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WO2017129139A1 - Ester d'acide sulfamique utilisé comme inhibiteur de l'indoleamine-2,3-dioxygénase, son procédé de préparation et utilisation associée - Google Patents

Ester d'acide sulfamique utilisé comme inhibiteur de l'indoleamine-2,3-dioxygénase, son procédé de préparation et utilisation associée Download PDF

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Publication number
WO2017129139A1
WO2017129139A1 PCT/CN2017/072730 CN2017072730W WO2017129139A1 WO 2017129139 A1 WO2017129139 A1 WO 2017129139A1 CN 2017072730 W CN2017072730 W CN 2017072730W WO 2017129139 A1 WO2017129139 A1 WO 2017129139A1
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compound
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formula
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Chinese (zh)
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王召印
郭巍
朱继东
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles

Definitions

  • the invention belongs to the technical field of medicinal chemistry, in particular to a sulfamate as a guanamine-2,3-dioxygenase inhibitor, a preparation method and use thereof, and more particularly to a sulfamate containing And IDO inhibitors of 1,2,5-oxadiazole structure, and preparation methods and uses thereof.
  • Indoleamine-2,3-dioxygenase is a monomeric enzyme containing heme found in the cell for the first time in 1967 by the Hayaishi group.
  • the cDNA encodes a protein. 403 amino acid composition with a molecular weight of 45 kDa, which is the rate-limiting enzyme of the leucine-kynurenine pathway catabolism and is widely expressed in many mammalian tissues (Hayaishi O. et al. Science, 1969, 164, 389). -396).
  • IDO In tumor cells, IDO often plays an important physiological role in inducing tumor microenvironmental immune tolerance, and its mediated tryptophan (Trp)-kynurenine (Kyn) metabolic pathway is involved in tumors. Immune escape, and IDO also plays an important role as an immune tolerance to induce tumor microenvironment.
  • Tryptophan is one of the important essential amino acids in mammals. It needs to be ingested in large quantities from food, maintain cell activation and proliferation, and synthesize proteins and some neurotransmitters. Therefore, its lack of dysfunction can lead to some important cells. IDO can catalyze the conversion of tryptophan to N-formyl kynurenine in vivo, degrading the content of tryptophan and causing deficiency of tryptophan in vivo, leading to tumor formation. Immunohistological studies have shown that the kynurenine pathway can lead to an increase in the excitotoxic quinolinic acid, as well as many serious human diseases such as Alzheimer's and other neurological diseases (Guillemin GJet al Neuropathol. and Appl. Neurobiol. 2005, 31, 395–404).
  • tryptophan dioxygenase TDO
  • IDO IDO
  • Kotake et al. purified proteins from rabbit intestines and found that TDO was mainly expressed in mammalian liver. It has not been found to be closely related to the immune system. TDO catalyzes the kynurenine pathway and converts tryptophan to N-formyl kynurenine [Higuchi K. et al J. Biochem. 1937, 25, 71-77; Shimizu T. et al J. Biol. .1978, 253, 4700-4706].
  • IDO dioxygenase
  • heme heme
  • IDO can inhibit local T cell immune responses in the tumor microenvironment by: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is transiently expressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, in the absence of tryptophan or kynurenine culture conditions, T cells undergo proliferation inhibition, decreased activity, and even apoptosis. And T There is a regulatory point in the cell that is very sensitive to the level of tryptophan. Under the action of IDO, tryptophan can be consumed, which leads to the arrest of T cells in the middle of G1 phase, thereby inhibiting the proliferation of T cells and inhibiting T cells.
  • T cells Once T cells stop proliferating, they may not be stimulated any more. This is the mechanism of IDO immunity in vivo (Mellor A. et al Biochem. Biophys. Res. Commun. 2005, 338(1): 20-24) (LeRond S. et al J. Exp. Med. 2002, 196(4): 447-457).
  • Another object of the present invention is to provide a process for the preparation of the compound.
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 3 -C 10 alkynyl, substituted or unsubstituted C 6 -C 20 aryl, or substituted or unsubstituted C 3 -C 14 heteroaryl;
  • R 1 and R 2 , or R 3 and R 4 may together form a three- to eight-membered carbocyclic ring or a three- to eight-membered heterocyclic ring (eg, a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, a seven-membered ring, and eight-membered ring).
