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WO2023236926A1 - Dérivé de 4-carbonylamino isoindolin-1-one, composition le comprenant et procédé d'utilisation associé - Google Patents

Dérivé de 4-carbonylamino isoindolin-1-one, composition le comprenant et procédé d'utilisation associé Download PDF

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Publication number
WO2023236926A1
WO2023236926A1 PCT/CN2023/098489 CN2023098489W WO2023236926A1 WO 2023236926 A1 WO2023236926 A1 WO 2023236926A1 CN 2023098489 W CN2023098489 W CN 2023098489W WO 2023236926 A1 WO2023236926 A1 WO 2023236926A1
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formula
acid
optionally
group
compound
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Chinese (zh)
Inventor
高清志
刘胜男
高香倩
张顺杰
张祥瑞
杜金平
杨柳
李扬
朱晓玲
韩建斌
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Tianjin Gudui Bio Pharm Co Ltd
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Tianjin Gudui Bio Pharm Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a class of 4-carbonylaminoisoindolin-1-one compounds, their preparation methods, pharmaceutical compositions containing them and their uses.
  • Targeted therapy and immunotherapy are new methods for treating cancer that have been proposed in recent years, bringing hope to patients with drug-resistant tumors and advanced tumors.
  • Molecular targeted drugs and immunotherapy drugs have been upgraded to become the main treatment methods for patients with hematological malignancies, completely changing the treatment model of the entire hematological disease. Therefore, developing more and more precise targeted therapies and immunotherapy methods is an essential way to prevent, treat and manage cancer and other diseases.
  • MM malignant hematopathy
  • Common clinical diseases include acute leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, etc.
  • multiple myeloma MM is a malignant disease characterized by abnormal proliferation of clonal plasma cells. Due to the malignant proliferation, extensive infiltration, and secretion of large amounts of monoclonal immunoglobulins by monoclonal plasma cells, a series of clinical symptoms such as extensive bone destruction, recurrent infections, anemia, hypercalcemia, and renal insufficiency are caused. At present, this disease mostly occurs in middle-aged and elderly people and is the second largest hematological malignant tumor.
  • MM is still incurable, and almost all patients will experience relapse, drug resistance and other problems throughout the course of the disease. Therefore, how to diagnose, treat and improve the efficacy and prognosis of patients with relapsed MM is a matter of great concern.
  • Newly diagnosed MM is usually sensitive to many cytotoxic drugs. Treatment is mainly induction chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The curative effect can usually be sustained, but most of them cannot escape the fate of relapse and progression. However, the emergence of new drugs such as thalidomide, bortezomib, and lenalidomide has changed the treatment options for multiple myeloma.
  • the main treatment options are bortezomib/lenalidomide/dexamethasone (VRD), bortezomib/cyclophosphamide/dexamethasone (VCD), bortezomib/thalidomide/dexamethasone (VTD) )wait.
  • VRD bortezomib/lenalidomide/dexamethasone
  • VCD bortezomib/cyclophosphamide/dexamethasone
  • VTD bortezomib/thalidomide/dexamethasone
  • MDS Myelodysplastic syndromes
  • AML acute myeloid leukemia
  • the immunomodulators thalidomide and lenalidomide are both glutamic acid derivatives, which mainly achieve targeted treatment of tumors through direct anti-tumor effects, immunomodulatory effects, anti-angiogenesis and other mechanisms.
  • Thalidomide was recalled by the FDA in the 1960s because it caused serious congenital malformations in infants. However, it is still used to treat multiple myeloma and other blood cancers. Of course, the drug is safe and serious. The side effects are still an unavoidable fact.
  • Lenalidomide a thalidomide derivative
  • Lenalidomide has been approved for the treatment of myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, and follicular lymphoma since it was developed and marketed by the American company Celegene in 2005. or diseases such as marginal zone lymphoma.
  • the FDA has added a black box warning to lenalidomide, which includes embryofetal toxicity, hematological toxicity (including significant neutropenia and thrombocytopenia), and venous and arterial thromboembolism.
