WO2022148317A1 - 2-氨基嘧啶类化合物及其药物组合物和应用 - Google Patents
2-氨基嘧啶类化合物及其药物组合物和应用 Download PDFInfo
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- WO2022148317A1 WO2022148317A1 PCT/CN2021/143765 CN2021143765W WO2022148317A1 WO 2022148317 A1 WO2022148317 A1 WO 2022148317A1 CN 2021143765 W CN2021143765 W CN 2021143765W WO 2022148317 A1 WO2022148317 A1 WO 2022148317A1
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- alkyl
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- pharmaceutically acceptable
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- metabolites
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the invention relates to the technical field of chemical medicine, in particular to a class of 2-aminopyrimidine compounds and their pharmaceutical compositions and applications.
- protein tyrosine kinases Since the late 1990s, protein tyrosine kinases have received increasing attention as emerging targets. Under normal circumstances, this type of protein with tyrosine kinase activity binds to ATP and phosphorylates on tyrosine residues at specific positions, which then causes the activation and transduction of important intracellular signaling pathways and participates in the regulation of cellular processes. Division, growth, proliferation, differentiation, aging, apoptosis and other life processes. The dysregulation of tyrosine kinases can lead to cell dysfunction, leading to a series of diseases in the body, including tumors and inflammatory diseases. Therefore, targeting protein tyrosine kinases has become an important aspect of precision medicine.
- Protein tyrosine kinases include receptor tyrosine kinases and non-receptor tyrosine kinases.
- the protein structure of receptor tyrosine kinases includes an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain and regulatory sequences, rather than the subcellular localization of receptor tyrosine kinases Unlike receptor tyrosine kinases, it does not include extracellular and transmembrane structures and is a class of cytoplasmic tyrosine kinase proteins.
- non-receptor tyrosine kinase After the non-receptor tyrosine kinase is activated in the cell, it binds to downstream signaling molecules and activates it, phosphorylates it, and exerts tyrosine kinase activity.
- Janus kinase (JAK for short) is a non-receptor tyrosine kinase, which includes four family members: JAK1, JAK2, JAK3 and Tyk2.
- this protein is named after the two-sided Roman god Janus (Janus). ) name.
- extracellular specific ligands such as cytokines, drivers, growth factors, etc.
- STATs signal transducers and activators of transcription
- Phosphorylated STATs undergo homodimerization or heterodimerization and then translocate to the nucleus, where they bind to specific DNA binding sites and regulate gene transcription, resulting in changes in cellular functions.
- JAK3 is only expressed in bone marrow, lymphoid and other tissue cells related to the hematopoietic system.
- interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 specifically bind to receptors containing ⁇ c chain (common gamma chain) receptor subunits, it will cause Changes in receptor conformation, thereby promoting JAK3-related receptors and JAK1-related receptors to approach each other and undergo dimerization and autophosphorylation.
- Activated JAK3 protein recruits and phosphorylates STAT1, STAT3, STAT5, or STAT6.
- STATs are transferred to the nucleus, affecting the transcription and translation of downstream targeted DNA, and participating in lymphocytes, T cells, and B cells. and NK cell growth, proliferation, development and differentiation, as well as important life processes such as immune regulation.
- Robust clinical studies have found that loss of function of JAK3 in humans causes severe combined immunodeficiency (SCID), while overactivation or mutation is associated with many autoimmune diseases and cancers (especially blood cancers such as leukemia) .
- SCID severe combined immunodeficiency
- overactivation or mutation is associated with many autoimmune diseases and cancers (especially blood cancers such as leukemia) .
- the study found that the JAK3-STAT5 signaling cascade is an important signaling pathway in the process of hematopoiesis.
- T-lymphocytic leukemia T-ALL
- JAK3 is one of the most important signaling pathways in this pathway.
- the most commonly mutated gene accounting for approximately 16.1% of T-ALL cases (Haematologica 2015, 100, 1301-1310).