  • R 1 and R 3 may together form a five- to eight-membered carbocyclic ring or a five- to eight-membered heterocyclic ring (such as a five-membered ring, a six-membered ring, a seven-membered ring, or an eight-membered ring), wherein the hetero atom may be sulfur, oxygen, NH or NR f;
  • R 5 is C 6 -C 20 aryl, 5- or 6-membered heteroaryl; R 5 may be substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, hydroxy, amino, nitro, aldehyde, -CF 3 , -CN, -SF 5 , NR a R b , carboxy, -COR a , -CO 2 C 1 -C 6 alkyl, - CONR a R b , -S(O)R a , -S(O) 2 R a , -S(O)(NH)R a , -S(O)(NR d )R a , -SO 2 NR a R b , -P(O)Me 2 , -P(O)(OMe) 2 ; wherein each R a and each R b are independently hydrogen, substituted or unsubstitute
  • X is a single bond, O, S, NH or NR d ;
  • R d and R f are independently C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 14 heteroaryl;
  • n is an integer from 2 to 8.
  • substitution means having one or more substituents selected from the group consisting of halogen, hydroxy, -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl group, a phenyl group, a benzyl group.
  • X is NH
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl; R 3 and R 4 may together form a three to eight membered ring or a three to eight membered impurity.
  • a ring wherein the hetero atom can be sulfur, oxygen, NH or NR f .
  • n is an integer from 2 to 6.
  • n is an integer from 2 to 6, and each R 3 is independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, Substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 3 -C 10 alkynyl, substituted or unsubstituted C 6 -C 20 aryl, or substituted or unsubstituted C 3 -C 14 Heteroaryl; each R 4 is independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 alkenyl a substituted or unsubstituted C 3 -C 10 alkynyl group, a substituted or unsubstituted C 6 -C
  • R 3 is hydrogen
  • R 4 is hydrogen
  • the compound is as shown in the formula (II),
  • Ar is a benzene ring, and Ar may be substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, amino, nitro, aldehyde, -CF 3 , -CN, -SF 5 , NR a R b , carboxyl group, -COR a , -CO 2 C 1 -C 6 alkyl group, -CONR a R b , -S(O)R a , -S( O) 2 R a , -S(O)(NH)R a , -S(O)(NR d )R a , -SO 2 NR a R b ;
  • R a , R b , R d , R 3 , R 4 , R 2 and R 1 are as defined above;
  • n is an integer of 2-6.
  • R 1 is H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 10 heteroaryl; R 1 It may be substituted by one or more halogens.
  • R 1 is C 1 -C 10 alkyl
  • R 2 is H, C 1 -C 10 alkyl
  • R 3 and R 4 are each independently hydrogen, C 1 -C 10 alkyl or R 3 and R 4 may together form a three to eight membered carbocyclic ring or a three to eight membered heterocyclic ring.
  • R 1 is H, C 1 -C 3 alkyl; and/or R 2 is H, C 1 -C 3 alkyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently H.
  • the prodrug of the compound of formula I is as shown in formula (III),
  • R 1 , R 2 , R 3 , R 4 , n and Ar are as described above;
  • Y is R 6 , OR 6 , NR a R b ;
  • R 6 is a substituted or unsubstituted C 6 -C 20 aryl group, a substituted or unsubstituted five- or six-membered heteroaryl group, a substituted or unsubstituted C 1 a -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 3 -C 12 heterocyclic group, wherein the hetero atom may be sulfur, oxygen, NH or NR f ;
  • R a and each R b are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 alkenyl a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 14 heteroaryl group; R a and R b may together form a three to eight membered ring or a four to eight membered heterocyclic ring.
  • the hetero atom may be sulfur, oxygen, NH or NR f ; N f is as defined above.
  • substituted means having one or more substituents selected from the group consisting of halogen, hydroxy, -NH 2, nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkane A C 1 -C 4 alkoxy group, a C 3 -C 6 cycloalkyl group, a C 2 -C 4 alkenyl group, a C 2 -C 4 alkynyl group, a phenyl group, a benzyl group.
  • each of groups such as X, R 1 , R 2 , R 3 , R 4 , Y and Ar are independently the formulas (I), (II), and (III) prepared in the examples. Corresponding groups in each specific compound.
