WO2017160069A1 - Nouveau dérivé de benzènesulfonamide et utilisation associée - Google Patents

Nouveau dérivé de benzènesulfonamide et utilisation associée Download PDF

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WO2017160069A1
WO2017160069A1 PCT/KR2017/002765 KR2017002765W WO2017160069A1 WO 2017160069 A1 WO2017160069 A1 WO 2017160069A1 KR 2017002765 W KR2017002765 W KR 2017002765W WO 2017160069 A1 WO2017160069 A1 WO 2017160069A1
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Prior art keywords
dimethyl
oxo
isopropyl
pyrazol
benzenesulfonamide
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PCT/KR2017/002765
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English (en)
Korean (ko)
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김성훈
한균희
양지선
이철호
김재현
정길수
한정민
김종현
Original Assignee
재단법인 의약바이오컨버젼스연구단
연세대학교 산학협력단
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Publication of WO2017160069A1 publication Critical patent/WO2017160069A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/42—Benzene-sulfonamido pyrazoles
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone

Definitions

  • the present invention relates to a novel benzenesulfonamide derivative or a pharmaceutically acceptable salt thereof and its use, and more particularly, to a novel benzenesulfonamide derivative having an inhibitory effect of mTORCl (Mammal i an target of rapamycin complex 1) and Its active ingredients include cancer, epilepsy, inflammatory diseases, immune diseases, diabetes, obesity, respiratory obstructive diseases, fibrosis, Pompe disease, lysosomal storage di sease, Alzheimer's disease, Parkinson's disease and Huntington's disease. It relates to a pharmaceutical composition for the prevention or treatment of any one disease selected from the group consisting of neurodegenerative diseases such as, cardiovascular diseases and parasitic infections.
  • neurodegenerative diseases such as, cardiovascular diseases and parasitic infections.
  • Amino acids not only serve as raw materials for protein synthesis, but also act as nutrients that regulate protein metabolism.
  • the activity of amino acids available intracellularly is mediated by mTORCl (mechani st ic target of rapamycin com lex 1).
  • MTORCl regulates various cellular reactions such as protein synthesis, autophagy, and cell growth, as well as cancer. It is also closely related to various human diseases such as obesity, diabetes, neurodegeneration (Guert in and Sabat ini, 2005; Zoncu et al., 2011; Lap 1 ante and Sabat ini, 2012; Oddo, 2012).
  • MTOR also known as FRAP (FKBP12 and rapamycin related proteins)
  • FRAP FKBP12 and rapamycin related proteins
  • This protein consists of C—terminal kinase domain, FKBP12-rapamycin binding domain, 20 N-terminal HEAT repeats involved in protein-protein interactions, FAT (FRAP— ATM-TRRAP) domain, and Several domains, including C-terminal FAT domains, also present in other PIKKs (Wul l schleger et al. (2006) Cel l, 124, 471-484).
  • mTOR kinases are central regulators of cell growth and proliferation and play an important role in cell metabolism and angiogenesis. mTOR is activated by the PI3K / Akt axis, which in turn is the downstream effector of the PI3K / Akt signaling pathway, especially cellular proteins. It phosphorylates two major regulators of the translation machinery, ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein (4E-BP1) (mTOR signaling pathways are described in Zoncu et al. (2011) Nature Rev. MoL Cel l Biol. 12, 21-35).
  • S6K1 ribosomal protein S6 kinase
  • 4E-BP1 eukaryotic initiation factor 4E binding protein
  • mTOR signaling pathways are mutated and degenerated in various human cancers, protein kinase Akt, mutation of lipid kinase PI3K and / or inactivation of tumor suppressor PTEN and TSC2 and proliferation and / or mutations affecting growth factor receptors are several events in the upstream of mTOR that result in constitutive inactivation of the PI3K / Akt / mT0R pathway and unregulated cell proliferation. (For a review of the role of protein mTOR in cancer, see Guert in and Sabat lni ( 2007) See Cancer Cel l 12, 9-22).
  • mTOR pathway Genetic mutations and amplifications affecting the mTOR pathway include glioblastoma, prostate cancer, nodular carcinoma, lung cancer (NSCLC), breast cancer, ovarian cancer, endometrial cancer, colon cancer, pancreatic cancer, head and neck cancer, skin cancer and hepatocellular carcinoma. Yuan and Cant ley (2008) Oncogene 27, 5497-5510; Whit taker et al. (2010) Oncogene 29, ' 4989-5005). mTOR employs several collaborators to form two multi-protein complexes essential for tumor growth.
  • the mTORCl complex makes a link between tumor gene signaling and protein synthesis, glycolysis, and lipid biosynthesis (Yecies and Ma ⁇ ing (2011) J ⁇ Mol. Med. 89, 221-228 .
  • the mT0RC2 complex has recently been identified as a kinase that phosphorylates Akt on the Ser-473 residue, acting as an essential activator of the kinase Akt.