- JAK3(M511I) exhibited cytokine-independent cell proliferation and transformation ability in Ba/F3 cells;
- the mice showed obvious clinical symptoms of T-ALL (dramatic increase in the number of white blood cells, enlargement of the spleen, thymus and lymph nodes, increased CD8+ T cells in peripheral blood and hematopoietic tissues, etc.), while the transplanted mice expressing wild-type JAK3 cells did not.
- Onset (Blood 2014, 124, 3092-3100)).
- JAK3 has become a potential new target for the treatment of hematological tumors, and the development of small-molecule inhibitors targeting JAK3 will provide an important strategy for alleviating or treating related diseases.
- JAK inhibitors have been approved for marketing in the United States, the European Union or Japan, namely: ruxolitinib (ruxolitinib, a JAK1/JAK2 inhibitor, approved by the FDA in 2011), tofacitinib ( Pan-JAK inhibitor, approved by FDA in 2012), baricitinib (baricitinib, JAK1/JAK2 inhibitor, approved by EU and FDA in 2017 and 2018), peficitinib (pan-JAK inhibitor, released in Japan in 2019) Approved for listing in 2019), fizotinib (fedratinib, a JAK2 inhibitor, approved by the FDA in 2019), upadacitinib (upadacitinib, a JAK1 inhibitor, approved by the FDA in 2019), delgocitinib (delgocitinib, Pan-JAK inhibitor, approved for marketing in Japan in 2020), filgotinib (JAK1 inhibitor, approved for marketing in EU and Japan in 2020).
- the five drugs approved by the FDA are all black-boxed due to serious side effects that may be clinically caused warn. Therefore, the development of highly selective JAK3 inhibitors can effectively reduce the toxic and side effects by reducing the interference to many cytokine pathways unrelated to the disease while maintaining the efficacy.
- JAK3 has a higher ATP affinity relative to other family members, making the development of selective JAK3 inhibitors challenging, but not impossible accomplish.
- JAK3 kinase contains a unique cysteine residue (Cys909) that has lipophilic function and can covalently bind to nucleophiles, while in the other three JAK subtypes The equivalent position of the type is serine.
- JAK3 irreversible JAK3 inhibitor
- PF-06651600 the IC50 value of the kinase level at the ATP concentration of 1mM: JAK3 is 33.1nM, other isoforms are all greater than 10 ⁇ M
- the compound is currently in phase III clinical trials for the treatment of alopecia areata, and has been approved by the US FDA as a breakthrough therapy.
- JAK3 selective inhibitor for clinical use, and it is of great clinical significance to develop high-activity, low-toxicity JAK3 small molecule inhibitors for the treatment of inflammatory diseases or hematological tumors.
- the present invention provides a new class of 2-aminopyrimidine compounds, which can selectively inhibit the activity of JAK3 kinase with high activity, thereby inhibiting the growth of various tumor cells. Proliferation can be used to treat tumors or inflammatory diseases associated with JAK3 kinase. Specifically, the following technical solutions are included.
- 2-aminopyrimidine compounds having the structure represented by formula (I) or their pharmaceutically acceptable salts, isotopic derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or Its prodrug molecules and metabolites:
- R 1 is selected from: H, halogen, cyano, one or more R 11 substituted or unsubstituted C 1 -C 6 alkyl, one or more R 11 substituted or unsubstituted C 3 -C 6 cycloalkyl , one or more R 11 substituted or unsubstituted C 1 -C 6 alkoxy, one or more R 11 substituted or unsubstituted C 3 -C 6 cycloalkoxy, carboxamide;
- n 0 or 1
- L is O or S
- each R 10 Each independently selected from: hydrogen, halogen, hydroxyl, one or more R 11 substituted or unsubstituted C 1 -C 3 alkyl, one or more R 11 substituted or unsubstituted C 1 -C 3 alkoxy , the heteroatom is O, S and/or N;
- the configurations of the chiral carbon atoms marked with * are independently S configuration or R configuration.
- the configurations of the chiral carbon atoms marked with * are independently S configuration or R configuration, and each R 10 is independently selected from: halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
- each R 10 is independently selected from: F, hydroxyl, methyl, methoxy, ethoxy, and isopropoxy.
