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WO2019034179A1 - Inhibiteur de l'ido à anneau indole et son procédé de préparation - Google Patents

Inhibiteur de l'ido à anneau indole et son procédé de préparation Download PDF

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WO2019034179A1
WO2019034179A1 PCT/CN2018/101217 CN2018101217W WO2019034179A1 WO 2019034179 A1 WO2019034179 A1 WO 2019034179A1 CN 2018101217 W CN2018101217 W CN 2018101217W WO 2019034179 A1 WO2019034179 A1 WO 2019034179A1
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stereoisomer
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朱义
李�杰
何桂佳
钟刚
杨秀娟
李志勇
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Sichuan Baili Pharmaceutical Co Ltd
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Definitions

  • the present invention relates to a class of tetrazolium phenyl hydrazine derivatives, which are useful as active ingredients for the treatment of immune activation and inflammation associated with indoleamine-2,3-dioxygenase activity. Diseases and cardiovascular diseases.
  • Tryptophan the essential amino acid in the human body, has two pathways: the serotonin pathway (about 5%) and the kynurenine pathway (about 95%) (Neuroch em Res, 1980, 5(3): 223-239).
  • Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are the rate-limiting enzymes of the tryptophan/kynurenine pathway, and IDO is widely present in In mammalian tissue cells other than the liver, TDO is mostly expressed in the liver.
  • Indoleamine-2,3-dioxygenase is the only one outside the liver that can catalyze the epoxidation of ruthenium in tryptophan molecules, thereby decomposing along the canine uric acid pathway into L-kynurenine, picolinic acid and quinolinic acid. And a variety of metabolites.
  • the expression of the enzyme and its related metabolites is mainly distributed in the T cell region of the thymic medulla and secondary lymphoid organs, and is scattered in some immune tolerance or immune special tissues, such as thymus, gastrointestinal mucosa, placenta and the like.
  • IDO and TDO protect tissues from immune response by immunosuppression.
  • INF- ⁇ produced by activated T cells induces activation of indoleamine-2,3-dioxygenase expression, thereby negatively regulating CD4+ T cells, CD8+ T cells, and NK cells.
  • IDO and TDO have high expression in a variety of tumor tissues, and their high expression is one of the causes of tumor immune tolerance, and is closely related to the poor prognosis of cancer patients. Both IDO and TDO can inactivate the tumor surveillance of the immune system and prevent tumor rejection. Tumor cells and specific types of immune cells use this mechanism to limit anti-tumor immune responses.
  • IDO is also associated with other chronic diseases associated with inflammation, cardiovascular diseases, neurodegenerative diseases, psychiatric diseases, viral infections, autoimmune diseases, and the like.
  • IDO small molecule inhibitors that have entered the clinical research stage are only micromolar (such as Newlink Genetics' Indoximod), and some have poor oral bioavailability (such as Incyte Corporation). Epacadostat), so there is a need for drugs with better inhibition and bioavailability to meet current clinical needs.
  • Epacadostat has affinity for IDO holoenzyme; Indoximod can relieve T cell function inhibition caused by decreased mTORC1 activity due to tryptophan deletion; Navoximod pair Simultaneous expression of IDO1/TDO tumors has an inhibitory effect; PF-06840003 is a non-competitive inhibitor of tryptophan, does not bind to the hemoglobin of the IDO enzyme; BMS-986205 binds to apo-IDO1 without cofactor And it produces inhibition.
  • a single dash "-" indicates a single bond
  • a hetero refers to a corresponding chemical structure containing atoms other than carbon atoms.
  • the present invention provides a tetrazolium phenyl hydrazine derivative which is a guanamine-2,3-dioxygenase inhibitor whose main function is by inhibiting guanamine-2,3-bis Oxygenase activity plays a role in regulating immune system function and inflammatory factors, specifically compounds of formula (I):
  • R 1 is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned
  • the hetero atom is an oxygen, sulfur or nitrogen atom.
  • R 2 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group.
  • R 3 is a substituted or unsubstituted aryl group, and the aryl group may be an all-carbon skeleton or a skeleton containing one or more hetero atoms such as oxygen, sulfur, nitrogen, etc.; wherein the substitution on the aryl group may be a mono- or poly-substitution, substitution
  • the group is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, C 1 -C 8 substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or not Substituted hetero
  • the substituents described above are independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azide, sulfonyl, acyl.
  • alkyl is C 1 -C 8 substituted or unsubstituted alkyl group, - (CH 2) n -Ar -, - (CH 2) n -Cy-, wherein Ar is a substituted or unsubstituted substituted Aryl or heteroaryl, Cy is substituted or unsubstituted cycloalkyl or heterocycloalkyl.
  • the alkynyl group described above is a C 2 -C 8 chain alkyl group containing one or more -(C ⁇ C)-.
