WO2007050963A1 - Nouveaux inhibiteurs de l'ido et leurs procedes d'utilisation - Google Patents

Nouveaux inhibiteurs de l'ido et leurs procedes d'utilisation Download PDF

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WO2007050963A1
WO2007050963A1 PCT/US2006/042137 US2006042137W WO2007050963A1 WO 2007050963 A1 WO2007050963 A1 WO 2007050963A1 US 2006042137 W US2006042137 W US 2006042137W WO 2007050963 A1 WO2007050963 A1 WO 2007050963A1
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methyl
dithiocarbamate
indol
ethyl
brassinin
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PCT/US2006/042137
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English (en)
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James B. Duhadaway
George C. Prendergast
William P. Malachowski
Alexander J. Muller
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Lankenau Institute For Medical Research
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Priority to EP06844228A priority Critical patent/EP1940787A4/fr
Publication of WO2007050963A1 publication Critical patent/WO2007050963A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/20—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/22—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • This invention relates to the field of oncology. Specifically, the invention provides novel chemotherapeutic agents and methods of using such agents for the treatment of cancer.
  • Tumors characteristically express atypical, potentially immunoreactive antigens that are collectively referred to as tumor antigens .
  • tumor antigens atypical, potentially immunoreactive antigens that are collectively referred to as tumor antigens .
  • Immunosuppression by tumors is poorly understood and mechanisms by which tumors may escape immune surveillance have been poorly explored.
  • cytotoxic T cells become tolerized by a reduction in local concentrations of tryptophan that are elicited by indoleamine 2 , 3-dioxygenase (IDO; EC 1.13.11.42) activity.
  • IDO has been implicated in tumor immunosuppression (Muller et al.(2005) Nat. Med., 11:312-9; Munn et al . (2004) Trends MoI. Med., 10:15-18; Uyttenhove et al . (2003) Nat. Med., 9:1269-74; Friberg et al . (2002) Intl. J. Cancer, 101:151-155) .
  • IDO is an extrahepatic oxidoreductase that catalyzes the initial and rate-limiting step in the degradation of tryptophan along the kynurenine pathway that leads to the biosynthesis of nicotinamide adenine dinucleotide (NAD + ) (Sono et al . (1996) Chem. Rev., 96:2841-87; Botting et al . (1995) Chem. Soc. Rev., 24:401-12; Sono et al . (1980) Biochem. Rev., 50:173-81).
  • NAD + nicotinamide adenine dinucleotide
  • IDO is a monomeric 45 kDa heme- containing oxidase that is active with the heme iron in the ferrous (Fe +2 ) form.
  • the ferric (Fe +3 ) form of IDO is inactive and substrate inhibition is believed to result from tryptophan (Trp) binding to ferric IDO (Sono et al . (1980) J. Biol. Chem., 255:1339-45; Kobayashi et al . (1989) J. Biol. Chem. , 264:15280-3).
  • the primary catalytic cycle of IDO does not involve redox changes, nevertheless IDO is prone to autooxidation and therefore a reductant is necessary to reactivate the enzyme.
  • Jn vivo IDO purportedly relies on a flavin or tetrahydrobiopterin co-factor. Jn vitro, methylene blue and ascorbic acid are believed to, substitute for the natural flavin or tetrahydrobiopterin co-factor.
  • IDO Inhibition of IDO has previously been targeted for other therapies, most notably neurological disorders (Botting et al . (1995) Chem. Soc. Rev., 24:401-12). Several metabolites of the kynurenine pathway are neurotoxic or are implicated in neurodegeneration, e.g. quinolinic acid, and therefore attention has focused on IDO. A recent review summarizes the range of compounds that have been tested as IDO inhibitors (Muller et al . (2005) Expert. Opin. Ther. Targets., 9:831-49).
  • novel inhibitors of indoleamine 2 , 3-dioxygenase (IDO) activity are provided.
