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WO2011045341A1 - Inhibiteurs d'ido et leurs utilisations thérapeutiques - Google Patents

Inhibiteurs d'ido et leurs utilisations thérapeutiques Download PDF

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Publication number
WO2011045341A1
WO2011045341A1 PCT/EP2010/065337 EP2010065337W WO2011045341A1 WO 2011045341 A1 WO2011045341 A1 WO 2011045341A1 EP 2010065337 W EP2010065337 W EP 2010065337W WO 2011045341 A1 WO2011045341 A1 WO 2011045341A1
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WO
WIPO (PCT)
Prior art keywords
cancer
ido
formula
represent
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/065337
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English (en)
Inventor
Ute Roehrig
Awad Loay
Olivier Michielin
Benoit Van Den Eynde
Luc Pilotte
Vincent Stroobant
Pierre Larrieu
Pierre Vogel
Vincent Zoete
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Ludwig Institute for Cancer Research Ltd
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Ludwig Institute for Cancer Research Ltd
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Filing date
Publication date
Application filed by Ludwig Institute for Cancer Research Ltd filed Critical Ludwig Institute for Cancer Research Ltd
Publication of WO2011045341A1 publication Critical patent/WO2011045341A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/20—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups being part of rings other than six-membered aromatic rings
    • C07C251/22—Quinone imines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to inhibitors of indoleamine 2,3-dioxygenase (IDO) and their use in the treatment of cancer or infections, either alone or in combination with additional therapeutic agents.
  • IDO indoleamine 2,3-dioxygenase
  • IDO indoleamine 2,3-dioxygenase
  • R 1 , R 2 and R 3 which may be the same or different, represent alkyl C 1-6 , - cycloalkyl C3 - 7, aryl or NHR 4 , wherein R 4 may represent any of the values that any of R 1 , R 2 or R 3 may represent;
  • R 3 may represent hydrogen
  • Aryl groups that R 4 may represent include benzene and 5- and 6-membered aromatic heterocycles, such as pyrrole, pyrazole and pyridine.
  • the aryl group may be substituted, eg by one, two or three substituents, eg as defined for R 1 , R 2 or R 3 above
  • the compound of formula I can be obtained by oxidation of an appropriately substituted l-amino-4 hydroxy-naphthalene derivative, eg using silver oxide in an inert solvent, such as chloroform.
  • Substituted aminonaphthalenes may be prepared from the corresponding unsubstituted aminonaphthalene by reductive amination, using the appropriate aledehyde or ketone and a hydride reducing agent, such as NaBH(OAc)3 in a polar aprotic solvent such as dichloroethane, as indicated in the following scheme:
  • Salts of compounds of formula I may be formed by reacting the free acid, or a salt thereof, with one or more equivalents of the appropriate base.
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a sumble in which the salt is soluble, e.g. ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying.
  • the reaction may also be a metathetical process or it may be carried out on an ton exchange resin.
  • Pharmaceutically acceptable salts of the compounds of formula I thereof include salts with strong acids, e.g., HCl, HBr, etc, and salts with weak acids, eg organic acids, for example carboxylic acids, such as acetic acid, benzoic acids, as well as sulphonic acids.
  • strong acids e.g., HCl, HBr, etc
  • salts with weak acids eg organic acids, for example carboxylic acids, such as acetic acid, benzoic acids, as well as sulphonic acids.
  • Non-toxic physiologically acceptable salts are preferred, although other salts are also useful, e.g. in isolating or purifying the product.
  • the compounds of formula I may be used alone or in combination with at least one additional therapeutic agent.
  • the at least one additional therapeutic agent may be an antineoplastic chemotherapy agent. Suitable antineoplastic chemotherapeutic agent is selected from the group consisting of cyclophosphamide, methotrexate, iluorouracil, doxorubicin, vincristine, ifosfamide, cisplatin, gemcytabine, busulfan, ara-C, and combinations thereof.