  • the heteroalkyl group described above is a substituted or unsubstituted C 1 -C 8 chain alkyl group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).
  • alkoxy group described above is -OR 4 wherein R 4 is a linear or branched substituted or unsubstituted C 1 -C 8 alkyl, alkenyl or alkynyl group.
  • the aryl group described above is a skeleton which may be an all carbon skeleton or a hetero atom containing one or more of oxygen, sulfur, nitrogen or the like, and may have one or more substituents thereon, and in some cases, any adjacent ones.
  • the two substituents may form a cyclic structure in which C 1 -C 6 has or does not contain a hetero atom (oxygen, sulfur or nitrogen).
  • the cycloalkyl group described above is a C 3 -C 7 carbocyclic group.
  • the heterocyclic group described above is a substituted or unsubstituted C 3 -C 7 carbocyclic group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).
  • the sulfonyl group described above is a substituted or unsubstituted C 1 -C 6 alkylsulfonyl group.
  • the compound (I) provided by the present invention is characterized in that R 3 is a substituted or unsubstituted phenyl group or a six-membered aromatic group containing one or more hetero atoms, wherein the hetero atom is N, O or S.
  • the invention provides a compound of formula (II):
  • R 1 is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned
  • the hetero atom is an oxygen, sulfur or nitrogen atom.
  • R 2 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group.
  • n 0 to 5.
  • R 3 is a substituted or unsubstituted aromatic phenyl group or a six-membered aromatic group containing one or more hetero atoms (nitrogen, oxygen or sulfur), wherein the substitution on the aryl group may be a mono- or poly-substitution, and the substituents are independently Selected from halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted heteroalkyl, C 1 -C 8 substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkyl, substituted or unsubstituted al
  • the substituents described above are independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azide, sulfonyl, acyl.
  • alkyl is C 1 -C 8 substituted or unsubstituted alkyl group, - (CH 2) n -Ar -, - (CH 2) n -Cy-, wherein Ar is a substituted or unsubstituted substituted Aryl or heteroaryl, Cy is substituted or unsubstituted cycloalkyl or heterocycloalkyl.
  • the alkynyl group described above is a C 2 -C 8 chain alkyl group containing one or more -(C ⁇ C)-.
  • the heteroalkyl group described above is a substituted or unsubstituted C 1 -C 8 chain alkyl group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).
  • alkoxy group described above is -OR 4 wherein R 4 is a linear or branched substituted or unsubstituted C 1 -C 8 alkyl, alkenyl or alkynyl group.
  • the aryl group described above is a skeleton which may be an all carbon skeleton or a hetero atom containing one or more of oxygen, sulfur, nitrogen or the like, and may have one or more substituents thereon, and in some cases, any adjacent ones.
  • the two substituents may form a cyclic structure in which C 1 -C 6 has or does not contain a hetero atom (oxygen, sulfur or nitrogen).
  • the cycloalkyl group described above is a C 3 -C 7 carbocyclic group.
  • the heterocyclic group described above is a substituted or unsubstituted C 3 -C 7 carbocyclic group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).
  • the sulfonyl group described above is a substituted or unsubstituted C 1 -C 6 alkylsulfonyl group.
  • the invention provides a compound of formula (III):
  • R 1 is an optionally substituted straight or branched alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted one with or without a hetero atom aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted amide alkyl group, the aforementioned
  • the hetero atom is an oxygen, sulfur or nitrogen atom.
  • R 2 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or Unsubstituted alkynyl group.
  • n 0 to 5.
  • R 3 is a substituted or unsubstituted aromatic phenyl group or a six-membered aromatic group containing one or more hetero atoms (nitrogen, oxygen or sulfur), wherein the substitution on the aryl group may be a mono- or poly-substitution, and the substituents are independently Selected from halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azido, sulfonyl, sulfonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted heteroalkyl, C 1 -C 8 substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkyl, substituted or unsubstituted al
  • the substituents described above are independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, azide, sulfonyl, acyl.
  • alkyl is C 1 -C 8 substituted or unsubstituted alkyl group, - (CH 2) n -Ar -, - (CH 2) n -Cy-, wherein Ar is a substituted or unsubstituted substituted Aryl or heteroaryl, Cy is substituted or unsubstituted cycloalkyl or heterocycloalkyl.
  • the alkynyl group described above is a C 2 -C 8 chain alkyl group containing one or more -(C ⁇ C)-.
  • the heteroalkyl group described above is a substituted or unsubstituted C 1 -C 8 chain alkyl group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).
  • alkoxy group described above is -OR 4 wherein R 4 is a linear or branched substituted or unsubstituted C 1 -C 8 alkyl, alkenyl or alkynyl group.