- R 6 is selected from: hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -NH-CN,
- W and X are both CH; Y and Z are independently selected from N or CR 6 , wherein R 6 is selected from: H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -NH-CN,
- W and X are both CH; Y is CR 6 , wherein R 6 is selected from: H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, Z is CH or N.
- W, X, and Z are all CH; Y is CR 6 , wherein R 6 is:
- R 2 is selected from: H, halogen, -(CH 2 ) m NR 3 R 4 , -(CH 2 ) m CR 3 R 4 R 5 ; wherein each m is independently 0, 1, 2 or 3;
- Each R 3 and each R 4 is independently selected from: H, one or more R 12 substituted C 1 -C 3 alkyl groups, or R 3 , R 4 and the N or C to which they are attached together form one or more The 5-11-membered monocyclic, fused, bridged or spiro ring containing 0, 1, 2 or 3 heteroatoms in the ring atom substituted by R 12 ;
- R 5 is selected from: H, cyano or C 1 -C 3 alkyl
- Each R 12 is independently selected from: H, hydroxy, acetyl, R 13 substituted or unsubstituted 4-8 membered heterocyclyl, halogen, hydroxy, amino, C 1 -C 3 alkyl, C 1 -C 3 Alkoxy, -NHR 13 , -N(R 13 ) 2 ; R 13 is C 1 -C 3 alkyl.
- R 2 is selected from the group consisting of: H, halogen, -(CH 2 ) m NR 3 R 4 , -(CH 2 ) m CR 3 R 4 R 5 ; wherein each m is independently 0 or 1;
- Each R 3 and each R 4 are independently selected from: H, C 1 -C 3 alkyl, hydroxy substituted C 1 -C 3 alkyl, -NHR 13 substituted C 1 -C 3 alkyl, -N( R 13 ) 2 substituted C 1 -C 3 alkyl, or R 3 , R 4 and the N or C to which they are attached together form one or more R 12 substituted ring atoms containing 0, 1, 2 or 3 heterocyclic atoms A 5- to 11-membered monocyclic, bridged or spirocyclic ring;
- R 5 is selected from: H, cyano or C 1 -C 3 alkyl
- Each R 12 is independently selected from: H, hydroxy, acetyl, R 13 substituted piperazinyl, C 1 -C 3 alkyl, -NHR 13 , -N(R 13 ) 2 ; R 13 is C 1 - C3 alkyl.
- R 2 is selected from the group consisting of: H, halogen,
- R 1 is selected from the group consisting of: H, halogen, cyano, carboxamido, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C6cycloalkoxy, haloC1 - C6alkyl , haloC1 - C6alkoxy.
- R 1 is selected from the group consisting of: H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
- R 1 is selected from the group consisting of: H, halogen, methyl, cyano, carboxamido, trifluoromethyl, difluoromethyl, methoxy, cyclopropyl, trifluoromethoxy.
- the 2-aminopyrimidine compound has the structure shown in the following formula (II):
- the present invention also provides the above-mentioned 2-aminopyrimidine compounds or their pharmaceutically acceptable salts, isotopic derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their precursors Application of drug molecules and metabolites.
- the tumor is a hematological tumor and a solid tumor
- the hematological tumor is multiple myeloma, B lymphoma, myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid Leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, histiocytic lymphoma, acute megakaryocyte leukemia, prolymphocytic leukemia, T lymphoblastic leukemia, T lymphoblastic lymphoma; said solid tumor
- non-small cell lung cancer small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, nasopharyngeal cancer, glioma
- the inflammatory disease is rheumatoid arthritis, atopic fibrosis,
- the present invention also provides a pharmaceutical composition for preventing and treating tumors and/or inflammatory diseases.
- a pharmaceutical composition for preventing and treating tumors and/or inflammatory diseases prepared from active ingredients and pharmaceutically acceptable carriers or auxiliary materials, the active ingredients include the above-mentioned 2-aminopyrimidine compounds or their pharmaceutically acceptable
- the present invention provides a class of 2-aminopyrimidine compounds with novel structures or their pharmaceutically acceptable salts, isotopic derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or Its prodrug molecules and metabolites can inhibit the kinase activity of Janus Kinase 3 (JAK3) with high efficiency and selectivity.