  • the compound is selected from the group consisting of:
  • R 1 , R 2 , R 3 , R 4 , and R 5 in the formula (I) are each independently selected from the corresponding groups of the specific compounds of the above table.
  • the compound is a specific compound prepared in the examples.
  • the compound is a racemate.
  • the compound is an enantiomer.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, benzenesulfonic acid Salt, p-toluenesulfonate (tosylate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, milk Acid, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.
  • R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined above.
  • the invention also provides a preparation method of the second compound of the general formula (I), comprising the following steps:
  • the invention also provides a process for the preparation of a third compound of the general formula (I), comprising the steps of:
  • the guanamine-2,3-dioxygenase mediated disease is a disease characterized by the pathology of an IDO-mediated tryptophan metabolism pathway.
  • the guanamine-2,3-dioxygenase mediated disease is cancer, eye disease, heart disorder, depression, anxiety, AIDS, Alzheimer's disease, and/or autoimmune disease.
  • the cancer includes, but is not limited to, colon cancer, breast cancer, gastric cancer, lung cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple Myeloma, chronic myeloid leukemia, hematological tumors, lymphoid tumors, including metastatic lesions in other tissues or organs remote from the primary site of the tumor.
  • a pharmaceutical composition comprising:
  • a pharmaceutically acceptable carrier is selected from:
  • a pharmaceutical composition comprising:
  • the anti-tumor drug includes, but is not limited to, an immunotherapeutic drug for cancer: PD-1 antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, any other chemotherapeutic drug or target To the treatment of the drug.
  • a method for preventing and/or treating a guanamine-2,3-dioxygenase-mediated disease comprising administering a compound of the formula (I) according to the first aspect to a patient Or the step of the pharmaceutical composition of the fourth or fifth aspect.
  • the indoleamine-2,3-dioxygenase mediated disease is cancer, the method further comprising administering to the patient an additional anticancer agent (also known as an antitumor drug, The steps of the antitumor drug as described above).
  • an additional anticancer agent also known as an antitumor drug, The steps of the antitumor drug as described above.
  • the compound of the formula (I) of the present invention has various pharmacological activities such as antitumor, treatment of neurodegenerative diseases (Alzheimer's disease), and anti-inflammatory.
  • the inventors have extensively and intensively studied, and for the first time, unexpectedly developed a novel compound containing a sulfamate and a 1,2,5-oxadiazole structure, which can be used as a highly potent IDO enzyme inhibitor for Prevention and/or treatment of indoleamine-2,3-dioxygenase mediated diseases can also be used as an anti-inflammatory drug.
  • the present invention has been completed.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group having from 1 to 10 carbon atoms, including straight-chain and branched hydrocarbon groups such as methyl (ie, CH 3 -), ethyl (ie, CH 3 CH 2 -).
  • n-propyl ie CH 3 CH 2 CH 2 -
  • isopropyl ie (CH 3 ) 2 CH-
  • n-butyl ie CH 3 CH 2 CH 2 CH 2 -
  • isobutyl ie (CH 3 ) 2 CHCH 2 -
  • sec-butyl ie (CH 3 )(CH 3 CH 2 )CH-
  • tert-butyl ie (CH 3 ) 3 C-
  • n-pentyl ie CH 3 ) CH 2 CH 2 CH 2 CH 2 -
  • neopentyl ie (CH 3 ) 3 CCH 2 -
  • the term includes a substituted or unsubstituted alkyl group.
  • substituted or unsubstituted means that the group may be unsubstituted or that H in the group is one or more (preferably 1-6, more preferably 1- Replaced by three substituents.
  • substituted or “substituted” means that the group has one or more (preferably 1-6, more preferably 1-3) substituents selected from the group consisting of: Halogen, hydroxy, -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
  • substituents selected from the group consisting of: Halogen, hydroxy, -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
  • cycloalkyl refers to a substituted or unsubstituted C 3 -C 12 cycloalkyl.
  • alkoxy refers to -O-alkyl, wherein the alkyl group can be saturated or unsaturated, can be branched, straight chain, or cyclic.
  • the alkoxy group has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy.
  • aryl refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms which has a monocyclic (eg phenyl) or fused ring (eg naphthyl) Or sulfhydryl), if the point of attachment is on the aromatic carbon, the fused ring may be non-aromatic (eg 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)-one-7 - base, etc.).