  • the aryl group described above is a skeleton which may be an all carbon skeleton or a hetero atom containing one or more of oxygen, sulfur, nitrogen or the like, and may have one or more substituents thereon, and in some cases, any adjacent ones.
  • the two substituents may form a cyclic structure in which C 1 -C 6 has or does not contain a hetero atom (oxygen, sulfur or nitrogen).
  • the cycloalkyl group described above is a C 3 -C 7 carbocyclic group.
  • the heterocyclic group described above is a substituted or unsubstituted C 3 -C 7 carbocyclic group containing one or more atoms other than carbon (oxygen, sulfur or nitrogen atom).
  • the sulfonyl group described above is a substituted or unsubstituted C 1 -C 6 alkylsulfonyl group.
  • the present invention surprisingly finds that a class of tetrazolium phenyl hydrazine derivatives can regulate the biological activity of IDO by inhibiting the IDO enzyme in biological cells, and can have other mechanisms of action due to slight differences in mechanism of action.
  • IDO inhibitors work synergistically to meet current demand for IDO modulators.
  • the structure of the oxime skeleton can be carried out by using 4-bromo-2-iodoaniline and R 2 -substituted ethyl acylacetate, and then passing the hydrogen on the N. Base substitution, amidation reaction and Suzuki reaction are obtained.
  • the synthetic route is shown in the following figure:
  • the citric acid intermediate when n ⁇ 1, can be prepared into an acid chloride, and the carboxylic acid which grows one carbon chain is obtained by Arndt-Eister reaction, and is condensed with the corresponding amine to be coupled with tetrazolium by the Suzuki reaction.
  • the azole group can obtain the target product; after the ring structure is constructed, the ester can be reduced and oxidized to form an aldehyde, and the carboxylic acid having a growth of 2 to 5 carbons can be obtained by a ylide reaction, and then the target compound can be obtained by amidation and Suzuki reaction.
  • the synthetic route is shown in the figure below:
  • the cyclohexylamine and the ethyl acetoacetate may be coupled to form an anthracene ring with p-benzoquinone, and then sequentially subjected to a Suzuki reaction and a Cruz rearrangement.
  • the synthetic route is shown in the figure below:
  • the synthetic route is shown in the following figure:
  • the compounds of the present invention can modulate the activity of indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • modulation refers to the ability to increase or decrease the activity of an enzyme or receptor.
  • the compounds described herein are useful in methods of modulating IDO by contacting the enzyme with any one or more of the compounds or compositions described herein. In some embodiments, the compounds described herein can be used as inhibitors of IDO. In a further embodiment, the compounds described herein are useful for modulating the IDO activity of a cell or individual in need of modulation of the enzyme by administering a modulatory (e.g., inhibitory) dose of a compound of the invention.
  • a modulatory e.g., inhibitory
  • the present invention provides a method of altering (e.g., increasing) the level of extracellular tryptophan in a mammal in a system comprising a cell-expressed IDO, such as a tissue, cell or living organism culture, comprising administering an effective amount of the present invention.
  • a cell-expressed IDO such as a tissue, cell or living organism culture
  • administering an effective amount of the present invention Compound or ingredient.
  • Methods for determining tryptophan levels and tryptophan degradation are routine methods in the art.
  • the invention provides methods of inhibiting immunosuppression (e.g., IDO-mediated immunosuppression) in a patient by administering to the patient an effective amount of a compound or component of the invention.
  • IDO-mediated immunosuppression is associated with cancer, tumor growth, metastasis, infectious diseases (such as viral infections), viral replication, and the like.
  • the present invention treats diseases associated with abnormal IDO activity or expression in an individual (e.g., a patient) by administering to the patient an effective amount of a compound or component of the present invention.
  • the disease includes any disease, disorder or condition that is directly or indirectly associated with abnormal expression or activity of the IDO enzyme.
  • diseases related to IDO include cancer, neurodegenerative disorders (eg, Alzheimer's disease, Huntington's disease, etc.), viral infections (eg, HIV infection, etc.), depression, trauma, cataracts, autoimmune diseases (eg, rheumatoid joints) Inflammation, asthma, multiple sclerosis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, etc.), organ transplantation (eg organ transplant rejection, etc.).
  • neurodegenerative disorders eg, Alzheimer's disease, Huntington's disease, etc.
  • viral infections eg, HIV infection, etc.
  • depression e.g., trauma, cataracts
  • autoimmune diseases eg, rheumatoid joints
  • Inflammation asthma, multiple sclerosis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, etc.
  • organ transplantation eg organ transplant rejection, etc.
  • cancer-associated tumor-specific immunosuppression treatable by the methods of the invention examples include colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testis, kidney, head and neck cancer, lymphoma , immunosuppression related to leukemia, melanoma, etc.