- the cells have strong signal inhibitory effects and cell proliferation inhibition effects, and can be used for preparing anti-tumor and therapeutic drugs for inflammatory diseases related to JAK3 kinase.
- Figure 1 shows the single crystal structure of Intermediate 3-1.
- FIG. 2 shows the single crystal structure of Intermediate 9.
- Figure 3 shows the results of the pharmacokinetic experiment of compound LS6-45.
- Figure 4 shows that compound LS6-45 inhibits the activation of JAK3 pathway in U937 cells.
- Figure 5 shows the results of the elution experiment of compound LS6-45.
- Figure 6 shows the effect of compound LS6-45 on U937 cell cycle arrest and apoptosis.
- Figure 7 shows the results of in vivo antitumor activity of the test compound LS6-45 in mice.
- any variable eg, R3 , R4, etc.
- the definition of each occurrence is independent of the definition of each other.
- combinations of substituents and variables are permissible so long as such combinations stabilize the compound.
- a line drawn into a ring system from a substituent indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atoms adjacent to the ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by the skill of the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
- alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- the definition of “ C1 - C6 " in " C1 - C6 alkyl” includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain arrangement.
- “ C1 - C6 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.
- cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
- cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.
- alkoxy refers to groups having an -O-alkyl structure, such as -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -O-CH 2 CH(CH 3 ) 2 , - OCH 2 CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 and the like.
- heterocyclyl is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent wherein one or more ring atoms are selected from N, O or S(O)m (where m is an integer from 0 to 2 ), the remaining ring atoms are carbon, such as: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydro oxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl , dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidine,
- halo means chlorine, fluorine, bromine and iodine.
- alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents can be unsubstituted or substituted.
- a C1 - C6 alkyl group can be substituted with one, two, or three substituents selected from OH, halogen, alkoxy, dialkylamino, or heterocyclyl groups such as morpholinyl, piperidinyl, and the like.
- the present invention provides a 2-aminopyrimidine compound having the structure represented by formula (I):
- R 1 is selected from: H, halogen, cyano, one or more R 11 substituted or unsubstituted C 1 -C 6 alkyl, one or more R 11 substituted or unsubstituted C 3 -C 6 cycloalkyl , one or more R 11 substituted or unsubstituted C 1 -C 6 alkoxy, one or more R 11 substituted or unsubstituted C 3 -C 6 cycloalkoxy, carboxamide;
- n 0 or 1
- L is O or S
- each R 10 Each independently selected from: hydrogen, halogen, hydroxyl, one or more R 11 substituted or unsubstituted C 1 -C 3 alkyl, one or more R 11 substituted or unsubstituted C 1 -C 3 alkoxy , the heteroatom is O, S and/or N;
- the present invention includes free forms of compounds of formula I or II, as well as pharmaceutically acceptable salts and stereoisomers thereof.
- Some of the specific exemplary compounds herein are protonated salts of amine compounds.
- the term "free form" refers to the amine compound in non-salt form.
- Included pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also typical pharmaceutically acceptable salts of all compounds of formula I or II in free form.
- the free forms of particular salts of the compounds can be isolated using techniques known in the art.
- the free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate.
- a suitable dilute aqueous base such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate.
- the free forms differ somewhat from their respective salt forms in certain physical properties such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
- the pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods.
- salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base and a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents.
- salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.
- pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
- conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Salts prepared from oxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulf
- salts derived from inorganic bases include aluminum salts, ammonium salts Salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred.
- Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-Ethylmorpholine, N-Ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine , piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
- deprotonated acidic moieties such as carboxyl groups in compounds can be anionic under physiological conditions, such charged charges can then be replaced by internally cationic protonated or alkylated basic moieties such as tetravalent
- the nitrogen atoms balance out, so it should be noted that the compounds of the present invention are potential inner salts or zwitterions.