  • Preferred aryl groups include phenyl and naphthyl.
  • the term includes substituted or unsubstituted forms wherein the substituents are as defined above.
  • cycloalkyl refers to a cyclic alkyl group having from 3 to 10 carbon atoms having a single or multiple ring (including fused systems, bridged ring systems, and spiro ring systems).
  • one or more of the rings may be a cycloalkyl, heterocyclic, aryl or heteroaryl group as long as the attachment site is a ring through a cycloalkyl group.
  • suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroaryl refers to an aromatic group having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, such heteroaryl groups may be monocyclic Pyridyl Or a furyl group or a fused ring (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and/or contain a hetero atom as long as the point of attachment is through aromatic heteroaryl The atom of the base.
  • the ring atom nitrogen and/or sulfur of the heteroaryl group is optionally oxidized to an N-oxide (N-O), a sulfinyl group or a sulfonyl group.
  • N-O N-oxide
  • Preferred heteroaryl groups include pyridinyl, pyrrolyl, indolyl, thienyl and furanyl. The term includes substituted or unsubstituted heteroaryl.
  • substituted heteroaryl refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the group consisting of The same substituent as defined by the aryl group.
  • heterocycle or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, partially saturated or unsaturated group (but not aromatic), Has a single ring or a fused ring (including a bridged ring system and a spiro ring system having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring, in a fused ring system, one or more
  • the ring may be a cycloalkyl, aryl or heteroaryl group as long as the point of attachment passes through the non-aromatic ring.
  • the nitrogen and/or sulfur atom of the heterocyclic group is optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.
  • substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclic” as used herein refers to a heterocyclic group substituted by 1 to 5 (eg, 1 to 3) substituents.
  • the substituent is the same as the substituent defined by the substituted cycloalkyl group.
  • stereoisomer refers to a chiralally different compound of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • tautomer refers to an alternative form of a compound having a different proton position, such as an enol-ketone and an imine-enamine tautomer, or a tautomeric form of a heteroaryl group.
  • Prodrug refers to any derivative of an embodiment compound that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the Examples, or an active metabolite or residue thereof.
  • Particularly preferred derivatives and prodrugs are those which, when administered to a subject, increase the bioavailability of the compound of the example (eg, the compound administered orally is more readily absorbed into the blood) or the parent compound relative to the parent species
  • Derivatives and prodrugs to the bioregional compartment such as the brain or lymphatic system.
  • Prodrugs include the ester form of the compounds of the invention.
  • the term "compound of the invention” refers to a compound of formula (I), formula (II) or formula (III), a deuterated compound thereof, a racemate, a stereoisomer thereof or a mutual variation thereof.
  • the present invention relates to a racemic mixture of these compounds, enriched in a mixture of any one of the enantiomers, and any of the separated enantiomers.
  • the racemic mixture refers to a mixture of two R and S enantiomers of 50%: 50%.
  • the isolated enantiomer is understood to be the pure enantiomer (ie 100%) or highly enriched in an enantiomer (purity ⁇ 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%) , ⁇ 85%, ⁇ 80%) of the mixture.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof, or a prodrug thereof,
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 alkenyl group, a substituted or unsubstituted C 3 -C 10 alkynyl group, a substituted or unsubstituted C 6 -C 20 aryl group, a substituted or unsubstituted C 3 -C 14 heteroaryl group; R 1 and R 2 , or R 3 and R 4 may together form a three- to eight-membered carbocyclic ring or a three- to eight-membered heterocyclic ring, or that R 1 and R 3 together may form a five- to eight-membered carbocyclic ring or a five- to eight-membered heterocyclic ring.
  • the hetero atom may be sulfur, oxygen, NH
  • R 5 is C 6 -C 20 aryl, 5- or 6-membered heteroaryl; R 5 may be substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, hydroxy, amino, nitro, aldehyde, -CF 3 , -CN, -SF 5 , NR a R b , carboxy, -COR a , -CO 2 C 1 -C 6 alkyl, - CONR a R b , -S(O)R a , -S(O) 2 R a , -S(O)(NH)R a , -S(O)(NR d )R a , -SO 2 NR a R b , -P(O)Me 2 , -P(O)(OMe) 2 ; wherein each R a and each R b are independently hydrogen, substituted or unsubstitute
  • X is a single bond, O, S, NH or NR d ;
  • R d and R f are independently C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 14 heteroaryl;
  • n 2 to 8.