  • LAT1 is the L-amino group A transmembrane transporter necessary for acid uptake into cells is abnormally highly expressed in a variety of malignant tumors (Reference: The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer, International Journal of Molecular Science (2019) .), therefore LAT1 is considered an important drug target for cancer treatment.
  • lenalidomide has poor solubility in water, low bioavailability, and high toxic and side effects, which are also the main problems that have been plaguing this drug. Therefore, the research goals of a new generation of immunomodulatory inhibitors are to develop reduced toxic and side effects, improve solubility, improve bioavailability, improve drug targeting, and increase drug concentration in tumor cells.
  • the invention provides a 4-carbonylaminoisoindoline-1-one compound, a compound represented by the following formula (I), or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (such as hydrate), or its clathrate, or its racemate, or its isotope label, or its nitrogen oxide. It has good anti-multiple myeloma activity and can effectively treat and/or prevent the growth and reproduction of multiple myeloma. Preparation methods, pharmaceutical compositions and uses comprising the compounds are also provided.
  • A is selected from -O-, -S-, -NH-, or A does not exist;
  • Q is selected from optionally substituted alkylene, or alkylene arylene
  • R 1 is selected from -H, alkyl, -C(O)R 4 , -C(S)R 4 , -C(O)OR 4 , -C(O)NHR 4 , -C(O)NR 4 R 4 ';
  • R 2 is selected from -H, optionally substituted alkyl, alkenyl, alkenyl alkylene, alkynyl, alkynyl alkylene base, aryl, arylalkylene, heteroaryl, heteroarylalkylene;
  • R 3 is selected from -H, hydroxyl, alkyl, alkenyl, alkenylalkylene, alkynyl, alkynylalkylene, aryl, arylalkylene, heteroaryl, heteroarylalkylene, Alkylene-OC(O)R 4 , alkylene-OC(O)OR 4 , alkylene-OC(O)NHR 4 , alkylene-OC(O)NR 4 R 4 ', or -OR 4 ;
  • R 4 and R 4 ' are the same or different, and each is independently selected from hydrogen, alkyl, alkenyl, alkenyl alkyl, alkynyl, alkynylalkyl, optionally substituted aryl, optionally substituted heteroaryl group, optionally substituted alicyclic group, optionally substituted alicyclic heterocyclic group, optionally substituted arylalkylene or optionally substituted heteroarylalkylene; or R 4 and R 4 ' form optionally Substituted 3-7 membered rings;
  • the “optionally substituted” refers to unsubstituted or substituted by one or more substituents, wherein the "optionally substituted alkylene", “optionally substituted alicyclic group”, “optionally substituted Aliphatic heterocyclyl”, “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted arylalkylene” and “optionally substituted heteroarylalkylene”
  • Each substituent is independently selected from hydroxy, amino, carboxyl, halogen, nitro, cyano, alkyl, alkoxy, aryl, heteroaryl, arylalkylene, heteroarylalkylene, aryl Oxygen, heteroaryloxy, cycloalkyl, alicyclic, cycloalkyloxy, heterocycloalkyloxy, arylalkoxy, heteroarylalkoxy, alkanoyloxymethyl , alkanoyloxy, alkoxyacyloxy or alkoxyacyl.
  • alkyl as well as “alkoxy”, “arylalkoxy”, “heteroarylalkoxy”, “alkanoyloxymethyl”, “alkoxyacyloxy”
  • alkyl part in “, “alkanoyloxy” and “alkoxyacyl” is each independently a C 1-20 linear or branched alkyl group, optionally, a C 1-17 linear or branched alkyl group.