- the present application provides a method for treating tumors or inflammatory diseases in humans or other mammals with a compound of Formula I or Formula II and pharmaceutically acceptable salts thereof.
- the compounds of the present application and pharmaceutically acceptable salts thereof can be used to treat or manage multiple myeloma, B lymphoma, myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloma Lineage leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, histiocytic lymphoma, acute megakaryocytic leukemia, prolymphocytic leukemia, T-lymphocytic leukemia, T-lymphoblastic lymphoma, non-small cell Lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, nasopharyngeal carcinoma, glioma, rheumatoid joint inflammation, atopic derma
- the present invention also provides a pharmaceutical composition, which comprises an active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier or adjuvant.
- the "active ingredient" in the present invention refers to the compound of formula I or formula II described in the present invention or a pharmaceutically acceptable salt, isotopic derivative, solvate thereof, or a stereoisomer, geometric isomer, Tautomers, or their prodrug molecules, metabolites.
- the "active ingredients" and pharmaceutical compositions of the present invention can be used as JAK protein kinase inhibitors, and can be used to prepare medicaments for preventing and/or treating tumors and/or inflammatory diseases.
- a “safe and effective amount” refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg of active ingredient/dose, more preferably 10-200 mg of active ingredient/dose.
- the "one dose” is one tablet.
- “Pharmaceutically acceptable carrier or excipient” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity.
- composition means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
- Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as hard Fatty acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
- gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate,
- the compound of formula I or formula II of the present invention can form a complex with a macromolecular compound or macromolecule through non-bonding interaction.
- the compound of formula I or formula II of the present invention as a small molecule, can also be linked with a macromolecular compound or a macromolecule through chemical bonds.
- the macromolecular compounds can be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides, and the like.
- the mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following:
- fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid;
- binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia;
- humectants for example, glycerin
- disintegrating agents for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate;
- absorption accelerators for example, quaternary amine compounds
- humectants such as cetyl alcohol and glyceryl monostearate
- adsorbents for example, kaolin
- Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
- the dosage form may also contain buffering agents.
- the solid dosage forms can also be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances and the like.
- the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- the compounds of the present invention may be administered alone or in combination with other therapeutic agents such as hypoglycemic agents.
- a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
- the administration dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
- the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
- the compounds of Formula I or Formula II may be used in combination with other drugs known to treat or ameliorate similar conditions.
- the administration mode and dosage of the original drug remain unchanged, while the compound of formula I or formula II is administered simultaneously or subsequently.
- a pharmaceutical composition containing one or more known drugs and a compound of formula I or formula II it is preferred to use a pharmaceutical composition containing one or more known drugs and a compound of formula I or formula II.
- Drug combinations also include administration of a compound of formula I or formula II with one or more other known drugs at overlapping time periods.
- the dose of the compound of formula I or formula II or known drugs may be lower than when they are administered alone.
- Drugs or active ingredients that can be used in combination with the compounds of formula I or II include, but are not limited to:
- the drugs or active ingredients that can be used in combination with the compounds of formula I or II include, but are not limited to: aldesleukin, alendronate, interferon, atranoin, allopurinol, Sodium allopurinol, Palonosetron hydrochloride, Hexamethylmelamine, Aminoglutide, Amifostine, Amrubicin, Amridine, Anastrozole, Dorasetron, aranesp, arglabin , Arsenic trioxide, Arnosine, 5-azacytidine, azathioprine, BCG or tic BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromine Urethane, bortezomib, busulfan, calcitonin, alezolizumab injection, capecitabine, carboplatin, casodex, cefesone, simole
- a novel 2-aminopyrimidine compound is provided.
- the compounds have a strong selective inhibitory effect on JAK3 kinase, can effectively inhibit the growth of various tumor cells, and can be used to prepare antitumor drugs.
- the compounds can effectively prevent the transmission of the JAK3-STAT5 signaling pathway, and can be used for the preparation of drugs for anti-inflammatory diseases.