  • the IDO-mediated immunosuppression associated with viral infections of the present invention is associated with viral infections selected from the group consisting of hepatitis C virus (HCV), human papillomavirus (HPV), and cytomegalovirus (CMV). , Epstein-Barr virus (EBV), poliovirus, varicella zoster virus, Coxsackie virus, human immunodeficiency virus (HIV).
  • HCV hepatitis C virus
  • HPV human papillomavirus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • poliovirus Epstein-Barr virus
  • varicella zoster virus varicella zoster virus
  • Coxsackie virus human immunodeficiency virus
  • IDO-mediated immunosuppression associated with an infectious disease is associated with tuberculosis or leishmaniasis.
  • a patient undergoing or having completed a course of chemotherapy and/or radiation therapy for a disease state may administer a therapeutically effective amount of a compound or component of the invention to a patient to inhibit immunosuppression due to a disease state. And / or its treatment benefits.
  • a method of treating a disease associated with IDO activity or expression by administering to a subject (eg, a patient) in need of a related treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • a subject eg, a patient
  • a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof can include any disease, disorder, or condition, such as overexpression or activity abnormality, that is directly or indirectly related to the expression or activity of an IDO enzyme.
  • IDO-related diseases can also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.
  • contacting refers to the association of a specified portion with an in vitro system or an in vivo system.
  • contacting an IDO enzyme with a compound or ingredient of the invention includes administering to a subject or patient (e.g., a human) having the IDO a compound of the invention, or introducing a compound of the invention into a sample comprising the IDO enzyme-containing cell or purified preparation.
  • the term "individual” or “patient” as used in the present invention refers to any animal or human including a mammal, preferably a mouse, a rat, another rodent, a rabbit, a dog, a cat, a pig, a cow, a sheep, a horse. Or primate, most preferably human.
  • terapéuticaally effective amount refers to the amount of active compound or drug that a researcher, physician, or veterinarian seeks in a tissue, system, animal, individual, or human to cause a biological or medical response, including disease prevention, relief.
  • a researcher, physician, or veterinarian seeks in a tissue, system, animal, individual, or human to cause a biological or medical response, including disease prevention, relief.
  • the compounds of the invention may be combined with one or more other therapeutic methods (eg, antiviral, chemotherapeutic or other anticancer drugs, immunopotentiators, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapies) Combination of drugs such as IL2, GM-CSF, etc. and/or tyrosine kinase inhibitors to treat IDO-related diseases, disorders or conditions (as described above) or to improve the treatment of disease states or conditions (eg cancer) Efficacy.
  • drugs may be used in combination with a compound of the present invention in one dosage form, or these drugs may be administered simultaneously or sequentially in different dosage forms.
  • Suitable antiviral drugs contemplated for use in combination with the compounds of the invention may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and others. Antiviral drugs.
  • nucleoside reverse transcriptase inhibitors include, but are not limited to, zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); Mifidine (3TC); abacavir (1592U89); adefovir dipivoxil [bisacrylamide (POM)-PMEA]; lobucarb (BMS-180194); BCH-10652; emtricitabine [ (-)-FTC]; ⁇ -L-FD4 (also known as ⁇ -L-D4C and the name ⁇ -L-2', 3'-dideoxy-5-fluoro-cytidine); DAPD((-) - ⁇ -D-2,6-diamino-decanedioxolane; and Lord's adenosine (FddA).
  • ZT zidovudine
  • ddI didanosine
  • ddC zal
  • Typical suitable non-nucleoside reverse transcriptase inhibitors include, but are not limited to, nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG- 1549; MKC-442[1-(ethoxy-methyl)-5-(1-methylethyl)-6-(benzyl)-(2,4-(1H,3H)-pyrimidine-II Ketone]; and (+)-caolin A (NSC-675451) and B.
  • Typical suitable protease inhibitors include, but are not limited to, saquinavir (Ro31-8959); ritonavir (ABT-538); Indo Nawei (MK-639); nelfinavir (AG-1343); amprenavir (141W94); rasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; -1549.
  • Other antiviral drugs include, but are not limited to, hydroxyurea, ribavirin, IL-2, IL-12, pentafoxif and Yissum (item number 11607).
  • Suitable chemotherapy or other anti-cancer drugs include, but are not limited to, alkylating agents (including, without limitation, nitrogen mustard, aziridine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uramus Tet, piperacin, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, piperac bromide, triethylene-melamine, triethylene thiophosphoramide, busulfan, Carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide; antimetabolites (including, without limitation, f-folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors) Such as methotrexate, 5-fluorouracil, fluorouridine, cytarabine, 6-anthracene, 6-thioguanine, fludarabine
  • cytotoxic drugs include, but are not limited to, noviben, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, cyclophosphamide, ifosfamide, and droloxifene.