  • the base optionally, is a C 1-10 linear or branched alkyl group, optionally, is a C 1-7 linear or branched alkyl group, optionally, is a methyl, ethyl, n-propyl group , isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or hexadecyl;
  • alkylene is each independently a C 1-20 linear or branched alkylene group, optionally, a C 1-17 linear or branched alkylene group , optionally, a C 1-10 linear or branched alkylene group, optionally, a C 1-8 linear or branched alkylene group, optionally, a C 1-6 linear or branched alkylene group Chain alkylene, optionally, C 1-3 straight Chain or branched alkylene, optionally methylene, ethylene, n-propylene, isopropylene, n-buty
  • the cycloalkyl part in the "cycloalkyloxy" and “cycloalkyl” is C 3-8 cycloalkyl, optionally, it is cyclopropyl, cyclobutyl, or cyclopentyl or cyclohexyl;
  • alkenyl part in the "alkenyl” and “alkenyl alkylene” is each independently a C 2 -C 20 linear or branched alkenyl group, optionally, a C 2 -C 15 linear or branched alkenyl group.
  • alkynyl part in the "alkynyl” and “alkynyl alkylene” is each independently a C 2 -C 20 linear or branched alkenyl group, optionally, a C 2 -C 15 linear or branched alkenyl group.
  • Branched chain alkynyl optionally, C 2 -C 10 linear or branched alkynyl, optionally, C 2 -C 8 linear or branched alkynyl, optionally, C 2 -C 6 straight chain or branched chain alkynyl, optionally, C 2 -C 4 straight chain or branched chain alkynyl;
  • the heterocyclic group in the "aliphatic heterocyclic group” and “heterocycloalkyloxy group” contains 1-3 heteroatoms selected from O, N, S, SO or SO 2 on the ring.
  • C 3-8 (preferably C 4-6 ) alicyclic group, optionally, oxiranyl, thiiranyl, aziridinyl, oxetanyl, thiocyclic group Butyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, or piperazinyl;
  • aryl group in the "aryl”, “arylalkylene”, “arylalkoxy”, and “aryloxy” is a 6-10 membered monocyclic or bicyclic fused aromatic ring Group; optionally phenyl or naphthyl;
  • the arylene group in the "alkylene arylene group” is a 6-10 membered monocyclic or bicyclic fused aromatic ring group; optionally, it is a phenylene group or a naphthylene group;
  • heteroaryl groups in the "heteroaryl”, “heteroarylalkylene”, “heteroaryloxy” and “heteroarylalkoxy” are each independently selected from O , N, S, SO or SO 2 5-10 membered monocyclic or bicyclic fused heteroaromatic ring groups with 1-3 heteroatoms, optionally, pyrrolyl, pyrazolyl, pyridyl, furyl , imidazolyl, thiazolyl, oxazolyl, oxazolyl, thiazolyl, 1H-azepinyl, quinolyl, isoquinolyl, indolyl, pyrimidinyl or pyrazinyl, or tris Azolyl.
  • R 2 is selected from -H, methyl, ethyl, tert-butyl, allyl, propargyl or benzyl;
  • R 3 is selected from -H, -OH,
  • amino acid moiety of the compound of formula (I) is in D configuration or L configuration.
  • the present invention is a pharmaceutical composition, which includes the compound of the above formula (I), or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (such as hydrate), or its package. compound, or its racemate, or its isotope label, or its nitrogen oxide, and pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials or other excipients.
  • the fillers of the pharmaceutically acceptable excipients include lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline
  • the binder includes sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, One or more combinations of polyethylene glycol, medicinal ethanol, and water
  • the disintegrant includes starch, crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl fiber
  • cellulose sodium carboxymethyl cellulose, and effervescent disintegrant.
  • the administration mode of the pharmaceutical composition includes: oral administration (for example, buccal cavity), sublingual administration, parenteral administration (for example, intramuscular, intravenous or subcutaneous), rectal administration (for example, by suppository or lotion), transdermally (e.g., skin electroporation), or by inhalation (e.g., aerosol), and in solid, liquid, or gaseous dosage forms, including tablets and suspensions Medication administration, etc.
  • Administration may be given as a single unit dose under continuous treatment, or as an ad hoc single dose treatment.
  • Therapeutic compositions may also be in the form of oil emulsions or dispersions, combined with lipophilic salts such as pamoic acid, or biodegradable sustained release compositions for subcutaneous or intramuscular administration.