  • the role of the complex mT0RC2 has recently been found to be particularly linked to cellular changes (Sparks and Guert in (2010) Oncogene 29, 3733-3744).
  • RCC renal cell carcinoma
  • the efficacy of rapalog in the treatment of cancer is less than expected, despite certain promising results. This restriction is due to the fact that the rapalog does not interact with the mT0RC2 complex and that certain aspects of mTORCl complex activity and in particular the phosphorylation of 4E-BP1 is resistant to rapamycin and its analogs. Benjamin et al, (2011) Nature Reviews Drug Discovery 10, 868-880.
  • inhibitors of mTOR kinase sites are devoid of these drawbacks (Feldman et al. (2009) PLoS Biology 7, 371-383), and are recognized as new generation mTOR pathway modulators, which have the potential to increase anticancer activity and broader therapeutic potential. . this has coverage though some of the dogs are currently being clinically tested (Garcia-Echeverria (2011) Biochem Soc Trans 39, 451-455; Richard et al (2010) Curr Drug Opinion Disc Dev. 13, 428—440. Other potential therapeutic indications have been proposed for mTOR inhibitors (Tsang et al. (2007) Drug Discovery Today 12, 112-124).
  • mTOR inhibitors may have neuroprotective effects in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease (Bov'e et al. (2011) Nature Reviews Neuroscience 12, 437-452).
  • mTOR overactivity is associated with age-related diseases (Harrison et al. (2009) Nature 460, 392), and other tropisms are renal, lung and liver fibrosis (Mehrad et al. (2009) Int. J. Biochem Cell Biol. 41, 1708-1718; Lieberthal and Levi ne (2009); Shouval (2011)), inflammatory and autoimmune diseases (Bhonde et al. (2008) Am. J. Physiol. Gastrointest. Liver Physiol.
  • mTOR inhibition also activates autophagy and causes certain diseases, especially metabolic and renal Mildly degenerative white-, bacterial and viral infections and cancers are sensitive to their inhibition (review in Rubinsztein et al. (2007) Nature 6, 304-312).
  • mTORCl regulates various upstream signals such as cell growth, protein synthesis, and growth factor regulation.
  • Tuberous Scleros is Complex (TSC) which transfers growth factors and energy signals to mTORCl, is a GTPase-activating protein (GAP) for Ras ike smal l GTPase, Rheb, and Rheb Negatively regulate mTORCl by promoting GTP hydrolysis of
  • Rheb can migrate to late endosomes / lysosomes and is required for mTORCl activation induced by amino acids.
  • Rag GTPases and Ragul ator compl ex act as amino acid inducible docking sites for mTORCl.
  • Mammals express four Rag GTPases (RagA, RagB, RagC, RagD).
  • Rag GTPases essentially form heterodimers of RagA / C or RagB / D to mediate amino acid-induced mTORCl activation.
  • everol imus an allosteric inhibitor of mTOR
  • has the effect of treating a carcinoma with a change in mTOR signal its resistance is shown.
  • Acquireable resistance due to activation of the mTOR mutation inhibits everol imus binding to mTOR.
  • the FRB domain, S2035, in mTOR is essential for FKBP12—rapamycin to bind, and mutations in this position result in rapamycin resistance.
  • a clear understanding of the mechanism of achievable resistance could be used in the development of new therapeutics to combat mutations that are resistant to mTOR inhibitors.
  • aminoacyl-tRNA-synthetases ARSs
  • ARSs aminoacyl-tRNA-synthetases
  • ARS promotes the binding of amino acids to the tRNA being treated. To maintain protein homeostasis, ARS must sensitize amino acid availability.
  • Leucine-tRNA-synthetase functions as a leucine sensor for mTORCl activation by interacting with RagD GTPase and acting as a GAP for RagD GTPase. Therefore, if LRS detects a substance that inhibits its function as a leucine sensor without affecting the original function of binding leucine to tRNA, it inhibits the binding of LRS and RagD to inhibit the activation of mTORCl. Inhibition and consequently will have an effect on potential therapeutic sympathy for mTOR inhibitors.