  • cytotoxic drugs including drugs of the same mechanism
  • cytotoxic drugs are also suitable: such as epiphyllotoxin; tumor enzyme; topoisomerase inhibitor; procarbazine; mitoxantrone; platinum complexes such as cisplatin and carboplatin; Biological response modifier; growth inhibitor; anti-hormone therapeutic; calcium leucovorin; tegafur; and hematopoietic growth factor.
  • Suitable other anticancer drugs include antibody therapy such as trastuzumab (Herceptin), costimulatory molecules such as CTLA-4, 4-1BB and PD-1 or cytokine antibodies (IL-10, TGF- ⁇ ) Etc.; drugs that block the migration of immune cells, such as chemokine receptor antagonists (CCR2, CCR4, and CCR6); drugs that enhance the immune system, such as adjuvant or adaptive T cell metastases.
  • antibody therapy such as trastuzumab (Herceptin), costimulatory molecules such as CTLA-4, 4-1BB and PD-1 or cytokine antibodies (IL-10, TGF- ⁇ ) Etc.
  • drugs that block the migration of immune cells such as chemokine receptor antagonists (CCR2, CCR4, and CCR6)
  • drugs that enhance the immune system such as adjuvant or adaptive T cell metastases.
  • Suitable anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.
  • compositions which are a combination of the compound of the present invention and a pharmaceutically acceptable carrier.
  • These compositions can be prepared in a manner well known in the pharmaceutical art and administered by a variety of routes depending on the area used for topical or systemic treatment and treatment. Administration may be topical (including ocular administration and mucosal administration such as intranasal, vaginal and rectal), pulmonary (such as by nebulizer, intratracheal, intranasal, epidermal and transdermal) inhalation or injection of powder Or aerosol), eye, oral or parenteral.
  • Methods of ocular administration may include topical administration (eye drops), subconjunctival, periocular or intravitreal injection, introduction of an ocular insert through a balloon catheter or surgical placement in the conjunctival sac, and the like.
  • parenteral administration include intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration.
  • Parenteral administration can be in the form of a single bolus dose or can be in the form of a continuous infusion pump or the like.
  • Methods for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, creams, powders, liquids, and powders. It may be necessary or desirable to use conventional pharmaceutical carriers, water, powder or oily bases, thickeners, and the like.
  • the pharmaceutical composition of the present invention may contain, as an active ingredient, one or more of the above compounds of the present invention in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient will generally be mixed with the adjuvant, diluted by the adjuvant or contained in a carrier such as a capsule, sachet, paper or other container.
  • a carrier such as a capsule, sachet, paper or other container.
  • the adjuvant may be a solid, semi-solid or liquid material, as an excipient, carrier or vehicle for the active ingredient.
  • the composition may be in the form of a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol (as a solid or liquid medium), and contains the highest activity.
  • the active compound of the present invention can be pulverized to provide a suitable particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is soluble in water, the particle size can be adjusted by comminution to provide a substantially uniform distribution in the formulation, such as about 40 mesh.
  • excipients used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystals.
  • Formulations may also include, but are not limited to, lubricants (such as talc, magnesium stearate, mineral oil, etc.), wetting agents, emulsifying and suspending agents, preservatives (such as methylparaben, propyl ester, etc.), Sweeteners and flavorings.
  • the compositions of the present invention can be formulated using procedures known in the art to provide rapid, slow or delayed release of the active ingredient after administration to a patient.
  • compositions of the present invention may also be formulated in unit dosage form such that they contain from about 5 to about 200 mg per dose, more usually from about 10 to about 100 mg of the active ingredient.
  • unit dosage form refers to a physically discrete unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect.
  • the active compounds of the present invention can be effective in a wide variety of dosage forms and are generally administered in a pharmaceutically effective amount. It is to be understood that the actual dose of the compound is usually determined by the physician according to the circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • a solid composition such as a tablet
  • the main active ingredient is mixed with a pharmaceutical adjuvant to form a pre-formulation composition containing a homogeneous mixture of the compounds described herein.
  • homogeneous as used in the appeal, it is meant that the active ingredient will generally be homogeneously dispersed in the composition such that the compositions are readily divided into equivalent unit dosage forms such as tablets, pills, capsules and the like.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, from 0.1 to about 500 mg of the active compound of the invention.
  • the tablets or pills may be coated or otherwise compounded to obtain a dosage form that has the advantage of prolonged action.
  • a tablet or pill can contain both an inner dose and an outer dose component, the latter being in the form of the former.
  • the two components can be separated by an enteric layer which serves to prevent disintegration in the stomach and complete passage of the inner component through the duodenum or delayed release.
  • enteric layer or coating including but not limited to various polymeric acids and mixtures of polymeric acids with shellac, cetyl alcohol, and cellulose acetate.