  • the pharmaceutical composition can be made into solid oral preparations, liquid oral preparations, injections and other dosage forms.
  • the solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated agents, granules, dry powders, capsules, syrups and solutions.
  • the injections include: small injections, large infusions, freeze-dried powder injections, etc.
  • the present invention provides a compound of the above formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a clathrate thereof, or Its racemate, or its isotope label, or its nitrogen oxide, or the use of the above pharmaceutical composition in the preparation of drugs for preventing and/or treating hematological diseases; preferably, the disease is selected from blood cancer and bone marrow cancer, lymphoma, Kaposi's sarcoma, or myelodysplastic syndrome.
  • the compounds provided by the present invention can be used to treat, prevent or manage primary or metastatic tumors.
  • the present invention also provides a compound of the above formula (I) or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or a clathrate thereof, or Methods for preparing racemates thereof, or isotope markers thereof, or nitrogen oxides thereof;
  • the method includes passing the compound of formula (A) and the compound of formula (B) through step A to obtain the compound of formula (C):
  • Step A Prepare formula (C) by substitution reaction of formula (A) and formula (B);
  • formula (A) and formula (B) are catalyzed by a base (such as potassium carbonate, cesium carbonate, sodium hydride, lithium bistrimethylsilylamide, etc.) in a suitable solvent (such as N, N-dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.), formula (C) is prepared through a substitution reaction at a temperature of 0°C to 25°C. .
  • a base such as potassium carbonate, cesium carbonate, sodium hydride, lithium bistrimethylsilylamide, etc.
  • a suitable solvent such as N, N-dimethylformamide, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc.
  • R3 is as described in formula (I), but is not H, OR4;
  • B is selected from Cl, Br, I, OTs, OMs;
  • formula (B) can adopt one of the following methods 1-8, but is not limited to the following methods:
  • Each Y is selected from -R 4 , -OR 4 , -NHR 4 , NR 4 R 4 ', wherein R 4 and R 4 ' are as described in formula (I).
  • formula (C) can be obtained through the reaction of the following step A':
  • Step A' S1 and S2 are subjected to condensation conditions to obtain S3, and then S3 is deprotected to obtain S4. Then S4 and S5 are substituted and ammonolyzed to methyl ester under alkali catalysis to obtain LN-S5, which is reduced by iron powder to obtain formula (C ).
  • Step B Perform acylation reaction between formula (C) and formula (D) to obtain formula (E).
  • formula (C) and p-nitrophenyl chloroformate are dissolved in (such as tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidone, etc.) and reacted under reflux conditions to obtain Formula (E);
  • Step C Prepare formula (G) by acylation reaction of formula (C) and formula (F);
  • formula (G) slowly drop formula (C) into a dichloromethane or acetonitrile solution of triphosgene at low temperature (preferably 0°C), and slowly raise the temperature to 30°C-60°C (preferably 45°C), wait until the reaction is completed, and concentrate under reduced pressure to obtain formula (G).
  • Step D Condensation reaction of formula (C) and formula (H) to obtain formula (J);
  • formula (C) and N, N'-carbonyldiimidazole are dispersed in tetrahydrofuran and reacted under reflux conditions. After the reaction is completed, concentrate under reduced pressure, add ethyl acetate and stir evenly to obtain a suspension, and reduce the pressure. Filter and wash or spin dry directly to get formula (J).
  • W is selected from any one of -OH, -SH and -NH 2 groups
  • R 5 is Cl, or
  • R 3 is as shown in formula (I);
  • R 2 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH 2 OH, or -CH 2 CHOHCH 2 OH, optionally deprotected using the following method:
  • Disperse formula (M) in a suitable solvent such as ethyl acetate or dioxane
  • a suitable solvent such as ethyl acetate or dioxane
  • hydrogen chloride gas or add other acids
  • react at room temperature or 40°C and precipitate a solid.
  • Add ether if there is no solid.
  • a solid precipitates and is filtered to obtain formula (N) in the form of a salt.