- Reduced iron powder (1.42g, 25.3mmol) and ammonium chloride (4.6g, 84.3mmol) were added to the mixed solvent of ethanol/water (volume ratio 2:1) of intermediate 7 (2.85g, 8.43mmol), refluxed React for 2 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, and most of the solvent was spin-dried, extracted with dichloromethane three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography. Solid 4 (2.2 g, 87% yield) was isolated.
- the synthesis method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol is used instead of isosorbide (2) to participate in the reaction.
- the synthesis method is the same as that of Example 1LS 3-96, except that 4-fluoro-2-methoxy-1-nitrobenzene is used instead of 2-chloro-1-fluoro-4-nitrobenzene (5) to participate in the reaction.
- the synthesis method is the same as that of Example 1LS 3-96, except that 1-fluoro-2-methoxy-4-nitrobenzene is used instead of 2-chloro-1-fluoro-4-nitrobenzene (5), and N- Methylpiperazine was used in the reaction instead of 1-methyl-4-(piperidinyl-4-yl)piperazine hydrochloride (6).
- the synthesis method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 1-(4-aminophenyl)cyclopentane-1-methyl Nitrile was involved in the reaction in place of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4).
- the synthetic method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 4-(4-methylpiperazin-1-yl)aniline 3-Chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4) was involved in the reaction.
- the synthesis method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 3-chloro-4-(4-methylpiperazine-1- yl)aniline instead of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4) was involved in the reaction.
- the synthesis method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 4-(4-(4-methylpiperazin-1-yl) ) piperidin-1-yl)aniline instead of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4) participated in the reaction.
- the synthesis method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 3-methoxy-4-(4-(4-methyl) Piperazin-1-yl)piperidin-1-yl)aniline instead of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4) participated in the reaction .
- the synthetic method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 2-chloro-4-(4-(4-methylpiperazine) -1-yl)piperidin-1-yl)aniline was involved in the reaction instead of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4).
- the synthesis method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 3,5-dichloro-4-(4-(4-methyl) Piperazin-1-yl)piperidin-1-yl)aniline instead of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4) reaction.
- the synthetic method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol replaces isosorbide (2), 5-methyl-6-(4-(4-methylpiperidine) Azin-1-yl)piperidin-1-yl)pyridin-3-amino instead of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4 )Reacted.
- the synthetic method is the same as that of Example 1LS 3-96, except that 1,4:3,6-dianhydromannitol is used instead of isosorbide (2), 5-((4-ethylpiperazin-1-yl)methane yl)pyridin-2-amino instead of 3-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (4) was involved in the reaction.
- the synthesis method is the same as the synthesis of compound 3-1 in Example 1, except that 1,4:3,6-dianhydromannitol (8) is used instead of isosorbide (2) to participate in the reaction.
- the synthesis method is the same as the synthesis of compound 11, except that the raw material 14 is used instead of m-nitroaniline (10) to participate in the reaction.
- Reduced iron powder (9 mg, 0.16 mmol) and ammonium chloride (3 mg, 0.055 mmol) were added to the mixed solvent of ethanol/water (volume ratio 2:1) of intermediate 17 (32 mg, 0.055 mmol), and the reaction was refluxed for 2 hours . After the reaction was completed, it was cooled to room temperature, filtered through celite, and most of the solvent was spin-dried, extracted with dichloromethane three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography. 18 was isolated as a light grey solid.
- the synthesis method is the same as that of Example 16LS 5-12, except that 4-fluoro-2-methoxy-5-nitroaniline is used instead of 4-fluoro-3-nitroaniline (14) to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that morpholine is used instead of 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6) to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that 2-methylaminoethanol is used instead of 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6) to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that 2-butenoic acid is used instead of acrylic acid (13) to participate in the reaction.
- the synthesis method is the same as the synthesis of Example 16LS 5-12, except that methacrylic acid is used instead of acrylic acid (13) to participate in the reaction.
- the synthesis method is the same as the synthesis of Example 16LS 5-12, except that 4-bromocrotonic acid is used instead of acrylic acid (13) to participate in the reaction, and the obtained intermediate 19 and 2M dimethylamine tetrahydrofuran solution are substituted to obtain.