  • an object of the present invention is to provide a compound represented by the following Chemical Formula 1 To provide acceptable salts: [Formula 1]
  • R 1 is substituted or unsubstituted phenyl; Halo; Or when straight or branched d—C 6 alkyl and R 1 is substituted phenyl the substituents are straight or substituted with a halogen atom, unsubstituted straight or branched d—C 6 alkyl and one or more halogen atoms or Branch type
  • C Ce alkyl is hydrogen; Or straight or branched d-Cs alkyl,
  • R 3 is hydrogen; Substituted or unsubstituted d-Cs straight or branched alkyl; C 5 -C 10 cycloalkyl; Substituted or unsubstituted C 5 -C 20 aryl; Dioxoanthracenyl; Or a heterocyclic ring or heteroaryl ring having one or more heteroatoms in the ring, where these substituents are linear or branched C 6C 6 alkyl; - (: 6 alkyloxy; d- C 6 alkyl, d- C 6 alkyloxy optionally substituted with amino group; substituted by morpholinyl d- C 6 alkyloxy; d- C 6 alkyloxy carbonyl Brassica; hydroxy-carbonyl d- C 6 alkyl; d-Cs alkyl substituted with one or more fluoro atoms; CrCs alkylamino; phenyl; straight or branched dC 6 alkyl,
  • R 2 and R 3 combine with each other to form a C 5 ⁇ C 20 hetero ring or heteroaryl ring containing one or more hetero atoms in the ring.
  • Another object of the present invention to provide a method for preparing a benzenesulfonamide derivative represented by the formula (1), another object of the present invention comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient
  • a pharmaceutical composition for the prevention or treatment of cancer another object of the present invention by administering to a subject in need of an effective amount to a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof cancer-related diseases
  • Another object of the present invention to provide a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of an anticancer agent.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 is substituted or unsubstituted phenyl; Halo; Or when straight or branched Ci-Cg alkyl and R 1 is substituted phenyl the substituents are straight or branched, substituted by halogen atoms, unsubstituted straight or branched d-Ce alkyl and one or more halogen atoms
  • R 2 is hydrogen; Or straight or branched dC 6 alkyl,
  • R 3 is hydrogen; Substituted or unsubstituted d— C 6 straight or branched alkyl; C 5 — C 10 cycloalkyl; Substituted or unsubstituted C 5 — C 20 aryl; Dioxoanthracenyl; Or a heterocyclic ring or heteroaryl ring having one or more heteroatoms in the ring, where these substituents are linear or branched dC 6 alkyl; dC 6 alkyloxy; d— C 6 alkyloxy substituted with d-alkyl amino group; DC 6 alkyloxy substituted with morpholine; d— C 6 alkyloxycarbonyl; Hydroxycarbonyl Cr ′′ C 6 alkyl; CrCs alkyl substituted with one or more fluoro atoms; d_C 6 alkylamino; phenyl; straight or branched d—C 6 alkyl, straight or branched Ci— C 6 Pheny
  • the present invention provides a method for preparing a benzenesulfonamide derivative represented by Formula 1.
  • the present invention provides a compound represented by Formula 1 or It provides a pharmaceutical composition for the prevention or treatment of cancer comprising a pharmaceutically acceptable salt as an active ingredient.
  • the present invention provides a method for treating cancer-related diseases by administering to a subject in need thereof an effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of an anticancer agent.
  • the present invention will be described in detail.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 is substituted or unsubstituted phenyl; Halo; Or when straight or branched d—C 6 alkyl and R 1 is substituted phenyl the substituents are straight or substituted with a halogen atom, unsubstituted straight or branched d—C 6 alkyl and one or more halogen atoms or Branch type One or more selected from the group consisting of Ci-C 6 alkyl, R 2 is hydrogen; Or straight or branched d—C 6 alkyl,
  • R 3 is hydrogen; Substituted or unsubstituted dC 6 straight or branched alkyl; rC 10 cycloalkyl; Substituted or unsubstituted C 5 -C 20 aryl; Dioxoanthracenyl; Or a heterocyclic ring or heteroaryl ring having one or more heteroatoms in the ring, where these substituents are linear or branched dC 6 alkyl; dC 6 alkyloxy; d- C 6 a d- C 6 alkyloxy optionally substituted with an alkyl group; C— C 6 alkyloxy substituted with morpholine; d— C 6 alkyloxycarbonyl; Hydroxycarbonyl d—C 6 alkyl; D—C 6 alkyl substituted with one or more fluoro atoms; C 6 alkylamino; Phenyl; Group consisting of straight or branched C r -C 6 alkyl, straight or
  • the sing-groups R 2 and R 3 combine with each other to form a C 5 — C 20 hetero ring or heteroaryl ring containing one or more hetero atoms in the ring.
  • Alkyl 'means an aliphatic hydrocarbon group that may be straight or branched, containing from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups include from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups include about 1, 2, 3, 4, 5 or 6 carbon atoms in the chain, the side chains comprising one or more lower alkyl groups such as methyl, Ethyl or propyl linear alkyl chain It means attached to. "Loweralkyl”'means a group having from about 1 to about 6 carbon atoms in the chain, which may be straight or branched, "alkyl” means one or more, which may be unsubstituted, or may be the same or different.
  • each substituent may be halogen, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, carboxy, etc.
  • alkyl is butyl or isobutyl Can be.
  • Aryl means an aromatic hydrocarbon ring system, examples of which include phenyl, indenyl, indanyl, naphthyl and fluorenyl, and may preferably be (6C) aryl,
  • Halogen may include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom or a brom atom.