  • R 2 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 OH, or -CH 2 CHOHCH 2 OH, optionally deprotected using the following method.
  • Disperse formula (O) in a suitable solvent such as methanol or ethanol
  • a suitable solvent such as methanol or ethanol
  • the free compound can also be obtained by dispersing the salt form of formula (N) in a suitable solvent (such as methanol or ethanol) and adding an equivalent amount of base.
  • the present invention provides the compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate, or its clathrate, or its racemate, or its Isotopic markers, or their nitrogen oxides or their pharmaceutical compositions are used in combination with one or more other active drugs ("second active compounds") in the preparation of drugs for the prevention and/or treatment of hematological diseases
  • second active compounds active drugs
  • the disease is selected from blood cancer and bone marrow cancer, lymphoma, Kaposi's sarcoma or myelodysplasia syndrome
  • the other active drug is dexamethasone and/or pentezomib.
  • the disease is selected from blood cancers and bone marrow cancers, such as acute and chronic leukemias and multiple myeloma, such as lymphoblastic leukemia, chronic myelogenous leukemia, myelogenous leukemia, lymphocytic leukemia, myeloid leukemia , adult T-cell leukemia, Kaposi's sarcoma, nuclear acute myeloid leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma , diffuse large B-cell tumor, low-grade follicular lymphoma.
  • the compounds provided by the invention can be used to treat, prevent or manage primary, metastatic, refractory or resistant tumors to chemotherapy or radiotherapy.
  • multiple myeloma refers to hematological diseases characterized by malignant plasma cells, including the following conditions: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk and high-risk multiple myeloma ; Newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma); transplant-eligible and transplant-ineligible multiple myeloma; smoldering (indolent) multiple myeloma (including Low-risk, intermediate-risk, and high-risk multiple myeloma); relapsed multiple myeloma; refractory and resistant multiple myeloma; active multiple myeloma; solitary plasmacytoma; extramedullary plasma Cytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; nonsecretory myeloma;
  • MGUS mono
  • the term “treating” or “treating” refers to alleviating or reducing the severity of symptoms associated with the disease or condition being treated, such as multiple myeloma.
  • the term “preventing” includes inhibiting the symptoms of a particular disease or condition, such as multiple myeloma.
  • the term “relapse” refers to a situation in which a patient whose multiple myeloma has gone into remission after treatment has a return of myeloma cells and/or a decrease in normal cells in the myeloma.
  • the terms “refractory and resistant” refer to situations in which a patient has residual myeloma cells and/or a decrease in normal cells in the bone marrow, even after intensive treatment.
  • Examples of the second active ingredient of the present invention may include one or more of the following substances: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, orbibin Tocilizumab, protease body inhibitors (e.g., bortezomib, carfilzomib, elsazomib, opozomib, or marezomib), histone deacetylase inhibitors (e.g., panobinostat, ACY241), BET inhibitors (eg GSK778).
  • protease body inhibitors e.g., bortezomib, carfilzomib, elsazomib, opozomib, or marezomib
  • histone deacetylase inhibitors e.g., panobinostat, ACY241
  • BET inhibitors eg GSK778
  • the compounds of the present invention may exist in isotopically traced or enriched forms, containing one or more atoms having an atomic weight or mass number different from that of the largest number of atoms found in nature.
  • Isotopes may be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.
  • Compounds containing other isotopes of these and/or other atoms are within the scope of this invention.
  • optical isomers used in this article refers to substances with identical molecular structures and similar physical and chemical properties, but different optical rotations. Includes optically isomeric mixtures in any ratio.
  • the compounds of formula (I) may contain one or more asymmetric carbon atoms, and may exist in the form of optically pure enantiomers, such as enantiomeric mixtures of racemates, optically pure diastereoisomers isomers, diastereomeric mixtures, diastereomeric racemates, or diastereomeric racemate mixtures.
  • the optically active form can be obtained, for example, by resolution of the racemate, by asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbents or eluents). The invention includes all such forms.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acid salts and organic acid salts.