  • substitution refers to the group having one or more substituents selected from: halogen, hydroxy, -NH 2, nitro, -CN, C 1 -C 4 alkyl, C 1- C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
  • X is NH
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl; R 3 and R 4 may together form a three to eight membered ring or a three to eight membered impurity.
  • a ring wherein the hetero atom can be sulfur, oxygen, NH or NR f .
  • n is from 2 to 6.
  • R 3 is hydrogen
  • R 4 is hydrogen
  • the compound of formula (I) is:
  • Ar is a benzene ring, and Ar may be substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, amino, nitro, aldehyde, -CF 3 , -CN, -SF 5 , NR a R b , carboxyl group, -COR a , -CO 2 C 1 -C 6 alkyl group, -CONR a R b , -S(O)R a , -S( O) 2 R a, -S ( O) (NH) R a, -S (O) (NR d) R a, -SO 2 NR a R b;
  • R a , R b , R d , R 3 , R 4 , R 2 and R 1 are as defined above;
  • n 2-6.
  • R 1 is H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 10 heteroaryl; R 1 It may be substituted by one or more halogens.
  • R 1 is C 1 -C 10 alkyl
  • R 2 is H, C 1 -C 10 alkyl
  • R 3 and R 4 are each independently hydrogen, C 1 -C 10 alkyl or R 3 and R 4 may together form a three to eight membered carbocyclic ring or a three to eight membered heterocyclic ring.
  • R 1 , R 2 , R 3 , and R 4 are each independently H.
  • the compound of the formula (I) is as shown in the formula (III),
  • R 1 , R 2 , R 3 , R 4 , n and Ar are as described above;
  • Y is R 6 , OR 6 , NR a R b ;
  • R 6 is a substituted or unsubstituted C 6 -C 20 aryl group, a substituted or unsubstituted five- or six-membered heteroaryl group, a substituted or unsubstituted C 1 a -C 12 alkyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 3 -C 12 heterocyclic group, wherein the hetero atom may be sulfur, oxygen, NH or NR f ;
  • R a and each R b are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 alkenyl a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 3 -C 14 heteroaryl group; R a and R b may together form a three to eight membered ring or a four to eight membered heterocyclic ring.
  • the hetero atom may be sulfur, oxygen, NH or NR f ; Nf is as defined above.
  • substituted means having one or more substituents selected from the group consisting of halogen, hydroxy, -NH 2, nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkane A C 1 -C 4 alkoxy group, a C 3 -C 6 cycloalkyl group, a C 2 -C 4 alkenyl group, a C 2 -C 4 alkynyl group, a phenyl group, a benzyl group.
  • the invention includes all stereoisomers of the compound.
  • the invention includes all tautomers of the compounds.
  • the invention also includes deuterated compounds resulting from the substitution of any one or more of the hydrogen atoms of the compound by its stable isotope oxime.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient in a safe and effective amount, And a pharmaceutically acceptable carrier.
  • the "active ingredient” as used in the present invention means a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, or a prodrug thereof.
  • the "active ingredient" and pharmaceutical compositions described herein are useful as IDO inhibitors.
  • a medicament for the preparation and prevention or/or treatment of a tumor is prepared.
  • a medicament for the preparation of a disease preventing and/or treating IDO mediated diseases is prepared.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • the compounds of the preferred embodiments of the invention may be administered as separate active agents or in combination with one or more other agents useful in the treatment of cancer.
  • the use of the compounds of the preferred embodiments of the invention in combination with known therapeutic agents and anticancer agents is also effective, and combinations of currently known compounds with other anticancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents can be found in the Cancer Principles and Practice of Oncology, VT Devita and S. Hellman (editor), 6th edition (February 15, 2001), published by Lippincott Will iams & Wilkins. Society. One of ordinary skill in the art will be able to discern effective combinations of agents based on the particular nature of the drug and the cancer involved.
  • Such anticancer agents include, but are not limited to, HDAC inhibitors, estrogen receptor modulators, androgen receptor modulators, retinol receptor modulators, cytotoxic/cytostatic agents, anti-proliferative Agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signal inhibitors, apoptosis inducers, and cell cycle checkpoints Reagent, CTLA4 antibody, PD-1 antibody, PD-L1 antibody, and the like.