  • the novel compounds have the formula :
  • R 1 is cycloalkyl, aryl, or wherein R 3 is -NH-, -0-, or -S-;
  • R 2 is alkenyl or -CH 2 -R 4 , wherein R 4 is hydrogen or aryl; and n is from 0 to about 3; with the proviso that the compound is not brassinin, N- [ (Naphth-2-yl) methyl ] -S-methyl-dithiocarbamate, or N- Benzyl-S-methyl-dithiocarbamate .
  • R 4 is selected from the group consisting of phenyl, naphthyl, and pyridyl .
  • R 1 is an aryl selected from the group consisting of indolyl, phenyl , naphthyl , indanyl , and adamantyl .
  • novel IDO inhibitors are provided as novel IDO inhibitor.
  • novel IDO inhibitors are selected from the group consisting of compounds 3-5, 12, 13, and 15-18.
  • methods for treating cancer in a patient.
  • the methods comprise administering an effective amount of a pharmaceutical composition comprising at least one IDO inhibitor in a pharmaceutically acceptable carrier medium, wherein at least one of the IDO inhibitors is selected from the group consisting of compounds 2-18, 20, 22-24, and 32 and compounds having the formula:
  • the method further comprises administering to the patient, concurrently or sequentially, an effective amount of at least one signal transduction inhibitor (STI) which may be administered in a pharmaceutically acceptable carrier.
  • the method further comprises administering to the patient, concurrently or sequentially, an effective amount of at least one chemotherapeutic agent which may be in a pharmaceutically acceptable carrier.
  • STI signal transduction inhibitor
  • methods for treating a chronic viral infection in a patient in need thereof by administering to the patient, concurrently or sequentially, an effective amount of at least one indoleamine 2,3- dioxygenase (IDO) inhibitor and at least one chemotherapeutic agent.
  • IDO indoleamine 2,3- dioxygenase
  • compositions comprising the above-described compounds are provided for administration in carrying out the above methods .
  • Figure IA shows the chemical structure of 3-butyl- ⁇ - carboline.
  • Figure IB shows the chemical structure of 1- methyl-tryptophan.
  • Figure 1C shows the chemical structure of brassinin 1 and identifies the four components of brassinin.
  • Figure 2 provides schemes for the synthesis of certain dithiocarbamates .
  • Figure 3 provides a scheme for the synthesis of 2- aminomethy1-naptha1ene .
  • Figure 4 provides a scheme for the synthesis of thioureas .
  • Figure 5 provides a scheme for the synthesis of brassitin.
  • Figure 6 provides a scheme for the synthesis of thioamide.
  • Figure 7 provides a scheme for the synthesis of thiazole .
  • Brassinin is a phytoalexin in the cruciferous plants and has demonstrated some anti-fungal and anti-cancer activity (Pedras et al . (2000) Phytochemistry, 53:161-76; Pedras et al . (2005) J. Org. Chem., 70:1828-34; Pedras et al . (1998) Phytochemistry, 49:1959-65; Mehta et al . (1995) Carcinogenesis, 16:399- 404) .
  • IDO inhibitor refers to an agent capable of inhibiting the activity of indoleamine 2 , 3-dioxygenase (IDO) and thereby reversing IDO-mediated immunosuppression.
  • IDO inhibitor may be a competitive, noncompetitive, or irreversible IDO inhibitor.
  • a competitive IDO inhibitor is a compound that reversibly inhibits IDO enzyme activity at the catalytic site (for example, without limitation, 1- methyl-tryptophan) ;
  • a noncompetitive IDO Inhibitor is a compound that reversibly inhibits IDO enzyme activity at a non-catalytic site (for example, without limitation, norharman) ;
  • an irreversible IDO inhibitor is a compound that irreversibly destroys IDO enzyme activity by forming a covalent bond with the enzyme (for example, without limitation, cyclopropyl/aziridinyl tryptophan derivatives) .
  • IDO inhibitors may include, without limitation, i) previously established (known) IDO inhibitors, including, but not limited to: 1-methyl-DL-tryptophan (IMT; Sigma- Aldrich; St. Louis, MO), ⁇ - (3-benzofuranyl) -DL-alanine (Sigma-Aldrich) , beta- (3-benzo(b) thienyl) -DL-alanine ( Sigma-Aldrich) , 6-nitro-L-tryptophan (Sigma-Aldrich) , indole 3-carbinol (LKT Laboratories; St.