  • Liquid forms which may be added to the compounds and compositions of the present invention for oral or parenteral administration include: aqueous solutions, suitable flavored syrups, aqueous or oily suspensions, and edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Flavored emulsions, elixirs and similar pharmaceutically acceptable carriers.
  • compositions for inhalation or insufflation include dissolving a compound of the invention in a pharmaceutically acceptable solution, suspension, water or organic solvent, or mixtures and powders thereof. Suitable pharmaceutically acceptable excipients may be included in the liquid or solid compositions.
  • the composition is administered by the oral or nasal respiratory route to produce a local or systemic effect.
  • the composition can be atomized using an inert gas.
  • the nebulizing solution can be directly inhaled by the atomizing device, or the nebulizing device can be connected to a mask or a intermittent positive pressure ventilator. Solutions, suspensions or powder compositions can be administered orally or nasally by means of a device for releasing the formulation in a suitable manner.
  • the amount of the compound or composition to be administered to a patient varies depending on the ingredient to be administered, the purpose of administration (e.g., prevention or treatment), the state of the patient, the mode of administration, and the like.
  • the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
  • the effective dose depends on the condition being treated and the judgment of the attending physician based on factors such as the severity of the disease, the age, weight and general condition of the patient.
  • composition administered to the patient may be in the form of the above pharmaceutical composition.
  • These compositions can be sterilized or sterile filtered by conventional sterilization techniques.
  • the aqueous solution may be packaged as it is or as a lyophilized preparation, and the lyophilized preparation is used after mixing with a sterile aqueous carrier prior to administration.
  • the pH of the compound formulation is generally between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be appreciated that the use of some of the above-described excipients, carriers or stabilizers will result in the presence of the drug in the form of a salt.
  • the therapeutic dose of the compound of the present invention may vary depending on the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of the compound of the present invention in a pharmaceutical composition may vary depending on various factors including dosage, chemical characteristics (e.g., hydrophobicity), route of administration, and the like.
  • the compounds of the invention may be provided in a physiologically buffered aqueous solution containing from about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges range from about 1 [mu]g/kg to about 1 g/kg body weight per day.
  • the dosage range is between about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage may depend on factors such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the adjuvant, and the route of administration.
  • the effective dose can be inferred by a dose response curve from an in vitro or animal model test system.
  • the compounds of the present invention may also be formulated in combination with one or more other active ingredients, and other active ingredients may include any drug, such as antiviral drugs, vaccines, antibodies, immunopotentiators, immunosuppressive agents, anti-inflammatory agents, and the like.
  • Another aspect related to the present invention relates to fluorescent dyes, spin labels, heavy metals or radiolabeled derivatives of said compounds which are useful not only for imaging but also for in vivo and in vivo detection for localization and quantification of tissue specimens (
  • the IDO enzyme in humans is included and used to recognize IDO enzyme ligands by inhibiting binding to the labeled compound.
  • the invention further provides IDO enzyme assays containing such labeled compounds.
  • the invention further provides isotopically labeled compounds of the compounds.
  • An “isotopically labeled” or “radiolabeled” compound is a compound of the invention in which one or more atoms are replaced or substituted with an atomic mass or mass number of atoms different from the atomic mass or mass number normally found in nature (ie, naturally occurring).
  • Suitable radionuclides include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • radionuclide contained in the radiolabeled compound will depend on the particular application of the radiolabeled compound. For example, for in vitro IDO enzyme labeling and competitive detection, compounds containing 3 H, 14 C, 82 Br, 125 I, 131 I or 35 S are generally used. For radiographic applications, compounds containing 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br are generally employed.
  • radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S or 82 Br.
  • the radiolabeled compounds of the invention can be used to identify or evaluate screening assays for compounds.
  • a newly synthesized or discovered compound i.e., a test compound
  • a test compound can be evaluated to reduce the ability of the radiolabeled compound of the present invention to bind to an IDO enzyme.
  • the ability of a test compound to compete with a radiolabeled compound for binding to an IDO enzyme is directly related to its binding affinity.
  • kits for treating diseases such as treating or preventing diseases or conditions associated with IDO, obesity, diabetes, and other diseases of the invention.
  • a kit is a container comprising one or more of the pharmaceutical compositions of the present invention, comprising a pharmaceutical composition having a therapeutically effective amount.
  • kits may also include suitable one or more of various conventional kit components, such as containers containing one or more pharmaceutically acceptable carriers, other containers readily apparent to those skilled in the art, and the like. Instructions for indicating the amount of the compound, administration of the drug, and/or compounding instructions for the compound may also be included in the kit as an insert or label.
  • DPBS Dunsen's phosphate buffer
  • EDTA ethylenediaminetetraacetic acid
  • NBS N-bromosuccinimide
  • Trypsin Trypsin
  • Figure 1 is a graph showing the antitumor effect of the compound.