  • Cycloalkyl 'otherwise means a saturated hydrocarbon ring.
  • Heteroaryl is an aromatic cycloalkyl (also referred to as heteroaryl) in some embodiments of a compound of Formula (II) with a heteroatom, wherein one to four of the ring carbon atoms are selected from solvates consisting of 0, S and N Or non-aromatic cycloalkylide-, in some embodiments, the heterocyclyl group contains 3 to 10 ring members, while such other groups include 3 to 5, 3 6, or 3 to 8 ring members Hold them. Heterocyclyl may also be combined with other groups at any ring atom (ie, heterocarbon ring any carbon atom or heteroatom). Heterocycloalkyl groups can be substituted or unsubstituted.
  • Heterocyclyl groups include unsaturated, partially saturated and saturated ring systems such as midazolyl, imidazolinyl and imidazolidinyl groups.
  • the term hyterocyclyl includes fused ring species, eg, fused aromatic and non-aromatic groups, for example benzotriazolyl, 2, 3—dihydrobenzo [1,4] dioxynyl and Benzo [1, 3] dioxolyl.
  • the term also includes, but is not limited to, crosslinked polycyclic ring systems containing heteroatoms such as quinuclidyl.
  • heterocyclyl group examples include aziridinyl, azetidinyl, pyridyl, imidazolidinyl, pyrazole lidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thio Phenyl, pyrillyl, pylinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, Isothiazolyl, thiadiazolyl, oxadiazolyl, pyreridyl, piperazinyl, morpholinyl, thiomorpholinyl tetrahydropyranyl (eg, tetrahydro-2H-pyranyl),
  • a "cycloalkylalkyl group” is a radical of the general formula -alkyl ⁇ cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
  • the cycloalkylalkyl group is an alkyl, cyclo Alkyl, or both alkyl and cycloalkyl moieties .
  • Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclonuxylethyl, and cyclonuxylpropyl No.
  • substituents include the exemplary compounds and embodiments disclosed herein. Examples of which can be found, and halogens (chloro, urethral, bromo or fluoro groups); alkyl; hydroxyl; alkoxy; al Sialic keel; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; INC Min; aminocarbonyl; acylamino; phosphonate Nei Sat; PO Spin; Thiocarbonyl; Sulfonyl; Sulfone; Sulfonamides; Ketones; Aldehydes; ester; Urea; urethane; Oxime; Hydroxyl amines; Alkoxyamines; Aralcoxiamine; N-oxides; Hydrazine; Hydrazide; Hydr
  • straight or branched dC 6 alkyl d— C 6 alkyloxy; dC in 6 alkylamino group value hwandoen dC 6 alkyloxy; D-Cs alkyloxy substituted with morpholine; d— C 6 alkyloxycarbonyl; Hydroxycarbonyl d—C 6 alkyl; DC 6 alkyl substituted with one or more fluoro atoms; dC 6 alkylamino; Phenyl; Straight or branched dC 6 alkyl, straight or branched d—C 6 alkyloxy, straight or branched dC 6 alkyloxycarbonyl, halogen or alkyl substituted with one or more fluoro atoms Phenyl substituted with one or more substituents selected from; Phenoxy; Phenoxy substituted with one or more substituents selected from the group consisting of straight or branched d—C 6 alkyl, halogen atoms and straight
  • the compound of Formula 1 may be selected from the following.
  • N1-cyclonuclear chamber 4 ⁇ isopropyl -2,3-dimethyl- 5-oxo-pyrazol-l-yl) benzenesulfonami
  • NI (3, 5-dimethoxyphenyl) -4— (4-isopropyl-2, 3-dimethyl-5-oxo-pyrazol- 1-yl) benzene sulfonamide;
  • N-cycloheptyl-4- (4—isopropyl-2, 3—dimethyl— 5—oxo—pyrazole— 1—yl) benzenesulfonami 4- (4 isopropyl— 2, 3—dimethyl-5—oxo-pyrazol— 1-yl) — N— [3- (trifluoromethyl) phenyl] benzenesulfonamide;
  • benzyl-4- (4—isopropyl-2, 3-dimethyl— 5-oxo-pyrazol-1—yl) benzenesulfonamide; methyl 2— [[4- (4-isopropyl-2, 3— dimethyl-5-oxo-pyrazol-1- yl) phenyl] sulfonyl amino furnace; - eu 2-phenyl-acetate;
  • N1 [2— (3, 5-dimethylphenoxy) ethyl] -4- (4-isopropyl— 2, 3-dimethyl— 5-oxo-pyrazol one 1-yl) benzenesulfonamide; 4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) - ⁇ 'propyl-benzenesulfonamide;
  • Methyl 6 (4- (4-isopropyl— 2, 3-dimethyl-5—oxo-2, 5-dihydro-1H-pyrazol-1-yl) phenylsulfonamido) -2 ⁇ naphthoate;
  • the benzosulfonamide derivatives of Formula 1 of the present invention may be used in the form of pharmaceutically acceptable salts.