  • IMT 1-methyl-DL-tryptophan
  • Sigma- Aldrich Sigma- Aldrich
  • St. Louis, MO ⁇ - (3-benzofuranyl) -DL-alanine
  • beta- (3-benzo(b) thienyl) -DL-alanine Sigma-Aldrich
  • 6-nitro-L-tryptophan Sigma-Aldrich
  • the IDO inhibitors include the novel IDO inhibitors of the present invention.
  • a “signal transduction inhibitor” is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis.
  • Signal transduction inhibitors include, but are not limited to, (i) bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec) ; (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (Iressa, SSI-774) and antibodies (Imclone: C225 [Goldstein et al . (1995), Clin Cancer Res.
  • ABX-EGF Abgenix: ABX-EGF
  • her-2/neu receptor inhibitors such as, for example, HerceptinTM ( trastuzumab) , and farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al . (1995), Nat Med. 1 (8) -.192-191)
  • FTI farnesyl transferase inhibitors
  • L-744,832 Zahl et al . (1995), Nat Med. 1 (8) -.192-191
  • inhibitors of Akt family kinases or the Akt pathway such as, for example, rapamycin (see, for example, Sekulic et al . (2000) Cancer Res.
  • cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-Ol (see, for example, Sausville (2003) Curr. Med. Chem. Anti-Cane Agents 3:47- 56) ; and (vi) phosphatidyl inositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al. (1994) J. Biol. Chem. 269:5241-5248).
  • the STI is selected from the group consisting of STI 571, SSI-774, C225, ABX-EGF, trastuzumab, L-744,832, rapamycin, LY294002, flavopiridal, and UNC-Ol.
  • the STI is L-744,832.
  • chemotherapeutic agent refers generally to any compound that exhibits anticancer activity.
  • Chemotherapeutic agents include, but are not limited to: alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nitroso ureas such as carmustine, lomustine, and streptozocin; platinum complexes such as cisplatin and carboplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine) ; DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teni
  • the chemotheraputic agent is selected from the group consisting of: paclitaxel (Taxol®) , cisplatin, docetaxol, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-Il, 5-fluorouracil (5-FU) , gemcitabine, estramustine, carmustine, adriamycin (doxorubicin), etoposide, arsenic trioxide, irinotecan, and epothilone derivatives.
  • a "therapeutically effective amount" of a compound or a pharmaceutical composition refers to an amount effective to prevent, inhibit, or treat the symptoms of a particular disorder or disease.
  • terapéuticaally effective amount may refer to an amount sufficient to modulate tumor growth or metastasis in an animal, especially a human, including without limitation decreasing tumor growth or size or preventing formation of tumor growth in an animal lacking any tumor formation prior to administration, i.e., prophylactic administration.
  • “Pharmaceutically acceptable” indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans .
  • a “carrier” refers to, for example, a diluent, adjuvant, excipient, auxilliary agent or vehicle with which an active agent of the present invention is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. "Concurrently" means (1) simultaneously in time, or
  • “Sequentially” refers to the administration of one component of the method followed by administration of the other component. After administration of one component, the next component can be administered substantially immediately after the first component, or the next component can be administered after an effective time period after the first component; the effective time period is the amount of time given for realization of maximum benefit from the administration of the first component .
  • cycloalkyl as employed herein, includes cyclic hydrocarbon groups containing 1 to 3 rings which may be fused of unfused. Cycloalkyl groups may contain a total of 3 to 20 carbons forming the ring(s), preferably
  • Cycloalkyl groups may contain one or more double bonds.
  • alkenyl refers to an unsubstituted or substituted hydrocarbon moiety comprising one or more carbon to carbon double bonds (i.e., the alkenyl group is unsaturated) and containing from 1 to about 12 carbon atoms or from 1 to about 5 carbon atoms, which may be a straight, branched, or cyclic hydrocarbon group. When substituted, alkenyl groups may be substituted at any available point of attachment.