  • the at least one additional therapeutic agent may be radiation therapy.
  • the radiation therapy may be localized radiation therapy delivered to the tumour or may be total body irradiation.
  • the compounds of the invention may be used as an adjuvant to the therapeutic vaccination of various cancers.
  • Cancers that may be mentioned include melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumours, lymphoma, sarcoma, ovarian cancer, and Kaposi's sarcoma.
  • cancers and tumours include adrcnocorticocancer, basal cell carcinoma, bladder cancer, bowel cancer, brain and CNS tumors, breast cancers, B- cell lymphoma, carcinoid tumours, cervical cancer, childhood cancers, chondrosarcoma, choriocarcinoma, chronic myeloid leukemia, rectal cancers, endocrine cancers, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, gastric cancer or carcinoma, gastrointestinal cancers, genitourinary cancers, glioma, gynecological cancers, head and neck cance s, hepatocellular cancer, Hodgkins disease, hypopharynx cancer, isJet cell cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer (including small-cell lung carcinoma and non-small-cell carcinoma), lymphoma, male breast cancer, melanoma, mesothelioma
  • IDO In addition to cancers, IDO plays a role in several diseases, including Clamydia psiltaci infection and Streptococcus pyogenes infection, systemic lupus erythematosus, rheumatoid arthritis, Alzheimer's disease, Huntington's disease, Parkinson's disease, lyme neuroborreliosis, late lyme encephalopathy, T urette's syndrome, systemic sclerosis, multiple sclerosis, coronary heart disease, T-cell mediated immune diseases, chronic infections (viral, bacterial, fungal and microbial), depression, neurological disorders, cancer tumors, and cataracts. Inhibitors of IDO may be used to treat these diseases.
  • IDO inhibitors may be used to treat include, but are not limited to, human immunodeficiency virus (HIV) and AIDS-related cancers.
  • HIV human immunodeficiency virus
  • HIV-related cancers include, but are not limited to, human immunodeficiency virus (HIV) and AIDS-related cancers.
  • the compounds may also be used as adjuvants to bone marrow transplantation or peripheral blood stem cell transplantation and in immunotherapy by adoptive transfer.
  • the infection may be selected from the group consisting of a viral infection, infection with an intracellular parasite, and infection with an intracellular bacteria.
  • Particular viral infections include human immunodeficiency virus or cytomegalovirus.
  • Particular intracellular parasite infections may be selected from the group consisting of Leishmania donovani, Leishmania tropica, Leishmania major. Leishmania aethiopica, Leishmania mexicana, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.
  • the at least one additional therapeutic agent may be a vaccine, for example, an anti-viral vaccine, a vaccine against HIV, a vaccine against tuberculosis, a vaccine against malaria
  • the vaccine may also be a tumour vaccine or a melanoma vaccine.
  • the tumour vaccine comprises genetically modified tumour cells or genetically modified cell lines. In such cases, preferably the genetically modified tumour cells or genetically modified cell line has been transfected to express granulocyte-macrophage stimulating factor (GM-CSF).
  • GM-CSF granulocyte-macrophage stimulating factor
  • the vaccine may comprise one or more immunogenic peptides, preferably immunogenic peptides of cancer-testis antigens (CTAgs).
  • CTAgs cancer-testis antigens
  • CTAg proteins include MAGE, BAGE, GAGE, SSX, NY-ESO-1, LAGE, SCP, CTSP, CT7, CT8, CT9, CT10 > CTI I, SAGE, OY-TES-1, NY-SAR-35 and NY-BR-1.
  • MAGE proteins include MAGE-A1, A3, A4, A5, A6, A8, A9, A10, A12, Bl, B2, B3, B4, CI, C2 and C3 proteins.
  • SSX proteins exist, including SSX1, SSX2, SSX3 and SSX5.
  • tumour vaccine may comprise dendritic cells.
  • additional therapeutic agent may be a cytokine, for example a granulocyte- macrophage colony stimulating factor (GM-CSF) or flt3-ligand.
  • GM-CSF granulocyte- macrophage colony stimulating factor
  • flt3-ligand flt3-ligand