  • Acid salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful as such salts.
  • Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, Aspartic acid, maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid and the like can be used.
  • the benzosulfonamide derivatives of the general formula (I) of the present invention may include not only pharmaceutically acceptable leathers, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
  • the present invention provides a method for preparing a benzosulfonamide derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. Method for producing a derivative of formula 1 according to the present invention as shown in Scheme 1
  • R1, R2, and R3 are as defined in Chemical Formula 1. Since the benzosulfonamide derivatives or pharmaceutically acceptable salts thereof of the present invention exhibit the effect of inhibiting the activity of mTOR by inhibiting the binding between LRS and RagD, it is possible to prevent various diseases in which the therapeutic effect is achieved by inhibiting mTOR. Or can be treated.
  • Non-limiting examples of diseases in which the therapeutic effect is achieved by inhibiting the mTOR in the present invention is cancer, epilepsy, inflammatory diseases, immune diseases, diabetes, obesity, respiratory obstructive diseases, fibrosis, pamp disease, lysosomal accumulation disease (lysosomal storage di sease), neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, cardiovascular disease / and / or parasitic infections, preferably cancer or epilepsy.
  • the compounds of the present invention have a very good effect of inhibiting the activity of mTORCl, which is known to be highly active in cancer cells, and exhibit cytotoxicity against various cancer cells, while It was confirmed that no cytotoxicity was observed for the cells.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the benzosulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention is to treat a cancer-related disease by administering to a subject in need of a benzosulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof Provides a way to do it.
  • the cancer provides a method characterized in that the cancer showing rapamycin resistance, the present invention also provides a use for the production of an anticancer agent of the benzosulfonamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof .
  • the cancer provides a use for the manufacture of a therapeutic agent, characterized in that the cancer showing rapamycin resistance,
  • LRSC leucyl tRNA synthetase functions as a key mediator of amino acid signaling to mTORCl. That is, LRS binds directly to Rag GTPase, an amino acid dependent signaling medium for mTORCl, and acts as a GTPase-act ivat mg protein (GAP) for Rag GTPase, thereby activating mTORCl.
  • GAP GTPase-act ivat mg protein
  • LRS Leucyl tRNA synthetase plays an important role in the activation of mTORCl derived from amino acids, so that LRS senses intracellular leucine concentrations and affects the activation of mTORCl derived from leucine.
  • Rag protein belongs to Rag subfami ly of Ras smal l GTPase and there are four kinds of RagA, RagB, RagC and RagD, of which A and B are orthologs of yeast Gtrlp GTPase and C and D are East's Gtr2p ortholog.
  • RagD combines with A or B to form a dimer and mediates mTORCl activity by amino acids. (Trends in Biochemi cal Sciences, 33: 565-568, 2008). Therefore, inhibiting the binding between LRS and RagD may inhibit the activation of mTORCl, which may have the effect of preventing or treating cancer. More specifically, the cancer is not limited thereto.
  • Melanoma leukemia, colorectal cancer, lung cancer, Liver cancer, stomach cancer, esophageal cancer, pancreatic cancer, gallbladder cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, chorionic cancer, ovarian cancer, breast cancer, thyroid cancer, brain cancer, head and neck cancer, skin cancer, lymphoma, aplastic anemia And the like.
  • Lymphomas include both Hodgkin's lymphoma and non-Hodgkin's lymphoma and include B-cell neoplasms such as Precursor B cel l neoplasm, and B-cell tumors (Precursor Hodgkin lymphoma such as T-cell and ⁇ -cell neoplasia (T—Cell AND NK-CELL NEOPLASMS) and Hodgkin's lymphoma (Cl ass i cal Hodgkin lymphoma) lymphoma, Hodgkin di sease).
  • B-cell neoplasms such as Precursor B cel l neoplasm
  • B-cell tumors Precursor Hodgkin lymphoma such as T-cell and ⁇ -cell neoplasia (T—Cell AND NK-CELL NEOPLASMS) and Hodgkin's lymphoma (Cl ass i cal Hodgkin lymphom
  • the benzosulfonamide derivative of Formula 1 of the present invention may exhibit an effective therapeutic effect against cancer showing rapamycin resistance.
  • the benzosulfone amide derivatives of Formula 1 showed an effect of inhibiting leucine-sensitive activity of LRS without affecting the enzymatic activity of LRS.
  • the expression level of LRS was positively correlated with the activation of Rag GTPase and mTORCl in colorectal cancer tissues and cells.
  • the benzosulfonamide derivative of Formula 1 of the present invention specifically binds to a position interacting with RagD in LRS and specifically inhibits the position of LRS as a lysosome, thereby inhibiting the activity of RagD GTPase and mTORCl, resulting in cancer It showed the effect of inhibiting growth. This effect is the same in cancer cells that are resistant to rapamycin.