- the synthetic method is the same as that of Example 16LS 5-12, except that N,N,N'-trimethylethylenediamine replaces 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6 )Reacted.
- the synthetic method is the same as that of Example 16LS 5-12, except that 3-methyl-3,9-diazaspiro[5,5]undecane is used instead of 1-methyl-4-(piperidin-4-yl ) piperazine hydrochloride (6) participates in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that 4-(dimethylamino)piperidine is used instead of 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6) to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that 2,5-dichloropyrimidine is used instead of 2,4,5-trichloropyrimidine to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that 5-methyl-2,4-dichloropyrimidine is used instead of 2,4,5-trichloropyrimidine to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that N-ethylpiperazine is used instead of 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6) to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that 3-(dimethylamino)pyrrole is used instead of 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6) to participate in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that (1S,4S)-2-oxo-5-azabicyclo[2.2.1]heptane is used instead of 1-methyl-4-(piperidine-4- yl)piperazine hydrochloride (6) participates in the reaction.
- the synthesis method is the same as that of Example 16LS 5-12, except that 2-methyl-2,5-diazabicyclo[2.2.1]heptane is used instead of 1-methyl-4-(piperidin-4-yl ) piperazine hydrochloride (6) participates in the reaction.
- the method of subsequent synthesis steps is the same as the synthesis of Example 16LS 5-12, except that the reaction raw materials are replaced to participate in the reaction.
- the synthesis method is the same as that of Example 32LS 6-16, except that N,N,N'-trimethylethylenediamine replaces 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6 )Reacted.
- the synthesis method is the same as that of Example 32LS 6-16, except that morpholine is used instead of 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6) to participate in the reaction.
- the method of subsequent synthesis steps is the same as the synthesis of Example 32LS 6-16, except that the reaction raw materials are replaced to participate in the reaction.
- the synthesis method is the same as that of Example 36LS 6-59, except that N,N,N'-trimethylethylenediamine replaces 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6 )Reacted.
- the synthesis method is the same as that of Example 36LS 6-59, except that N-ethylpiperazine is used instead of 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (6) to participate in the reaction.
- Example 36LS 6-59 The synthetic method is the same as that of Example 36LS 6-59, except that compound 9 is replaced by intermediate 3-2, and 1-methyl-4-(piperidine) is replaced by N,N,N'-trimethylethylenediamine (34).
- Perid-4-yl)piperazine hydrochloride (6) participates in the reaction.
- the synthetic method is the same as that of Example 39 LS 6-88, except that N-ethylpiperazine is used instead of N,N,N'-trimethylethylenediamine (34) to participate in the reaction.
- Step 4 The synthesis of intermediates 45, 46, 47 and the target product LS6-121 is the same as that of LS5-12, except that the reaction raw materials are correspondingly replaced to participate in the reaction.
- the synthetic method is the same as that of Example 32LS 6-16, except that iodoethane is used to replace methyl iodide, and N,N,N'-trimethylethylenediamine is used to replace 1-methyl-4-(piperidin-4-yl ) piperazine hydrochloride (6) participates in the reaction.
- the synthetic method is the same as the synthesis of Example 32LS 6-16, except that iodoisopropane is used to replace methyl iodide, and N,N,N'-trimethylethylenediamine is used to replace 1-methyl-4-(piperidine-4- yl)piperazine hydrochloride (6) participates in the reaction.
- the kinase inhibitory activity of the compounds of the present invention against four members of the JAK family was tested with reference to the Z'-Lyte assay method, wherein the ATP concentration of each kinase was Km ; Family members have higher ATP affinity, so this example also tested the kinase inhibitory activity of the compounds against JAK3 when the ATP concentration was 1 mM.