  • substituents may include, but are not limited to, alkyl, halo, haloalkyl, alkoxyl, alkylthio, hydroxyl, methoxy, carboxyl, oxo, epoxy, alkyloxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, alkylurea, and thiol.
  • the alkenyl group comprises alternating double and single bonds such that bonds are conjugated.
  • alkenyl groups include, without limitation, allyl and 1, 3-butadienyl .
  • aryl refers to monocyclic and bicyclic aromatic groups containing 6 to
  • aryl groups include, without limitation, phenyl, naphthyl, such as 1- naphthyl and 2-naphthyl, indolyl, and pyridyl, such as 3- pyridyl and 4-pyridyl.
  • Aryl groups may be optionally substituted through available carbon atoms with 1 to about 4 groups.
  • substituents may include, but are not limited to, alkyl, halo, haloalkyl, alkoxyl, alkylthio, hydroxyl, methoxy, carboxyl, oxo, epoxy, alkyloxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, alkylurea, and thiol.
  • the aromatic groups may be heteroaryl .
  • Heteroaryl refers to an optionally substituted aromatic ring system that includes at least one, and preferably from 1 to about 4 sulfur, oxygen, or nitrogen heteroatom ring members.
  • novel compounds are provided which are capable of inhibiting IDO activity and thereby suppressing tumor growth.
  • the novel IDO inhibitor has the formula:
  • R 1 is cycloalkyl, aryl, or wherein R 3 is -NH-, -0-, or -S-;
  • R 2 is alkenyl or -CH 2 -R 4 , wherein R 4 is hydrogen or aryl; and n is from 0 to about 3; with the proviso that the compound is not brassinin, N- [ (Naphth-2-yl) methyl] -S-methyl-dithiocarbamate, or N- Benzyl-S-methyl-dithiocarbamate .
  • R 4 is selected from the group consisting of phenyl, naphthyl, and pyridyl. In another embodiment, R 4 is naphthyl.
  • n is 3.
  • R 1 is selected from the group consisting of indolyl, phenyl, naphthyl, indanyl and adamantyl .
  • R 1 is indolyl.
  • the novel IDO inhibitors are selected from the group consisting of compounds 2-6, 9-18, 20, and 22-24, described hereinbelow.
  • the novel IDO inhibitors are selected from the group consisting of compounds 3-5, 12, 13, and 15-18.
  • R 2 is:
  • the novel IDO inhibitor is:
  • the present invention provides pharmaceutical compositions comprising at least one of the IDO inhibitors of the instant invention in a pharmaceutically acceptable carrier. Such a pharmaceutical composition may be administered, in a therapeutically effective amount, to a patient in need thereof for the treatment of cancer.
  • the pharmaceutical compositions may comprise at least one IDO inhibitor of the instant invention in addition to at least one established (known) IDO inhibitor.
  • at least one of the IDO inhibitors of the pharmaceutical composition is selected from the group consisting of compounds of formula (I) and compounds 2-6, 9-18, 20, and 22-24.
  • the present invention provides a method for the treatment of cancer by administering to a patient, in need thereof, a therapeutically effective amount of the compounds of the instant invention, preferably in the form of a pharmaceutical composition.
  • a therapeutically effective amount of the compounds of the instant invention preferably in the form of a pharmaceutical composition.
  • at least one the IDO inhibitors administered in the method of treating cancer is selected from the group consisting of compounds of formula (I) and compounds 2-18, 20, and 22-24.
  • the pharmaceutical composition may further comprise at least one signal transduction inhibitor (STI) (see, e.g., PCT/US04/05155 and PCT/US04/05154) .
  • STI signal transduction inhibitor
  • Suitable STIs include, but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec) ; (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (Iressa, SSI-774) and antibodies (Imclone: C225 [Goldstein et al . (1995), Clin Cancer Res.
  • Her-2/neu receptor inhibitors such as, for example, HerceptinTM ( trastuzumab) and farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al . (1995), Nat Med. 1 (8) -.192-191) ;
  • FTI farnesyl transferase inhibitors
  • Akt family kinases
  • rapamycin see, for example, Sekulic et al . (2000) Cancer Res.
