growth inhibition in immune-deficient mice (NOD/SCID) are shown on the left.
  • Mice were treated with either control (DMSO) or 30 mg/kg of Compound G.
  • Compound G greatly reduced tumor growth in immune-competent mice, indicating that Sigma1 inhibition of PD-L1 results in potent anti-tumor immune activity.
  • a pharmaceutical composition described in Example 2 and the PD-L1 inhibitor atezolizumab (MPDL3280A) are administered to human non-small cell lung cancer (NSCLC) patients orally in combination with chemotherapy.
  • NSCLC non-small cell lung cancer
  • Patients are monitored for tumor regression as well as levels of IL-6 and PD-L1 expression in whole blood and tumor biopsies.
  • Patients are given the treatment combination for standard treatment cycles 4-6 cycles. After 6 months from start of the treatment, the tumors in patients receiving the combination treatment are measured and/or evaluated.
  • the combination therapy shrinks tumors in the majority of patients. Levels of IL-6 and/or PD-L1 are decreased after administration of the combination.
  • Example 7 Combination of Compound used in Example 2 and anti-PD-1 antibodies shrink tumor size in lung cancer patients and increase survival in lung cancer patients
  • Patients are administered a combination, either simultaneously or sequentially, of the compound used in Example 2 and an anti-PD-1 antibody to a human with non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the patients are previously treated with chemotherapy, or not previously treated with chemotherapy.
  • Patients are monitored for tumor regression and survival. Tumor size and median survival are evaluated in the patients. Tumors are found to have been reduced in size as compared to a regimen without the compound of Example 2.
  • the median survival increases as compared to a regimen without the compound of Example 2. as compared to a regimen without the compound of Example 2, this result is replicated regardless of the anti-PD-1 antibody that is used.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Certains modes de réalisation de l'invention concernent des méthodes de traitement de maladies ou troubles divers au moyen de composés de modulation de Sigma1 seuls ou en combinaison avec d'autres agents thérapeutiques.
PCT/US2016/066610 2015-12-18 2016-12-14 Méthodes de modulation de niveaux d'il-6 et de pd-l1 WO2017106312A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562269269P 2015-12-18 2015-12-18
US62/269,269 2015-12-18

Publications (1)

Publication Number Publication Date
WO2017106312A1 true WO2017106312A1 (fr) 2017-06-22

Family

ID=59057808

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/066610 WO2017106312A1 (fr) 2015-12-18 2016-12-14 Méthodes de modulation de niveaux d'il-6 et de pd-l1

Country Status (1)

Country Link
WO (1) WO2017106312A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023196838A1 (fr) * 2022-04-06 2023-10-12 Sanofi Biotechnology Compositions et méthodes de traitement de la polymyalgie rhumatismale par administration d'un antagoniste de l'il-6r
EP4125373A4 (fr) * 2020-03-30 2024-04-17 Thomas Jefferson University Composés, compositions et méthodes pour le traitement, l'amélioration ou la prévention des infections virales

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074809A1 (fr) * 2007-12-13 2009-06-18 University Of Dundee Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical
US20150166472A1 (en) * 2012-07-19 2015-06-18 Drexel University Novel sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US20150290207A1 (en) * 2014-03-19 2015-10-15 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074809A1 (fr) * 2007-12-13 2009-06-18 University Of Dundee Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical
US20150166472A1 (en) * 2012-07-19 2015-06-18 Drexel University Novel sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US20150290207A1 (en) * 2014-03-19 2015-10-15 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
T ANAKA, T ET AL.: "Anti-interleukin-6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases", FEDERATION OF EUROPEAN BIOCHEMICAL SOCIETIES LETTERS, vol. 585, 2011, pages 3699 - 3709, XP028118458 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4125373A4 (fr) * 2020-03-30 2024-04-17 Thomas Jefferson University Composés, compositions et méthodes pour le traitement, l'amélioration ou la prévention des infections virales
EP4126011A4 (fr) * 2020-03-30 2024-07-24 Univ Jefferson Méthodes de traitement, d'amélioration ou de prévention d'infections virales
WO2023196838A1 (fr) * 2022-04-06 2023-10-12 Sanofi Biotechnology Compositions et méthodes de traitement de la polymyalgie rhumatismale par administration d'un antagoniste de l'il-6r

Similar Documents

Publication Publication Date Title
JP7206314B2 (ja) Jak及びpi3k阻害剤併用によるb細胞悪性腫瘍の処置
US20200325130A1 (en) Proteolysis Targeting Chimera Compounds and Methods of Preparing and Using Same
ES2732026T3 (es) Sal de adición de ácido de un compuesto inhibidor de Trk
US20230242505A1 (en) Process, compositions, and crystalline forms of substituted pyridinone-pyridinyl compounds
US11926635B2 (en) P38α mitogen-activated protein kinase inhibitors
US10316038B2 (en) Pyrrolopyrimidine ITK inhibitors for treating inflammation and cancer
US20180215705A1 (en) hTRPV1 CHEMICAL AGENTS
WO2017106312A1 (fr) Méthodes de modulation de niveaux d'il-6 et de pd-l1
EP3885347A1 (fr) Dérivé de dihydropyrrolopyrazole
WO2018186366A1 (fr) Nouvel inhibiteur de kinase dépendante de la cycline 8 et/ou 19
IL296700A (en) Process, preparations and crystalline forms of substituted pyridinone-pyridinyl compounds
EP4168003A2 (fr) Composés pour la dégradation ciblée de la kinase de lymphocytes t inductible par l'interleukine-2 et méthodes d'utilisation
CN115996911A (zh) 具有p2x4受体拮抗活性的取代的n-苯乙酰胺
NZ743251A (en) Salt forms and polymorphs of (r)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl) acetamido) pyridazin-3-yl)-2-fluorobutyl)-n-methyl-1h-1,2,3-triazole-4-carboxamide
EA042264B1 (ru) Лечение b-клеточных злокачественных новообразований с применением комбинации ингибиторов jak и pi3k

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16876561

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16876561

Country of ref document: EP

Kind code of ref document: A1