  • the benzosulfonamide derivative of Formula 1 of the present invention effectively prevents or treats cancers that exhibit resistance to rapamycin due to mTOR mutations.
  • treatment of the compound of the present invention in cells expressing mTOR mutations (L2427P) associated with epilepsy results in (i) hydrolysis of RagD GTP and lysosomal of LRS.
  • the translocat ion was inhibited, and the activity of (ii) mTORCl was also inhibited.
  • the compound of the present invention was administered to an interstitial animal model, the number of epileptic seizures was significantly reduced compared to the control group.
  • the compound of the present invention appears to have a very high blood-brain barrier (BBB) permeability and is highly likely to be developed as a prophylactic agent for brain diseases.
  • BBB blood-brain barrier
  • the pharmaceutical composition according to the present invention may be formulated in various ways depending on the route of administration by methods known in the art together with pharmaceutically acceptable carriers.
  • 'Pharmaceutically acceptable is a non-toxic composition that is physiologically acceptable and, when administered to humans, does not inhibit the action of the active ingredient and usually does not cause gastrointestinal disorders, allergic reactions such as dizziness or similar reactions.
  • the carriers include all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and hemp Microsomes are included.
  • the composition of the present invention may be formulated according to methods known in the art in the form of injections, transdermal and nasal inhalants with suitable parenteral carriers.
  • injectables must be sterilized and protected from contamination of microorganisms such as bacteria and fungi.
  • suitable carriers for injectables include, but are not limited to, solvents including water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycols), combinations thereof and / or vegetable oils. Or a dispersion medium. More preferably, suitable carriers include Hanks' solution, Ringer's solution, and triethane containing amines.
  • PBS phosphate buf fered sal ine
  • sterile water for injection 10% ethanol, 40% propylene glycol, and isotonic solutions such as 53 ⁇ 4 dextrose
  • Butane may further include various antibacterial and antifungal agents such as phenol, sorbic acid, thimerosal and the like.
  • the injection may in most cases further include an isotonic agent, such as sugar or sodium chloride.
  • ointments creams, lotions, gels, external preparations, pastas, liniments, Aerosols and the like.
  • 'transdermal administration means a topical administration of a composition of the present invention to the skin to deliver an effective amount of the active ingredient contained in the composition into the skin, for example, to prepare a composition of the present invention in an injectable formulation. This can be administered by lightly applying the skin directly to the skin with a 30-gauge thin needle.
  • the aerosol from a pressurized pack or nebulizer using a suitable propellant, for example ⁇ dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas It can be delivered conveniently in the form of a spray.
  • a suitable propellant for example ⁇ dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • gelatin capsules and cartridges used in inhalers or inhalers may be used as compounds and lactose or starch.
  • Formulations may be made to contain suitable powder based powder mixtures.
  • compositions according to the invention may also contain one or more buffers (eg saline or PBS), carbohydrates (eg glucose, mannose, sucrose or textane), antioxidants, bacteriostatic agents, chelating agents (eg For example, EDTA or glutathione), adjuvants (eg, aluminum hydroxide), suspending agents, thickening agents and / or preservatives may be further included.
  • buffers eg saline or PBS
  • carbohydrates eg glucose, mannose, sucrose or textane
  • antioxidants eg glucose, mannose, sucrose or textane
  • bacteriostatic agents eg For example, EDTA or glutathione
  • adjuvants eg, aluminum hydroxide
  • suspending agents eg, thickening agents and / or preservatives may be further included.
  • compositions of the present invention may be variously formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. It can be administered in combination with a known compound which is effective in preventing or treating cancer.
  • the term 'effective amount' of the present invention when administered to an individual, refers to an amount that exhibits an effect of improving, treating, preventing, detecting, or diagnosing cancer, and the term 'individual' includes an animal, preferably a mammal, particularly a human. It may be an animal, cells, tissues, organs, etc. derived from the animal. The subject may be a patient in need of treatment.
  • treatment is intended to inhibit the occurrence or recurrence of a disease, alleviate symptoms, reduce direct or indirect pathological consequences of a disease, Reduced, improved, improved, alleviated or improved prognosis. More specifically, the term "treatment” of the present invention refers generically to ameliorating symptoms of cancer, which may include curing, substantially preventing, or ameliorating such a disease, It may include, but is not limited to, alleviating, healing or preventing one symptom resulting from, or most of the symptoms resulting from.
  • Benzenesulfonamide derivatives of Formula 1 according to the present invention inhibit the binding between LRS and RagD and thus inhibit the mTORCl activation, thereby inhibiting mTOR Cancer, epilepsy, inflammatory disease, immune disease, diabetes, obesity, respiratory obstructive disease, fibrosis, pamp disease, lysosomal storage di sease, Alzheimer's disease, Parkinson's disease and Huntington Neurodegenerative diseases such as diseases, cardiovascular diseases and parasitic infections can be very useful in the development of a prophylactic or therapeutic agent for any disease selected from the group consisting of parasitic infections.