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered in an amount effective to increase the delayed type hypersensitivity reaction to tumour antigen, delay the time to relapse of post-transplant malignancy, increase relapse free survival time post-transplant, and/or increase long-term post- transplant survival.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered prior to full hematopoetic reconstitution.
  • the compounds of formula I or a pharmaceutically acceptable salt thereof for use in the method will generally be administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition including preferably less than 80% w/w, more preferably less than 50% w/w, e.g. 0.1 to 20%, of the compound of formula 1 or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier,
  • the compounds of formula I or a pharmaceutically acceptable salt thereof is to be used in aqueous solution, e.g. for infusion, it may be necessary to incorporate other excipients, In particular there may be mentioned chelating or sequestering agents, antioxidants, tonicity adjusting agents, pH-modifying agents and buffering agents.
  • Solutions containing the compound of formula I or a pharmaceutically acceptable salt thereof may, if desired, be evaporated, e.g. by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use.
  • the compound of formula I or a pharmaceutically acceptable salt thereof preferably is in a form having a mass median diameter of from 0.01 to ⁇ .
  • the compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, e.g. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol, sweetening and colouring agents and flavourings. Where appropriate, the compositions may be formulated in sustained release form.
  • the content of the compound of formula I or a pharmaceutically acceptable salt thereof in a pharmaceutical composition is generally about 0,01 -about 99.9wt%, preferably about 0.1-about 50wt%, relative to the entire preparation,
  • the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is determined in consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment then, and other factors. While the dose varies depending on the target disease, condition, subject of administration, administration method and the like, for oral administration as a therapeutic agent for the treatment of cancer in a patient suffering from such a disease is from 0.01 mg - 10 g, preferably 0.1 - 100 mg, is preferably administered in a single dose or in 2 or 3 portions per day.
  • the compound of formula I or a pharmaceutically acceptable salt thereof may be used at their normal therapeutic doses, e.g., as set out in pharmacopoeias or prescribing guides, such as the Physicians' Desk Reference (PDR).
  • PDR Physicians' Desk Reference
  • the compound of formula I or a pharmaceutically acceptable salt thereof supplements the activity of the additional therapeutic agent(s) in a synergistic fashion, such that the additional therapeutic agent(s) can be administered at a lower dose than is normally used.
  • Reagents were purchased from Acros, Fluka, Senn, Sigma-Aldrich or Merck and used without further purification. For extraction and chromatography all solvents were distilled prior to use. Anhydrous THF, diethyl ether, and toluene were distilled from sodium and benzophenone, dichloromethane from CaH 2 , and methanol from magnesium, Reactions were monitored by thin layer chromatography (TLC) using silica gel plates (Merck 60 F254).
  • TLC thin layer chromatography
  • UV spectra were recorded on a Kontron Uvikon 810 CW spectrophotometer, IR spectra were recorded on a Perkin Elmer Paragon 1000 FT-IR spectrometer. Mass spectra were recorded on a Nermag R 10- IOC in chemical ionisation mode. Electrospray mass analyses were recorded on a Finnigan MAT SSQ 710C spectrometer in positive ionisation mode. 'H-NMR spectra were recorded on a Broker DPX-400 FT, Broker ARX-400 FT, or Broker AMX-600 spectrometer. All 1 H signal assignments were confirmed by COSY spectra.
  • 13 C-NMR spectra were recorded on a Broker DPX-400 FT (100.61 MHz) or on a Broker ARX-400 FT (100.61 MHz) spectrometer. All 13 C signal assignments were confirmed by HMQC spectra. Chemical shifts are given in ppm, relative to an internal standard such as residual solvent signals. Coupling constants are given in Hertz. High resolution mass spectra were recorded by ESI-TOF-HRMS or MALDI-TOF-HRMS.