  • Reagents and solvents were purchased from commercial sources, and the reaction was monitored using a 0.25 mm HSGF254 thin layer chromatography silica gel plate and flash column chromatography using 200-300 mesh particle size thin layer chromatography silica gel.
  • Nuclear magnetic resonance spectroscopy was performed using a Bruker Avance III NMR spectrometer.
  • Mass spectrometry was performed using Agilent LC/MS chromatographs 1260-6110 and 1260-6120. All reactions were magnetically stirred at room temperature unless otherwise stated.
  • reaction solution is added with water to quench the reaction, and then diluted with a large amount of water, extracted with EA (150 mL ⁇ 4), the organic phase is combined, DMF is washed away with a large amount of water, and then washed with saturated brine, anhydrous sulfuric acid The mixture was dried over sodium sulfate. EtOAc was evaporated.
  • the reaction solution was cooled to room temperature, diluted with 10 g/L KOH solution, a small amount of solid was precipitated, washed with EA (100 mL), the organic phase was dark yellow, and the aqueous phase was light. The point plate organic phase product is less, retaining the aqueous phase.
  • the aqueous phase was adjusted to pH 4-5 with 1N HCl. A large white solid was precipitated, which was extracted with EA (60 mL ⁇ 3).
  • the organic phase was combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated.
  • the product was purified by silica gel column chromatography using a solvent mixture of EA and hexanes as eluent.
  • Examples 2 to 5 The following compounds were obtained by a reaction method similar to that of Compound 1, by reacting Intermediate Compound 1C with the corresponding amine, and then by Suzuki reaction.
  • Example 7 4-Bromo-2-iodoaniline with corresponding After the cyclization, the intermediate compound 6E is coupled with the corresponding amine using a synthetic method similar to that of the compound 6.
  • the positive drug INCB024360 was purchased from MedChem Express.
  • the Hela cells were obtained from the cell bank of the Chinese Academy of Sciences. The complete medium was prepared by our laboratory.
  • DPBS, 0.25% Trypsin ⁇ EDTA and Trypan Blue were all from Thermo Fisher Scientific (China) Co., Ltd.
  • Gibco TM the microplate reader is Molecular Device's SpectraMax 190
  • the cell counter is the Countstar of Shanghai Ruiyi Biotech Co., Ltd.
  • the cell centrifuge is TDL-40B of Shanghai Anting Scientific Instrument Factory.
  • INF- ⁇ (R&D, 28-IF-100) was dissolved in sterile purified water to a concentration of 0.2 mg/mL;
  • the sample was dissolved in DMSO (Amresco, CAT #N182) to a concentration of 10 mM;
  • Hela cells were cultured in MEM medium (Gibco), 90%;
  • Streptomycin solution (100 ⁇ , Hyclone), 1%;
  • the temperature is 37 °C.
  • INF- ⁇ was diluted with medium to a final concentration of 50 ng/mL, and then medium containing 50 ng/mL INF- ⁇ . Dilute the drug to 1 uM and 0.1 nM while setting the control: 50 ng/mL INF- ⁇ medium + cell negative control and blank control containing 0.1% DMSO: 50 ng/mL INF- ⁇ medium with only 0.1% DMSO; The original medium of the 96-well plate was aspirated, and 200 ul of the drug group and the control group were added to each well, and three replicate wells were set at each concentration, and the cells were incubated for 48 hours under normal culture conditions.
  • IDO inhibition rate [1-(OD drug group - OD blank control group) / (OD negative control group - OD blank control group)] ⁇ 100%
  • the OD drug group was a drug-added well; the OD-negative control group was a 50 ng/mL INF- ⁇ medium cultured in 0.1% DMSO; the OD blank control group was a 50 ng/mL INF- ⁇ medium without cells in 0.1% DMSO. .
  • control 50 ng / mL INF- ⁇ medium containing 0.1% DMSO + cell negative control and blank control: only
  • the supernatant was placed in a 96-well round bottom plate, 10 ul of 6.1 N trichloroacetic acid was added, mixed, placed at 50 ° C for 30 min; then at 2500 rpm
  • INF- ⁇ was diluted with medium to a final concentration of 50 ng/mL, and then medium containing 50 ng/mL INF- ⁇ .
  • the cells were incubated for 48 h under normal culture conditions. After 48h, absorb 140ul/well of cell culture supernatant in 96-well round bottom plate, add 10ul of 6.1N trichloroacetic acid, mix and place at 50 °C for 30min; then centrifuge at 2500rpm for 10min; absorb 100ul of supernatant in new 96-well flat bottom plate; finally add 100ul 2% 4-dimethylaminobenzaldehyde solution, mix, stand at room temperature for 10min, avoid detection at 480nm, use Calcusyn software to calculate the CI value of the combination.