  • Figure 2 shows the EC50 of cytotoxicity of benzenesulfonamide derivatives against various cancer cells.
  • FIG. 3 shows the hydrolysis of RagD GTP and the lysosomal translocat of LRS when the LRS is deleted (FIG. 3A) or treated with a compound according to the invention (FIG. 3B) in NIH3T3 cells expressing an mTOR mutation associated with epilepsy (L2427P). Western blot confirmed that the ion is reduced.
  • Figure 4 shows that the NIH3T3 cells expressing mTOR mutations (L2427P) associated with epilepsy reduced the activity of niTORCl when treated with a compound according to the present invention by Western blot (FIG. 4A) and quantified it graphically (FIG. 4B).
  • Figure 5 is a result of measuring the number of expression of interstitial seizures after administering a compound, rapamycin or a control according to the invention in an epileptic animal model.
  • BBB blood-brain barrier
  • Example 1-13 4- (4-isopropyl-2, 3-dimethyl-5-oxo-pyrazol-1 ⁇ yl) ⁇ > ⁇ [2- (2- hydroxyphenyl) ethyl] benzenesulfonamide Produce
  • Example 1_1 4 Preparation of 4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl)-[2- (2-hydroxyphenoxy) ethyl] benzenesulfonamide
  • the target compound was obtained by reaction in the same manner as in Example 1-1 using 2- (2-methoxyphenoxy) ethanamine as a starting material. (Yield 92.4%)
  • the reaction mixture was reacted in the same manner as in Example 1-1, using 4-phenylbutanyl 1-amine as a starting material to obtain a target compound.
  • the reaction product was reacted in the same manner as in Example 1-1 using 2 ⁇ (4-chlorophenyl) ethanamine as a starting material to obtain the target compound.
  • Example 1-1 The same method as Example 1-1, using thiophene-2-ylmethanamine as starting material. Reaction to give the desired compound.
  • Example 1-30 The preparation of 4— (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) —N— (2-naphthylmethyl) benzenesulfonamide The reaction compound was reacted in the same manner as in Example 1-1 using naphthalene # 2-ylmethanamine as a starting material to obtain a target compound.
  • the reaction mixture was prepared in the same manner as in Example 1-1, using 5 ilfluoropyridin ⁇ 2-amine as a starting material, to obtain the target compound.
  • N, N-dimethylbenzene—1,4-diamine was used as a starting material to react the same method as in Example 1-1 to obtain the target compound.
  • the desired compound was obtained by reaction in the same manner as in Example 1-1, using methyl 3-aminobenzoate as starting material.
  • Example 1 38 Preparation of ethyl 3 — [[4- (4-isopropyl—2,3—dimethyl-5-oxo-pyrazol-1-yl) phenyl] sulfonylamino] benzoate
  • Example 1-1 4-isopropylaniline was used as a starting material and reacted in the same manner as in Example 1-1, to obtain a target compound.
  • 3-fluoroaniline was used as a starting material to react the same method as in Example 1-1 to obtain the target compound.
  • Naphthalene— 1-amine was used as a starting material and the reaction was carried out in the same manner as in Example 1-1 to obtain the target compound.
  • Example 1-46 N — [(3-fluorophenyl) methyl] —4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide Produce (3-fluorophenyl) methanamine was used as a starting material and the reaction was carried out in the same manner as in Example 1-1, to obtain the target compound.
  • the reaction mixture was reacted in the same manner as in Example 1-1 using mylruidine as a starting material to obtain a target compound.
  • the reaction mixture was reacted in the same manner as in Example 1-1, using 0-erluidine as a starting material, to obtain a target compound.
  • Example 1-62 N- (2, 4-dimethylphenyl) -4 - Preparation of (4-isopropyl-2, 3-dimethyl-5-oxo-1-yl) benzenesulfonamide 2,4—dimethylaniline was used as a starting material, and reaction was carried out in the same manner as in Example 1-1, to obtain a target compound.
  • 3-ethylaniline was used as a starting material and reacted in the same manner as in Example 1-1, to obtain a target compound.
  • Example 1-78 Ethyl 4- [[4— (4-isopropyl— 2, 3 ⁇ dimethyl-5-oxo-pyrazol-1—yl) phenyl] sulfonylamino] piperidine-1- Preparation of Carboxylate Reaction was carried out in the same manner as in Example 1-1, using ethyl 4-aminopiperidine— 1—carboxylate as starting material, to obtain the target compound.
  • 2-chloropyridin-4-amine was used as a starting material to react the same method as in Example 1-1 to obtain the target compound.