  • pharmaceutically acceptable non-toxic acids including inorganic acid salts and organic acid salts.
  • solvate refers to a compound that is further bound by non-covalent intermolecular forces to a stoichiometric or non-stoichiometric amount of a solvent.
  • the solvent is water
  • the solvate is a hydrate.
  • DIPEA N,N-diisopropylethylamine
  • HATU 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate
  • LiHMDS lithium bistrimethylsilylamide
  • TBS tert-butyldimethylsilyl
  • RPMI-8226 human multiple myeloma cells
  • NCI-H929 human myeloma cells
  • Figure 1 shows the expression of LAT1 in different cells.
  • the synthesis method of formula (L) combine Boc protected amino acid (1.0 equivalent), cesium carbonate (0.5 equivalent) and ethyl iodide, or 1-iodobutane, or 1-iodohexane, or isopropyl iodide , or TBS-protected hydroxyethyl iodide, or 4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (1.1 equivalent) was dispersed in DMF, stirred at room temperature overnight, and extracted. , column chromatography yields product formula (L).
  • Step A Synthesize using Step A, Step C (or Step D) and Step E.
  • Example 95 Disperse the product of Example 95 in methanol, then add palladium carbon, and react at room temperature in a hydrogen environment. After the reaction is completed, filter out the palladium carbon, add the reaction liquid dropwise to tert-butyl methyl ether, and precipitate a solid to obtain a salt.
  • the acid acid product was a white solid with a yield of 55.31%.
  • Test method Use a 5 mL centrifuge tube to take about 0.5 mL of distilled water, and slowly add the dry compound until it cannot be dissolved (it will shake at 25°C and remain turbid). Filter the solution into another 5 mL clean weighed EP tube, weigh it again, and calculate the weight of the solution. Lyophilize the filtrate, weigh and calculate the solute mass of the remaining solid, calculate the mass of the solvent, and then calculate the solubility of the compound in water. The results are listed in Table 1.
  • Test 2 In vitro anti-multiple myeloma activity test
  • Test method Collect MM.1S cells in the logarithmic phase, seed them in a 96-well plate at a density of 2 ⁇ 10 4 cells/well, incubate them in a 37°C, 5% CO 2 incubator for 2 hours, and then add them to a final concentration of 0.0001 to 50 ⁇ M of compound, 4 duplicate wells of each compound, and incubated for 72 h in a 37°C, 5% CO2 incubator. After the incubation, 20 ⁇ L of 5 mg/mL MTT solution was added to the cell wells. After 4 hours, the supernatant was discarded, 150 ⁇ L of DMSO was added, and the absorbance value at 570 nm wavelength was measured .
  • the absorbance value measured in the blank well without cells is A blank
  • the absorbance value measured in the cell well without drug treatment is A control
  • the IC 50 value is less than 0.05 ⁇ M for A; the IC 50 value is greater than 0.05 ⁇ M and less than 0.1 ⁇ M for B; the IC 50 value is greater than 0.1 ⁇ M and less than 0.5 ⁇ M for C; the IC 50 value is greater than 0.5 ⁇ M and less than 1 ⁇ M for D.
  • Test Method This test evaluates the effect of dexamethasone as a single agent in combination with a compound of the invention or lenalidomide on the proliferation inhibition of lenalidomide-resistant multiple myeloma NCI-H929 cells.
  • the test uses MTT colorimetric method to detect cell survival rate, the method is as in test 2.
  • the compound of the present invention has strong cell proliferation inhibitory activity on lenalidomide-resistant NCI-H929 cells, and when used in combination with the second active component dexamethasone, it can achieve synergistic inhibition of NCI-H929 cell proliferation. Effect.
  • the results are shown in Table 3. Among them, the IC 50 value is less than 0.01 ⁇ M for A; the IC 50 value is greater than 0.01 ⁇ M and less than 0.05 ⁇ M for B; the IC 50 value is greater than 0.05 ⁇ M and less than 0.1 ⁇ M for C; the IC 50 value is greater than 0.1 ⁇ M and less than 0.5 ⁇ M for D.