  • the at least one STI and the at least on IDO inhibitor may be in separate pharmaceutical compositions.
  • the at least one IDO inhibitor and at least one STI may be administered to the patient concurrently or sequentially.
  • the at least one IDO inhibitor may be administered first
  • the at least one STI may be administered first
  • the at least one IDO inhibitor and the at least one STI may be administered at the same time.
  • the compounds may be administered in any order.
  • compositions of the invention may further comprise at least one chemotherapeutic agent.
  • chemotherapeutic agents are described hereinabove .
  • Preferred chemotherapeutic agents include, but are not limited to: paclitaxel (Taxol®) , cisplatin, docetaxol, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-Il, 5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, adriamycin (doxorubicin) , etoposide, arsenic trioxide, irinotecan, and epothilone derivatives.
  • the chemotherapeutic agent is paclitaxel.
  • the at least one chemotherapeutic agent and the at least on IDO inhibitor may be in separate pharmaceutical compositions.
  • the at least one IDO inhibitor and at least one chemotherapeutic agent may be administered to the patient concurrently or sequentially.
  • the at least one IDO inhibitor may be administered first, the at least one chemotherapeutic agent may be administered first, or the at least one IDO inhibitor and the at least one chemotherapeutic agent may be administered at the same time.
  • the compounds may be administered in any order .
  • Cancers that may be treated using the present protocol include, but are not limited to: cancers of the prostate, colorectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma) , mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, breast, muscle, connective tissue, lung (including small-cell lung carcinoma and non-small-cell carcinoma) , adrenal gland, thyroid, kidney, or bone; glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma.
  • the present invention further provides a pharmaceutical composition for the treatment of a chronic viral infection in a patient comprising at least one IDO inhibitor, optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent, in a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions may comprise at least one IDO inhibitor of the instant invention in addition to at least one established (known) IDO inhibitor.
  • at least one of the IDO inhibitors of the pharmaceutical composition is selected from the group consisting of compounds of formula (I) and compounds 2- 18, 20, and 22-24.
  • a method for treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.
  • at least one of the IDO inhibitors administered in the method of treating a viral infection is selected from the group consisting of compounds of formula (I) and compounds 2-18, 20, and 22- 24.
  • Suitable antiviral agents include, without limitation: acyclovir; gangcyclovir; foscarnet; ribavirin; and antiretrovirals such as, for example, nucleoside analogue reverse transcriptase inhibitors (e.g., azidothymidine (AZT), ddl, ddC, 3TC, d4T) , non- nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine) , nucleotide analogue reverse transcriptase inhibitors, and protease inhibitors.
  • nucleoside analogue reverse transcriptase inhibitors e.g., azidothymidine (AZT), ddl, ddC, 3TC, d4T
  • non- nucleoside reverse transcriptase inhibitors e.g., efavirenz, nevirapine
  • nucleotide analogue reverse transcriptase inhibitors
  • the at least one IDO inhibitor and at least one chemotherapeutic agent may be administered to the patient concurrently or sequentially.
  • the at least one IDO inhibitor may be administered first
  • the at least one chemotherapeutic agent may be administered first
  • the at least one IDO inhibitor and the at least one STI may be administered at the same time.
  • the compounds may be administered in any order.
  • any antiviral agent or STI may also be administered at any point in comparison to the administration of an IDO inhibitor.
  • the compounds of this combination treatment may also be administered for localized infections.
  • the at least one IDO inhibitor, optionally, at least one chemotherapeutic agent, and, optionally, at least one antiviral agent may be administered to treat skin infections such as shingles and warts.
  • the compounds may be administered in any pharmaceutically acceptable topical carrier including, without limitation: gels, creams, lotions, ointments, powders, aerosols and other conventional forms for applying medication to the skin.
  • Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV) , human papilloma virus (HPV) , cytomegalovirus (CMV) , herpes simplex virus (HSV) , Epstein-Barr virus (EBV) , varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV) .