  • the coding region for human IDO was cloned into a derivative of plasmid pET9 (Novagen).
  • the recombinant plasmid, pETlDO encodes a histidine tag at the N-terminus of IDO.
  • the bacterial strain BL21 AI (Invitrogen) was used for overexpression of IDO and transformed with the plasmid pETIDO.
  • the transformed cells were grown on a rotary shaker at 37 C and 220 rpm to an OD600 of 1.2, in LB medium supplemented with kanamycin 25 ⁇ g ml, L-tryptophan 50 ⁇ g/ml and bovine hemin (Sigma) 10 ⁇ .
  • the culture was cooled in a water/ice bath and supplemented again with L-tryptophan 50 ⁇ g/ml, bovine hemin 10 ⁇ .
  • the expression of his-tagged IDO was induced by the addition of 1% (w/v) arabinose. Induced cells were grown at 20 C, 60 rpm for 20 h. Cells (3 J culture) were collected by centrifugation, resuspended in 40 ml of Mes 25 mM, KCl 150 raM, imidazole 10 mM, protease inhibitors (complete EDTA free, Roche Applied Science), pH 6.5, and disrupted with a French press. The extract was clarified by centrifugation and filtration on a 0.22 ⁇ m filter.
  • the enzyme was purified by IMAC using Ni 2+ as ligand and an IMAC HITRAP column (5 ml; GE Healthcare). Briefly, the extract was loaded on the column with buffer Mes 25 mM, KCI 150 mM, imidazole 10 mM, pH 6.5. The column was washed with 50 ml of the same buffer with imidazole adjusted to 100 mM. Finally, the protein was eluted with Mes 25 mM, KCI 150 mM, EDTA 50 mM, pH 6.5. The buffer was then exchanged to Mes 25 mM, KCI 150 mM, pH 6.5 using a HITRAP desalting column (GE Healthcare). The purity of the enzyme was estimated to be > 95% based on SDS PAGE gel and Coomassie blue staining. The ratio of absorbance 404 nm/280 nm of the protein was around 1.9. Enzymatic Assay
  • the enzymatic inhibition assays were performed as described by Takikawa et al. [Takikawa, O.; Kuroiwa, T.; Yamazaki, F.; Kido, R. J Biol Chem, 1988, 263, 2041- 2048.] with some modifications. Briefly, the reaction mixture (100 ⁇ l) contained potassium phosphate buffer (100 mM, pH 6.5) ascorbic acid (20 mM), catalase (200 units/ml), methylene blue (10 ⁇ ), purified recombinant IDO (2 ng/ ⁇ l), and L- Trp (200 ⁇ ). The inhibitors were serially diluted ranging from 0.1 to 1000 ⁇ .
  • a plasmid construct encoding murine IDO was transfected into mouse mastocytoma line P815B.
  • a plasmid construct encoding human IDO was transfected into human HEK-293 cells, and clone 293-hIDO clone 17 [Uyttenhove et al] was selected and used in the assay.
  • the assay was performed in 96-well flat bottom plates seeded with 2 x 10 5 cells in a final volume of 200 ⁇ l. To determine whether compounds were significant IDO inhibitors, the cells were incubated overnight at 37 °C in HBSS (Hanks Balanced Salt Solution, Invitrogen) supplemented with 50 ⁇ L-Trp and 2, 20 or 200 ⁇ of the compound.
  • HBSS Horbal Balanced Salt Solution, Invitrogen
  • the cells were incubated for 8 h at 37 °C in HBSS supplemented with 80 ⁇ L-Tryptophan and a titration of the compound ranging from 0.312 to 80 ⁇ or from 1.56 to 400 ⁇ , The plates were then centrifuged for 10 min at 300 g, and 150 ⁇ l of the supernatant were collected. The supernatant was analyzed by HPLC to measure the concentration of tryptophan and kynurenine. For HPLC analysis, 50 ⁇ l of supernatant were mixed with 500 ⁇ l acetonitrile to precipitate the proteins.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des composés de formule (I) (dans laquelle R1, R2 et R3, qui peuvent être identiques ou différents, représentent alkyle en C1-6, cycloalkyle en C3-7, aryle ou NHR4, R4 pouvant représenter l'une quelconque des valeurs que l'un quelconque de R1, R2 ou R3 peut représenter ; de plus, R3 pouvant représenter hydrogène ; l'invention porte également sur des sels pharmaceutiquement acceptables de ces composés, sur leur utilisation thérapeutique, par exemple dans le traitement du cancer.
PCT/EP2010/065337 2009-10-13 2010-10-13 Inhibiteurs d'ido et leurs utilisations thérapeutiques Ceased WO2011045341A1 (fr)