  • Test method 293T cells (6 ⁇ 10 5 ) in the logarithmic growth phase were inoculated into a 6-well cell culture plate and cultured overnight in a cell culture incubator. Use PEI reagent to transfect the constructed LAT1-pQCXIP plasmid fused with protein C tag into cells. Place it in a cell culture incubator for 6 hours, discard the supernatant, and add 2 ml of complete culture medium to continue culturing; 48 hours after transfection, observe the expression of green fluorescent protein under a fluorescence microscope, and use puromycin at concentrations of 8 ⁇ g/mL and 5 ⁇ g/mL. After 13 days of screening, 293T cells stably and highly expressing LAT1 were obtained.
  • 293T and LAT1-293T steady-state cell lines were used to conduct this experimental study.
  • the cells were evenly spread into a 6-em culture dish. When the cells were full the next day, 293T and LAT1-293T cells were collected using trypsin digestion.
  • the cells were resuspended in PBS and preincubated at 37°C for 2 hours. Adjust the cell concentration to 1 ⁇ 10 7 cells/ml with physiological saline, and dispense into 1.5 ml centrifuge tubes, 200 ⁇ L/tube.
  • Test results As shown in Table 3, the content of the compound of the present invention in the lysate of 293T cells that highly express LAT1 was significantly higher than that of ordinary 293T cells, indicating that the compound of the present invention has significant LAT1 targeting.
  • NOD/SCID female mice aged 6 to 8 weeks were used, and the experimental animals were purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd. Animals were housed in an IVC system in an SPF-grade environment. All experimental animals had free access to food and water, and the room temperature was 20-25°C, the temperature was 40-70%, and the day-night light-dark alternation time was 12h/12h. Human multiple myeloma RPMI-8226 cells were cultured in 1640 culture medium containing 10% fetal calf serum.
  • RPMI-8226 cells Collect RPMI-8226 cells in the exponential growth phase, resuspend them in 1640 culture medium to 1 ⁇ 10 8 cells/mL, add an equal volume of Matrigel, and inoculate 0.2 mL/mouse subcutaneously into the axilla of the mouse to establish tumor-bearing nude mice.
  • Model When the tumors grow to 150-300mm3 , mice are randomly divided into groups for administration according to tumor size and body weight. The calculation formula of tumor volume is: long diameter ⁇ short diameter 2 /2.
  • This test is divided into 9 groups, namely, physiological saline group, compound 73 administration group, compound 82 administration group, compound 90 administration group, compound 109 administration group, compound 169 administration group, compound 174 administration group, Compound 176 administration group, lenalidomide administration group, 7 animals in each group.
  • Oral administration once a day, the dose of lenalidomide is 100 mg per kilogram of body weight, other drugs are at equimolar concentrations compared with lenalidomide, the administration volume is 10 mL/kg, and the dose is continuous for 14 After 5 days, the drug was stopped and observed for 5 days. The tumor diameter was measured twice a week to observe the anti-tumor effect of the test drug and the changes in the animal's weight.
  • the compound of the present invention has a superior tumor inhibitory effect, which fully demonstrates the selective accumulation and selective accumulation of the compound of the present invention in tumor cells and tumor tissues. Targeting.
  • Test 6 In vivo anti-tumor efficacy test II
  • NCI-H929 cells Human multiple myeloma NCI-H929 cells were cultured in 1640 culture medium containing 10% fetal calf serum. Collect NCI-H929 cells in the exponential growth phase, resuspend them in 1640 culture medium to 5 ⁇ 10 7 cells/mL, add an equal volume of Matrigel, and inoculate 0.2 mL/mouse subcutaneously into the axilla of the mouse to establish tumor-bearing nude mice. Model. When the tumors grow to 150-300mm3 , mice are randomly divided into groups for administration according to tumor size and body weight. The calculation formula of tumor volume is: long diameter ⁇ short diameter 2 /2.