  • the compounds of the preferred embodiments are also effective when administered concurrently with radiation therapy.
  • the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any of the accepted modes of administration of agents having similar effects.
  • the actual amount of the compound (i.e., active ingredient) of the preferred embodiment is determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors. .
  • the drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.
  • the therapeutically effective dose can generally be the total daily dose administered to the patient in a single or divided dose, for example, from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about daily. 30 mg / kg body weight.
  • a Dosage unit composition can include its dosage factor to form a daily dose. The choice of dosage form will depend on various factors such as the mode of administration and the bioavailability of the drug substance.
  • the compounds of the preferred embodiments can be administered as a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous). Or subcutaneous).
  • the preferred mode of administration is oral, and a convenient daily dose can be adjusted depending on the degree of bitterness.
  • the compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions.
  • Another preferred mode of administration of the preferred embodiment compounds is inhalation. This is an effective method of delivering a therapeutic agent directly to the respiratory tract (see, e.g., U.S. Patent No. 5,607,915).
  • Suitable pharmaceutically acceptable carriers or excipients include, for example, treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • the liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Preferred liquid carriers, particularly carriers for injectable solutions include water, saline, aqueous dextrose and ethylene glycol.
  • Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.
  • pharmaceutically acceptable salt refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ by final isolation and purification of the compound of formula I, or by separately reacting a suitable organic or inorganic acid or base with a basic or acidic functional group.
  • Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sul
  • the nitrogen-containing basic group can be quaternized by the following reagents: alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide; dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Base halides such as benzyl and phenethyl bromide. A water soluble or oil soluble or dispersible product is thus obtained.
  • alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide
  • dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate
  • long chain halides
  • Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid.
  • the base addition salt can be prepared in situ upon final isolation and purification of the compound of formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a hydroxide, carbonate or carbonate of a pharmaceutically acceptable metal cation. Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including However, it is not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • the term "pharmaceutically acceptable prodrug” refers to a prodrug of a compound of those preferred embodiments, which is rapidly converted in vivo to a parent compound of the above formula, for example, hydrolyzed in blood.
  • pharmaceutically acceptable prodrug refers to a prodrug of a compound of those preferred embodiments, which is rapidly converted in vivo to a parent compound of the above formula, for example, hydrolyzed in blood.
  • the compound of the present invention can be used as a highly potent IDO enzyme inhibitor
  • the synthesis method is mild, the operation is simple and easy, the yield is high, and the derivatization is easy, and it is suitable for industrial scale production;
  • Propyl cyanohydrin (32.0 g, 485 mmol) was dissolved in 600 mL of water and heated to complete dissolution. Under ice cooling, sodium nitrite (38.0 g, 533 mmol) and 6N hydrochloric acid (5.5 mL) were added. Under the ice bath After reacting for 0.5 hour, the mixture was heated to room temperature for 2 hours. The reaction solution was cooled in an ice bath, and a 50% aqueous solution of hydroxylamine hydrochloride (99.0 g, 1500 mmol) was added dropwise to the reaction mixture, stirred for half an hour, and then allowed to react to room temperature for 1 hour. The reaction was heated to reflux for 2 hours.
  • the compound L (60 mg, 0.13 mmol) was dissolved in 2 mL of tetrahydrofuran, and 0.5 mL of a 2N sodium hydroxide solution was added thereto in an ice bath, and the mixture was reacted at room temperature for 1 hour, and the pH was adjusted to 4-5 with 2N hydrochloric acid. The mixture was extracted with EtOAc (3 mL).EtOAc.
  • Example 3 Compound K (50 mg, 0.13 mmol) was reacted with ethylamine sulfonyl chloride according to the procedure of Example 2, and then hydrolyzed to afford Example 3 as a white solid.
  • Example 4 (50 mg, 0.13 mmol) was reacted with isopropylaminosulfonyl chloride according to the procedure of Example 2, and then hydrolyzed to afford Example 4 as a white solid.
  • the first step 2,2-dimethoxyethanol (50 mg, 0.47 mmol) was dissolved in 3 mL of dichloromethane, and ice-cooled, sodium hydrogen (38 mg, 0.94 mmol) was added. After stirring for half an hour, slowly add two. Methylaminosulfonyl chloride (138 mg, 0.94 mmol) was stirred at room temperature for 4 hr, then concentrated, evaporated, evaporated, evaporated, evaporated Product M of a white solid.