  • HCV hepatitis C virus
  • HPV human papilloma virus
  • CMV cytomegalovirus
  • HSV herpes simplex virus
  • EBV Epstein-Barr virus
  • varicella zoster virus varicella zoster virus
  • coxsackie virus human immunodeficiency virus
  • the pharmaceutical compositions comprising at least one IDO inhibitor of the instant invention may be administered to a patient to prevent arterial restenosis, such as after balloon endoscopy or stent placement.
  • the pharmaceutical composition further comprises at least one taxane (e.g., paclitaxel (Taxol) ; see e.g., Scheller et al . (2004) Circulation, 110:810- 814) .
  • compositions of the present invention can be administered by any suitable route, for example, by injection, by oral, pulmonary, nasal or other modes of administration.
  • pharmaceutical compositions of the present invention comprise, among other things, pharmaceutically acceptable diluents, preservatives, solubilizers , emulsifiers, adjuvants and/or carriers.
  • compositions can include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate) , pH and ionic strength; and additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite) , preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol) .
  • the compositions can be incorporated into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of components of a pharmaceutical composition of the present invention. See, e.g.,
  • composition of the present invention can be prepared, for example, in liquid form, or can be in dried powder form (e.g., lyophilized) .
  • compositions of the present invention can be delivered in a controlled release system, such as using an intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref . Biomed. Eng. (1987) 14:201; Buchwald et al . , Surgery (1980) 88:507; Saudek et al . , N. Engl. J. Med. (1989) 321:574).
  • polymeric materials may be employed (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press: Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.) , Wiley: New York (1984); Ranger and Peppas, J. Macromol. Sci . Rev. Macromol . Chem. (1983) 23:61; see also Levy et al . , Science (1985) 228:190; During et al . , Ann. Neurol. (1989) 25:351; Howard et al . , J. Neurosurg. (1989) 71:105) .
  • a controlled release system can be placed in proximity of the target tissues of the animal, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, (1984) vol. 2, pp. 115-138) .
  • a controlled release device can be introduced into an animal in proximity to the site of inappropriate immune activation or a tumor.
  • Other controlled release systems are discussed in the review by Langer (Science (1990) 249:1527-1533).
  • a saturated solution of NH 3 in CH 3 OH was made by bubbling anhydrous NH 3 into an Erlenmyer flask with a predetermined volume of CH 3 OH.
  • Concentrated refers to the removal of solvent with a rotary evaporator at normal water aspirator pressure followed by further evacuation with a two-stage mechanical pump unless otherwise indicated. Yields refer to chromatographically and spectroscopically pure (>95%) compounds, except as otherwise indicated. All new compounds were determined to be >95% pure by NMR, HPLC and/or GC. Melting points were determined using an open capillary and are uncorrected. 1 H and 13 C NMR spectra were recorded at 300 and 75 MHz, respectively.
  • Normal phase HPLC NP-HPLC
  • NP-HPLC Normal phase HPLC
  • IPA or gradient
  • Indole-3-methanamine (25) Indole-3-carboxaldehyde (189 mg, 1.3 itimol) and NH 4 OH • HCl (113 mg, 1.63 mmol) were dissolved in a Parr flask with 15 mL of MeOH, which was previously saturated with anhydrous ammonia. The flask was stoppered and placed on a Parr shaker for 5 hours. To the resulting solution was added 200 mg of Raney Nickel (50% slurry in H 2 O) and the flask was pressurized to 60 psi with H 2 and allowed to shake overnight. The next day, the resulting mixture was filtered through celite and volatiles were removed to yield a yellow solid, 190 mg (100% yield) . The product was unstable, so it was used immediately in subsequent reactions without further purification. 1 H NMR
  • Brassinin (1) (Takasugi et al . (1988) Bull. Chem. Soc . Jpn., 61:285-89). Brassinin was formed from 25 according to the general method. The crude yellow solid was chromatographed on silica with EtOAc/hexanes (1:3) and the resulting yellow solid was further purified by recrystallization from CH 2 Cl 2 /hexanes to yield rose colored crystals (43% yd) . m.p. 132-133 0 C.