  • This test is divided into 9 groups, namely the normal saline group, the compound 73 administration group, the compound 82 administration group, the compound 90 administration group, the compound 109 administration group, the compound 169 administration group, and the compound 174 administration group. , compound 176 administration group, lenalidomide group, 7 animals in each group.
  • Oral administration once a day, the dose of lenalidomide is 100 mg per kilogram of body weight, other drugs are at equimolar concentrations compared with lenalidomide, the administration volume is 10 mL/kg, and the dose is continuous for 14 After 1 day, the drug was stopped and observed for 1 day. The tumor diameter was measured twice a week to observe the anti-tumor effect of the test drug and the changes in the animal's weight.
  • the results are shown in Table 5 and Figure 3.
  • the compounds provided by the present invention have superior tumor inhibitory effects compared with the clinical control drug lenalidomide, which fully demonstrates the selectivity of the compounds of the present invention in tumor cells and tumor tissues. Accumulation and targeting.

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Abstract

L'invention concerne un composé de 4-carbonylamino isoindolin-1-one représenté par la formule (I), ou un isomère optique ou un sel pharmaceutiquement acceptable ou un solvate (tel qu'un hydrate) ou un composé d'inclusion ou un racémate ou un marqueur isotopique ou un oxyde d'azote de celui-ci, et une composition pharmaceutique et une utilisation associée. Le composé a une bonne activité anti-myélome multiple, et peut traiter et/ou prévenir de manière efficace la croissance et la reproduction du myélome multiple.
PCT/CN2023/098489 2022-06-07 2023-06-06 Dérivé de 4-carbonylamino isoindolin-1-one, composition le comprenant et procédé d'utilisation associé Ceased WO2023236926A1 (fr)

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CN202211670364.1A CN117186061A (zh) 2022-06-07 2022-12-23 4-羰基氨基异吲哚啉-1-酮衍生物、包括其的组合物及使用方法

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170056510A1 (en) * 2013-09-10 2017-03-02 Synta Pharmaceuticals Corp. Targeted therapeutics
US20170319708A1 (en) * 2014-10-24 2017-11-09 Fl Therapeutics Llc 3-Substituted Piperidine-2, 6-Diones and Non-Covalent Complexes with Albumin
CN107739389A (zh) * 2017-11-03 2018-02-27 华东师范大学 3位取代的(1‑氧代异吲哚啉‑2‑基)哌啶‑2,6‑二酮类化合物及其合成方法
CN109705044A (zh) * 2018-12-18 2019-05-03 江西润泽药业有限公司 乌苯美司衍生物与具有抗肿瘤活性化合物的协同前药衍生物及其制备方法和应用
WO2019218904A1 (fr) * 2018-05-18 2019-11-21 四川科伦博泰生物医药股份有限公司 Dérivé d'acide aminé non naturel, son procédé de préparation et son utilisation
CN111285850A (zh) * 2018-12-06 2020-06-16 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170056510A1 (en) * 2013-09-10 2017-03-02 Synta Pharmaceuticals Corp. Targeted therapeutics
US20170319708A1 (en) * 2014-10-24 2017-11-09 Fl Therapeutics Llc 3-Substituted Piperidine-2, 6-Diones and Non-Covalent Complexes with Albumin
CN107739389A (zh) * 2017-11-03 2018-02-27 华东师范大学 3位取代的(1‑氧代异吲哚啉‑2‑基)哌啶‑2,6‑二酮类化合物及其合成方法
WO2019218904A1 (fr) * 2018-05-18 2019-11-21 四川科伦博泰生物医药股份有限公司 Dérivé d'acide aminé non naturel, son procédé de préparation et son utilisation
CN111285850A (zh) * 2018-12-06 2020-06-16 中国科学院上海药物研究所 一类异吲哚啉类化合物、其制备方法、药物组合物及其应用
CN109705044A (zh) * 2018-12-18 2019-05-03 江西润泽药业有限公司 乌苯美司衍生物与具有抗肿瘤活性化合物的协同前药衍生物及其制备方法和应用

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