  • Example number Fa 50% corresponding CI 2:8 0.92 2: INCB 024360 0.89 8: INCB 024360 0.80
  • Human monocytes were collected from peripheral monocytes by leukocyte isolation, and human monocytes were added with 10% fetal bovine serum and 2 mM L- in 96-well culture plates at a density of 1 ⁇ 10 6 cells/well. Glutamine was cultured overnight in RPMI 1640 medium. After adherent cells were retained, they were cultured for 7 days with 250 ng/ml IL-4, 100 ng/ml GM-CSF. The cells were matured for 2 days with a combination of 50 ng/mL INF- ⁇ and 50 ⁇ g/mL LPS cytokines to induce dendritic cell maturation.
  • the final concentration was obtained using 100-200 U/mL IL-2, 100 ng/mL anti-CD3 antibody and human RPMI 1640 replacement medium from normal donor human allogeneic T cells and different dilutions of IDO compounds.
  • An IDO inhibitor between 500 and 1 ⁇ M was cultured for another two days.
  • BrdU was added to an overnight shock and T cell proliferation was measured using a colorimetric cell proliferation ELISA kit.
  • the cells were continuously cultured for 18 hours in a 10 ⁇ M BrdU labeling solution, the labeling medium was removed, 200 ⁇ L of FixDenat/well was added, and the mixture was incubated at room temperature for 30 minutes to remove the FixDenat solution, and incubated with 100 ⁇ L/well of anti-BrdU-POD antibody conjugate solution. In minutes, remove the antibody conjugate, wash the cells 3 times with 200 ⁇ L/well of washing solution, add 100 200 ⁇ L/well of substrate solution, read the plate data with a microplate reader, and record multiple readings at different time points to ensure data online.
  • Compounds of the invention having an IC50 of less than about 100 [mu]M are considered to be active compounds.
  • a mouse CT26 xenograft model of colorectal cancer was established, and a certain concentration of compound 5, compound 161 and INCB024360 (positive drug) were administered to evaluate the effect of each compound on CT26 mouse xenografts.
  • CT26 cells cultured in vitro were inoculated subcutaneously into the back of nude mice. After the tumors were grown, they were randomly divided into 6 groups, 7 to 8 per group. Different drugs were given (except for special instructions, 2 times a day), regular The body weight was measured, the tumor volume was measured, and the efficacy against the CT26 model was evaluated by examining the antitumor efficacy of each compound. The results showed that compound 8 was superior to compound 2 and positive drug, and had certain antitumor effect.

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Abstract

L'invention concerne un inhibiteur de l'IDO à anneau indole et son procédé de préparation, un composé tenant lieu de principe actif pour médicament indiqué pour le traitement de maladies telles que l'activation immune associée à l'activation de l'indole-amine 2,3-dioxygénase, les maladies inflammatoires et les maladies cardiovasculaires.
PCT/CN2018/101217 2017-08-18 2018-08-18 Inhibiteur de l'ido à anneau indole et son procédé de préparation Ceased WO2019034179A1 (fr)

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WO2021067801A1 (fr) * 2019-10-03 2021-04-08 Ifm Due, Inc. Composés et compositions pour traiter des états pathologiques associés à une activité de sting
US11618749B2 (en) 2018-07-03 2023-04-04 Ifm Due, Inc. Compounds and compositions for treating conditions associated with STING activity
US12152018B2 (en) 2021-01-08 2024-11-26 Ifm Due, Inc. Compounds and compositions for treating conditions associated with STING activity

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CN1795187A (zh) * 2003-03-27 2006-06-28 兰肯瑙医学研究所 新型ido抑制剂及其使用方法
CN102883607A (zh) * 2010-03-01 2013-01-16 Gtx公司 用于治疗癌的化合物
CN103619834A (zh) * 2011-04-29 2014-03-05 赛诺菲 N-[(1h-吡唑-1-基)芳基]-1h-吲哚或1h-吲唑-3-甲酰胺的衍生物、其制备及其作为p2y12拮抗剂的用途

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CN102883607A (zh) * 2010-03-01 2013-01-16 Gtx公司 用于治疗癌的化合物
CN103619834A (zh) * 2011-04-29 2014-03-05 赛诺菲 N-[(1h-吡唑-1-基)芳基]-1h-吲哚或1h-吲唑-3-甲酰胺的衍生物、其制备及其作为p2y12拮抗剂的用途

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11618749B2 (en) 2018-07-03 2023-04-04 Ifm Due, Inc. Compounds and compositions for treating conditions associated with STING activity
WO2021067801A1 (fr) * 2019-10-03 2021-04-08 Ifm Due, Inc. Composés et compositions pour traiter des états pathologiques associés à une activité de sting
US12152018B2 (en) 2021-01-08 2024-11-26 Ifm Due, Inc. Compounds and compositions for treating conditions associated with STING activity

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