  • N-Benzyl-S-methyl-dithiocarbamate (8) (Mohanta et al. (2000) Tetrahedron, 56:629-637; Burrows et al . (1952) J. Chem. Soc. Abs . , 4118-22; Thorn et al . (1962) The Dithiocarbamates and Related Compounds; Elsevier: New York, 1962, p. 78) .
  • the general method was used with benzylamine and the crude product was chromatographed with EtOAc/hexanes (1:10) to yield an off-white oil (74% yield).
  • N-4-Fluoropheneth.yl-S-methyl-dithiocarbamate (10) The general method was used with 4-fluorophenethylamine and the solvent was CH 2 Cl 2 - The volatiles were removed and the residue was dissolved in EtOAc . The organic layer was washed with IM H 2 SO 4 (40 mL) , H 2 O (40 mL) and brine (30 mL) . The resulting organic solution was dried with Na 2 SO 4 and filtered. The volatiles were removed to yield a beige solid which was chromatographed with EtOAc/hexanes (8/92) to yield a white solid (89% yield), m.p. 59-60 0 C.
  • N, S-Dimethyl-N-phenethyldithiocarbamate (11) was used with N-methylphenthylamine and the solvent was CH 2 Cl 2 .
  • the crude product was chromatographed with EtOAc/hexanes (1/19) to yield a white oil (85% yield).
  • 2-Naphthamide (27) (See Fig. 3). 2-Naphthoyl chloride (2.21 g, 11.6 mmol) was dissolved in a MeOH/NH 3 solution (2 M, 20 mL) and was allowed to stir overnight. Volatiles were removed and the resulting white solid was triturated with EtOAc. The solid was filtered and washed with cold EtOAc to yield a white solid which was used without further purification (1.98 g, 100% yield) . m.p.
  • N-benzyl-S- (naphthoquinon-2-yl) -dithiocarbamate) (32) .
  • NEt 3 208.4 mg, 2.05 mmoles
  • CS 2 142.5 mg, 1.87 mmoles
  • 1,4- naphthoquinone 296.1 mg, 1.87 mmoles
  • Brassinin dithiocarbamate analogs were synthesized by adding an amine to carbon disulfide at 0 0 C, stirring for one hour, and then adding an alkyl halide. Modification of the indole core or alkane linker occurred by substituting different amines. Certain amines were commercially available while others required synthesis as described hereinabove.
  • the indole-3-methanamine 25 of brassinin 1 was prepared through the reductive amination of indole-3-carboxaldehyde. Although there are several different reductive amination procedures reported in the literature, the procedure described in Mehta et al . was determined to be the most effective (Mehta et al .
  • 2-Aminomethyl-naphthalene 28 was also synthesized in three steps from 2-naphthoic acid ( Figure 2) . Modifications of the S-alkyl piece occurred by substituting various alkyl halides for iodomethane, e.g. 12-18 ( Figure 3) .
  • the ⁇ -bromoketones 31 were generated from the corresponding ⁇ -diazoketone derivative 30, which was synthesized in three steps from indole-3-acetic acid following a literature procedure (Lutz et al . (1947) J. Org. Cher ⁇ . , 12:767-70; Cuevas-Yanez et al . (2004) Tetrahedron, 60:1505-1511) .
  • Brassinin analogs were analyzed for inhibition of extracted and purified ⁇ -interferon-induced human IDO.
  • the assay was conducted according to a literature protocol, with ascorbic acid and methylene blue serving the role of reductant (Littlejohn et al . (2000) Protein Expression and Purification, 19:22-29; Sono et al . (1989) J. Biol. Chem., 264:1616-1622). Catalase was added to prevent IDO decomposition from peroxide side products (Ohnishi et al . (1977) J. Biol. Chem., 252:4643-4647).
  • the enzyme assay monitored for formation of N- formylkynurenine by hydrolyzing the formyl group and spectrophotometrically analyzing for the conjugated imine generated from kynurenine and 4- (dimethylamino) benzaldehyde .