  • the second step compound M (53 mg, 0.16 mmol), triethylsilane (125 uL, 0.78 mmol), methanesulfonic acid (80 uL, 1.23 mmol) was dissolved in 5 mL of dichloromethane, then iced, 4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl) 1,2,4-oxazolidine-5(4H)-one (50 mg , 0.23 mmol), slowly rose to room temperature for 9 hours. The aqueous sodium hydrogencarbonate solution was adjusted to pH 7, and then washed with water and a saturated NaCI solution, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column, and the mobile phase was 3:1 to 1:1 n-hexane/ethyl acetate. 50 mg of product N as a white solid.
  • the third step the compound N (50 mg, 0.10 mmol) was dissolved in 3 mL of tetrahydrofuran, then ice-cold, 0.5 mL of 2N sodium hydroxide solution was added, and the reaction was slowly warmed to room temperature for 3 hours, then the reaction mixture was concentrated under reduced pressure, and ethyl acetate was added. The ester and water were added to the concentrate, and the organic phase was separated by stirring. The organic phase was dried with MgSO 4 and evaporated. 25 mg of product as a white solid.
  • the compound NN (500 mg, 1.46 mmol) was added to the reaction flask, and trifluoroacetic acid (5.0 mL) and aqueous hydrogen peroxide (5 mL) were added at room temperature, and the mixture was heated at 60 ° C for 12 hours, and the starting materials disappeared, and ethyl acetate was added. (20 mL) and water (20 mL), EtOAc (EtOAc)EtOAc. Concentrated by filtration to give crude compound (500 mg, 91% yield)
  • the target compound was obtained.
  • the IDO gene was amplified by PCR, and the amplified PCR product was recovered. Then, the pET28a plasmid (purchased from Shanghai Baoman Biotechnology Co., Ltd.) and the IDO gel recovery product were digested with EcoR I and Xho I restriction enzymes. (37 ° C, digestion 2h), running gelatin, recovery, T4 ligase linkage overnight ligation product added to DH5 ⁇ competent state, placed on ice for 30min, 42 °C heat shock 90s, shaken plate, pick monoclonal, PCR identification , sequencing identification, all correct, that is, the pET28a-IDO plasmid was successfully constructed.
  • the constructed BL21 containing the pET28a-IDO plasmid was shaken at 37 ° C to an OD 600 of 0.6-0.8, and added to a final concentration of 7 ⁇ M hemin and 1 mM IPTG (isopropyl- ⁇ -D-thio Galactoside was induced at 28 ° C for 4 h; after induction, the cells were collected by centrifugation at 6000 ° C at 4 ° C, and the collected cells were washed once with 20 mM PBS (pH 6.5), and the cells were collected by centrifugation.
  • IPTG isopropyl- ⁇ -D-thio Galactoside
  • the collected cells were resuspended with lysate (20 mM PBS pH 6.5), sonicated (40% lysis for 20 min, placed on ice), and the lysed bacteria were centrifuged at 13,000 rpm for 15 min, the precipitate was discarded, and the supernatant was retained.
  • the nickel column was equilibrated with lysate (20 mM PBS pH 6.5) for 3 column volumes, and then the lysed supernatant was applied to a nickel column. After loading, it was washed with a rinse solution (20 mM PBS pH 6.5, 20 mM imidazole).
  • the compound was firstly diluted 3-fold, and 1 ⁇ L of each concentration was added to a 96-well plate; 50 ⁇ L of the formulated IDO enzyme solution (final concentration 600 ng/100 ⁇ L) was added: 25 ⁇ L of the substrate 1 mixed solution was added, and 25 ⁇ L of the substrate was added. The mixed solution initiates the reaction. The final OD 321 nm reading was 60 min.
  • Hela cells (100 ⁇ L) were seeded in 96-well plates in an amount of 5 ⁇ 10 3 per well and grown overnight. On the next day, after the compound was diluted, 1 ⁇ L was added to a 96-well plate, and then 100 ⁇ L of a medium containing human interferon ⁇ (final concentration: 50 ng/mL) was added to a 96-well plate to give a final volume of 200 ⁇ L. After 48 hours of incubation, 140 ⁇ L of supernatant from each well was transferred to a new 96-well plate. 10 ⁇ L of 6.1 N trichloroacetic acid was added to each well and mixed at 50 ° C for 30 minutes.