Applications Claiming Priority (2)

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GBGB0917927.6A GB0917927D0 (en) 2009-10-13 2009-10-13 Ido inhibitors and therapeutic uses thereof
GB0917927.6 2009-10-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017140835A1 (fr) 2016-02-19 2017-08-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques destinées au traitement de l'obésité
WO2018071873A2 (fr) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Méthodes et compositions d'immunothérapie impliquant des modulateurs de la voie métabolique du tryptophane
CN109956942A (zh) * 2017-12-25 2019-07-02 上海翔锦生物科技有限公司 色胺酮类衍生物及其用途

Citations (6)

* Cited by examiner, † Cited by third party
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US2769821A (en) * 1953-05-21 1956-11-06 American Cyanamid Co 1,4-naphthoquinoneimine compounds and methods of preparing the same
US2769820A (en) * 1953-05-21 1956-11-06 American Cyanamid Co Certain new 1,4-naphthoquinoneimines and methods of preparing the same
JPS6339862A (ja) * 1986-08-04 1988-02-20 Otsuka Pharmaceut Factory Inc ピリジルアミノフエノ−ル誘導体
WO2008052352A1 (fr) * 2006-11-03 2008-05-08 The University Of British Columbia Inhibiteurs quinone substitués d'indoléamine 2,3-dioxygénase (ido), leurs synthèses et leurs utilisations
WO2008115804A1 (fr) * 2007-03-16 2008-09-25 Lankenau Institute For Medical Research Nouveaux inhibiteurs ido et leurs procédés d'utilisation
WO2009127669A2 (fr) * 2008-04-15 2009-10-22 Ludwig Institute For Cancer Research Ltd Inhibiteurs de l'ido et ses utilisations thérapeutiques

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US2769820A (en) * 1953-05-21 1956-11-06 American Cyanamid Co Certain new 1,4-naphthoquinoneimines and methods of preparing the same
JPS6339862A (ja) * 1986-08-04 1988-02-20 Otsuka Pharmaceut Factory Inc ピリジルアミノフエノ−ル誘導体
WO2008052352A1 (fr) * 2006-11-03 2008-05-08 The University Of British Columbia Inhibiteurs quinone substitués d'indoléamine 2,3-dioxygénase (ido), leurs synthèses et leurs utilisations
WO2008115804A1 (fr) * 2007-03-16 2008-09-25 Lankenau Institute For Medical Research Nouveaux inhibiteurs ido et leurs procédés d'utilisation
WO2009127669A2 (fr) * 2008-04-15 2009-10-22 Ludwig Institute For Cancer Research Ltd Inhibiteurs de l'ido et ses utilisations thérapeutiques

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CARRENO M C ET AL: "Product Class 9: Benzo-1,2-, Benzo-1,4-, Naphtho-1,2-, and Napththo-1,4-quinone Imines and Diimines", 1 January 2006, SCIENCE OF SYNTHESIS : HOUBEN-WEYL METHODS OF MOLECULAR TRANSFORMATIONS, STUTTGART [U.A.] : THIEME, DE, PAGE(S) 629 - 734, ISBN: 978-1-58890-460-7, XP008132731 *
F.J. BULLOCK: "Antiprotozoal Quinones. IV. 2-Amino-1,4-naphthoquinone Imines as Potential Antimalarials", JOURNAL OF MEDICINAL CHEMISTRY., vol. 13, no. 3, 1970, USAMERICAN CHEMICAL SOCIETY. WASHINGTON., pages 550 - 552, XP002622028, ISSN: 0022-2623 *
ROBERT LANTZ: "Réaction de l'ammoniaque et des amines sur un derivé de l'hydroxy-2 naphtoquinone-1,4: l'hydroxy-2 N4-phényl naphtoquinone-1,4 imine-4 (anilino beta-naphtoquinone)", BULLETIN DE LA SOCIETÉ CHIMIQUE DE FRANCE, vol. 3, 1972, pages 1052 - 1054, XP002622030 *
SCANLAN ET AL., CANCER IMMUN., vol. 4, 2004, pages 1
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017140835A1 (fr) 2016-02-19 2017-08-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques destinées au traitement de l'obésité
WO2018071873A2 (fr) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Méthodes et compositions d'immunothérapie impliquant des modulateurs de la voie métabolique du tryptophane
EP4190335A1 (fr) 2016-10-13 2023-06-07 Juno Therapeutics, Inc. Procédés et compositions d'immunothérapie impliquant des modulateurs de la voie métabolique du tryptophane
US11896615B2 (en) 2016-10-13 2024-02-13 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
CN109956942A (zh) * 2017-12-25 2019-07-02 上海翔锦生物科技有限公司 色胺酮类衍生物及其用途

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