  • the inhibition assays were performed in a 96-well microtiter plate as previously described with a small modification (Littlejohn et al . (2000) Prot. Expr . Purif., 19:22-29). Briefly, the reaction mixture contained 50 mM potassium phosphate buffer (pH 6.5), 40 mM ascorbic acid, 400 ⁇ g/ml catalase, 20 ⁇ M methylene blue and purified recombinant IDO(I) optimized based on its activity. The reaction mixture was added to the substrate, L-tryptophan (L-Trp) , and the inhibitor.
  • L-tryptophan L-tryptophan
  • the L-Trp was serially diluted from 200 to 25 ⁇ M and the inhibitors were tested at two concentrations, 200 and 400 ⁇ M.
  • the reaction was carried out at 37 0 C for 60 minutes and stopped by adding 30% (w/v) trichloroacetic acid.
  • the plate was heated at 65° C for 15 minutes to convert formylkynurenine to kynurenine and then was spun at 6000 g for 5 minutes. Finally 100 ⁇ l supernatant from each well was transferred to a new 96 well plate and mixed with 2% (w/v) p-dimethylamino-benzaldehyde in acetic acid.
  • the yellow color generated from the reaction with kynurenine was measured at 490 nm using a Synergy HT microtiter plate reader (Bio-Tek, Winooski, VT) .
  • the data was analyzed using Graph Pad Prism 4 software (Graph Pad Software Inc., San Diego, CA).
  • the inhibitory constants shown are an average of two or three trials.
  • the array of analogs tested allowed for an evaluation of the four components of the brassinin structure and resulted in some important discoveries (Table 1) .
  • Indole derivatives can also be a liability given the neuroactivity of some indole containing compounds, e.g., serotonin and related indolealkylamines .
  • Linker variation was possible and, in the brassinin series, it was found that the longer linker lead to more potent compounds, c.f. 1 vs . 2 vs . 4. However, analogs that modified two brassinin components may not replicate this trend (c.f. 13 vs. 15) .
  • the results with the alkane linker modifications and the indole core changes indicate the IDO active site is rather accommodating .
  • ⁇ -carboline a non-competitive inhibitor, binds to the heme iron at the active site, but not in the same space as the substrate (Sono et al . (1989) Biochemistry, 28:5392-5399).
  • the ⁇ - carboline reportedly acts as a nitrogen donor ligand and competes with O 2 for binding to the heme iron. It is possible that the large aromatic S-alkyl pieces are binding in the same pocket that accommodates the tricyclic aromatic ⁇ -carboline structure. Nevertheless, the pyridyl analogs 17 and 18 failed to demonstrate stronger inhibition despite their similarity to the pyridyl ring of ⁇ -carboline.

Abstract

L'invention concerne de nouveaux inhibiteurs de l'indoleamine 2, 3-di oxygénase (IDO), des compositions comprenant ces inhibiteurs, et leurs procédés d'utilisation.
PCT/US2006/042137 2005-10-27 2006-10-27 Nouveaux inhibiteurs de l'ido et leurs procedes d'utilisation WO2007050963A1 (fr)

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WO2010020676A1 (fr) * 2008-08-20 2010-02-25 Vib Vzw Utilisation d’inhibiteurs de la topoisomérase de type i pour traiter des infections virales
US7705022B2 (en) 2005-10-27 2010-04-27 Lankenau Institute For Medical Research IDO inhibitors and methods of use thereof
CN102180845A (zh) * 2011-03-29 2011-09-14 郑州大学 含丁烯内酯结构的苄氨基二硫代甲酸酯类化合物、其制备方法及其用途
WO2011131135A1 (fr) 2010-04-21 2011-10-27 北京大学 Hétéroaryl(alkyl)dithiocarbamates, leurs méthodes de synthèse et leurs applications
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US11414460B2 (en) 2019-07-19 2022-08-16 Institute For Systems Biology KRAS-specific capture agents, compositions, and methods of making and using
US11719705B2 (en) 2017-06-15 2023-08-08 Indi Molecular, Inc. IL-17F and IL-17A-specific capture agents, compositions, and methods of using and making
US11723944B2 (en) 2015-03-16 2023-08-15 Indi Molecular, Inc. Botulinum neurotoxin-specific capture agents, compositions, and methods of using and making
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