  • test results of the IDO enzyme inhibitory activity and the cell inhibitory activity of the compound of the present invention are shown in Table 1.
  • the gavage administration was formulated as a suspension in 1% MC and intravenously in DMSO: 30% PEG400 (5:95). Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • Administration by intragastric administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 5 min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h;
  • venous blood was taken from the posterior venous plexus of the rat eye, placed in an EDTA-2K test tube, centrifuged at 11,000 rpm for 5 min, and the plasma was separated and frozen in a refrigerator at -20 °C.
  • the concentration of the compound of Example 1 in rat plasma was determined by LC/MS/MS method.
  • the peak concentration C max and T max is time to peak found
  • AUC 0-t value calculated by the trapezoidal method;
  • AUC 0- ⁇ AUC 0-t + C t / k e ,
  • C t is the blood concentration of the last measurable time point,
  • k e is Eliminate the rate constant;
  • Average residence time MRT AUMC / AUC.
  • Absolute bioavailability F (AUC gavage ⁇ D vein ) / (AUC vein ⁇ D gavage ) ⁇ 100%
  • each animal took about 25 ⁇ L of blood through the eyelids, and EDTAK 2 was anticoagulated.
  • the time of collection was: before administration of the test substance (0 hr) and after administration of the test substance for 15 min, 30 min, 1 h, 2 h, 4h, 6h, 8h and 24h.
  • Blood samples were collected and placed on ice, and plasma was centrifuged within 1 hour (centrifugation conditions: 5000 rpm, 10 minutes, 4 ° C). The collected plasma was stored at –20 °C prior to analysis.
  • the data acquisition and control system software is Analyst 1.5.1 software (Appl ied Biosystem).
  • the peak integration method of the spectrum sample is automatic integration; the ratio of the peak area of the sample to the peak area of the internal standard is used as an index, and the concentration of the sample is used for regression. Regression mode: linear regression, the weight coefficient is 1/X 2 .
  • Pharmacokinetic parameters were analyzed by non-compartmental model analysis using WinNonl in Professional v6.3 (Pharsight, USA).
  • C max is the measured maximum blood concentration, and the area under the blood concentration-time curve AUC (0 ⁇ t) is calculated by the trapezoidal method, and T max is the peak time of the blood drug concentration after administration.
  • the pharmacokinetic study of the compound of Example 1 after oral administration (dose of 30.0 mg/kg) in ICR mice showed that the average peak time of the blood concentration of the compound of Example 1 in mice was 0.25 hr.
  • the peak concentration was 809.3 ⁇ 254ng/mL
  • AUC 0 ⁇ t was 982 ⁇ 151hr*ng/mL
  • the average residence time in MRT was 6.76 ⁇ 4.13hr.
  • the concentration of the compound of Example 1 administered to ICR mice at various time points in plasma (PO, 30 mg/kg) is shown in Table 6.
  • the pharmacokinetic parameters after administration were calculated using the WinNonlin V6.3 non-compartment model.

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Abstract

La présente invention concerne un ester d'acide sulfamique utilisé comme inhibiteur de l'indoleamine-2,3-dioxygénase, son procédé de préparation et une utilisation associée. La structure de l'inhibiteur de la présente invention est représentée par la structure générale I, dans laquelle les définitions de X, R1, R2, R3, R4, R5 et n sont présentées dans la description et les revendications. L'invention concerne également un procédé de préparation de l'inhibiteur. Le composé de formule générale I de la présente invention peut être utilisé comme inhibiteur de l'indoleamine-2,3-dioxygénase dans la préparation d'un médicament destiné à prévenir et/ou à traiter des maladies à médiation par l'indoleamine-2,3-dioxygénase.
PCT/CN2017/072730 2016-01-28 2017-01-26 Ester d'acide sulfamique utilisé comme inhibiteur de l'indoleamine-2,3-dioxygénase, son procédé de préparation et utilisation associée Ceased WO2017129139A1 (fr)

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CN109678813A (zh) * 2017-10-18 2019-04-26 中国科学院上海有机化学研究所 吲哚胺-2,3-双加氧酶抑制剂盐及其制备方法
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