  • Biphenyl] -2-2-amine was used as a starting material to react the same method as in Example 1-1 to obtain the target compound.
  • 2-methylnaphthalene-l-amine was used as a starting material to react the same method as in Example 1-1 to obtain the target compound.
  • the desired compound was obtained by reaction in the same manner as in Example 1-1-1 using 2- (5-methoxy-lH-indole-3-yl) ethanamine as starting material.
  • the target compound was obtained in the same manner as in Example 1-1, using 2methyl-1H ⁇ indole-5-amine as a starting material.
  • 6-Methoxybenzo [d] thiazole-2-amine was used as a starting material, and reaction was carried out in the same manner as in Example 1-1, to obtain a target compound.
  • Example 1-106 Preparation of N- (3,5-dichlorophenyl) '4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-l-yl) benzenesulfonamide 3, 5-dichloroaniline was used as a starting material, and the reaction was carried out in the same manner as in Example 1-1, to obtain the target compound.
  • the reaction product was reacted in the same manner as in Example 1-1 using 4yethynylaniline as a starting material, to obtain the target compound (yield 79 bend43 ⁇ 4).
  • the target compound was obtained in the same manner as in Example 1-1, using 2 '(3—chlorophenyl) ethanamine as a starting material. (Yield 73.1)
  • the target compound was obtained in the same manner as in Example 1-1, using (2 ⁇ (trifluoromethyl) phenyl) methanamine as a starting material. (Yield 77.3)
  • Example 1-124 Preparation of ⁇ (3-chlorophenyl) -4- (4-isopropyl-2,3-dimethyl-5-oxo-pyrazol-1-yl) benzenesulfonamide Reaction was carried out in the same manner as in Example 1-1, using ternary chloroaniline as a starting material, to obtain the target compound. (Yield 88.8%)
  • the desired compound was obtained in the same manner as in Example 1-1, using 2 (2-bromophenyl) ethanamine as a starting material.
  • Example 1-135 4- (4-isopropyl-2, 3-dimethyl-5-oxo-pyrazol- 1-yl) -N- [2- [4- (trifluoromethyl) phenyl] ethyl ] Preparation of Benzenesulfonamide
  • the desired compound was obtained by reaction in the same manner as in Example 1-1, using 2 [[4] (trifluoromethyl) phenyl] ethanamine as starting material.
  • Example 1-136 4- (4—Isopropyl ⁇ 2, 3-dimethyl-5-oxo-pyrazol-1—yl) — N— [4— (trifluoromethyl) phenyl] benzenesulfonamide Manufacture
  • Example 1-138 Preparation of 4- (4 ⁇ chloro-2, 3-dimethyl-5-oxo-pyrazol-1-yl) -N '(2-phenoxytyl) benzenesulfonamide Preparation of 1, 4— (4 ⁇ chloro-2,3—dimethyl—5—oxo-pyrazol-iyl) benzenesulfonyl chloride
  • Example 1-1 Preparation of 4 -— (4-chloro-2, 3-dimethyl-5-oxo-pyrazol-1xyl) -N-[(4-fluorophenyl) methyl] benzenesulfonamide
  • 2,3—dihydro—1,4-benzodioxin-6-amine was used as a starting material to react the same method as in Examples 1-127 to obtain the target compound.
  • Example 1-162 4- (4-Bromo-2,3-dimethyl-5-oxo-pyrazol-1xyl) — of N- (5-chloro-2—fluoro-phenyl) benzenesulfonamide Produce
  • the reaction product was reacted in the same manner as in Example 1-127, using dibasic aminophenol as a starting material, to obtain a target compound.

Abstract

La présente invention concerne un nouveau dérivé de benzènesulfonamide ou un sel pharmaceutiquement acceptable de celui-ci et une utilisation de celui-ci et, plus spécifiquement, un nouveau dérivé de benzènesulfonamide ayant une cible mammifère de l'effet inhibiteur du complexe de rapamycine 1 (mTORC1) et une composition pharmaceutique le contenant en tant que principe actif. Le dérivé de benzènesulfonamide de formule chimique 1 selon la présente invention est extrêmement efficace pour inhiber l'activation de mTORC1 par l'inhibition de la liaison entre LRS et RagD, et le dérivé de benzènesulfonamide est donc très favorablement utilisé dans le développement d'un agent prophylactique ou thérapeutique pour l'une quelconque des maladies choisies dans le groupe constitué par le cancer, l'épilepsie, les maladies inflammatoires, les maladies immunitaires, le diabète, l'obésité, les maladies respiratoires obstructives, la fibrose, la maladie de Pompe, une maladie de surcharge lysosomale, les maladies neurodégénératives (telles que la maladie d'Alzheimer, la maladie de Parkinson et la maladie de Huntington), des maladies cardiovasculaires et les infections parasitaires, pour lesquelles des effets thérapeutiques peuvent être obtenus par inhibition de mTOR.
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