- Test method First, the test compound was prepared into a 10 mM stock solution with DMSO, and serially diluted to 10 concentrations with a 3-fold gradient, for use. After diluting 5X reaction buffer into 1X reaction buffer (50 mM HEPES pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA) with deionized water, a mixture of kinase and peptide substrate was prepared with 1X reaction buffer , and phosphorylated peptide substrate solution, the kinase concentration was determined according to enzyme titration, and the final concentration of peptide substrate and phosphorylated peptide substrate was 2 ⁇ M.
- 1X reaction buffer 50 mM HEPES pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA
- ATP ATP to meet the test requirements (Note: According to the recommended concentration of the instructions, the ATP concentration of JAK1 kinase test is 75 ⁇ M, the ATP concentration of JAK2 kinase test is 25 ⁇ M, the ATP concentration of JAK3 kinase test is 10 ⁇ M, and the ATP concentration of TYK2 kinase test is 25 ⁇ M).
- the emission wavelengths at 460nm and 535nm were detected respectively.
- the phosphorylation rate of the substrate was obtained, and the activity of the kinase and the inhibitory effect on the kinase were further calculated. Impact.
- Table 3 Listed in Table 3 are compound numbers (corresponding to compound numbers in Examples 1-44) and corresponding kinase activity results.
- a ATP concentration is Km ; b ATP concentration is 1 mM
- kinase activity assay (Table 3) that the compounds of the present invention exhibit relatively high selective inhibitory activity against JAK3 subtype kinases.
- Some compounds (such as LS 5-12, LS 5-77, LS 5-62, LS 5-66, LS 5-74, LS 5-88, LS 5-91, LS 5-102, LS 5-143, LS 5-150, LS 5-152, LS 5-154, LS 6-45, LS 6-49, LS 6-77, LS 6-88, LS 6-105, LS 6-121, LS 7-13, LS 7-18, etc.) showed potent and selective JAK3 kinase inhibitory activity, and also maintained potent activity when the ATP concentration was 1 mM.
- Cell lines human chronic myeloid leukemia cell K562, human acute myeloid leukemia cell U937, human T lymphoblastic leukemia cell HuT78, human T lymphoblastic lymphoma cell line Jurkat. Cells were purchased from the Chinese Academy of Sciences Stem Cell Bank or ATCC.
- CCK-8 cell counting kit-8
- tumor cells in logarithmic growth phase were seeded in 96-well plates at a density of 1*10 4 cells/well, adherent cells were cultured overnight, and cells were suspended Direct drug stimulation.
- Test compounds of different concentrations maximum working concentration 10 ⁇ M, 10 gradients diluted at a ratio of 1:3) were added, and two duplicate wells were set for each concentration, with a final volume of 200 ⁇ L.
- 10 ⁇ L of CCK-8 reagent was added to each well, and the incubation was continued for 1-3 hours.
- the drug-induced inhibition of cell growth was calculated according to the following formula:
- Inhibition rate (%) (OD control-OD drug addition)/OD control ⁇ 100%
- the median inhibitory concentration ( IC50 ) was calculated.
- Vehicle intravenous 5% DMSO+10% polyethylene glycol-15 hydroxystearate+85% normal saline, oral 0.5% hydroxypropyl methylcellulose.
- Animals in the oral administration group were fasted overnight (10-14 hours) before administration, and fed 4 hours after administration. Weigh before administration, and calculate the dosage according to body weight.
- the drugs were administered by intravenous injection (iv, 5 mg/kg) or oral gavage (po, 15 mg/kg), respectively.
- Blood was collected from the jugular vein at time points 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, and 8h after administration. About 0.20 mL of each sample was collected, anticoagulated with heparin sodium, placed on ice after collection, and kept at 1 Plasma was centrifuged within hours (centrifugation conditions: 6800 g, 6 minutes, 2-8°C).
- Plasma samples were stored in a -80°C freezer prior to analysis.
- the biological sample analysis method and the analysis of all samples are completed by the analytical laboratory of Medicipua Pharmaceutical Technology (Shanghai) Co., Ltd., and the intra-day accuracy evaluation of the quality control samples is performed at the same time as the samples are analyzed, and more than 66.7% of the quality control samples are required. The accuracy is between 80-120%.
- the pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0, and the pharmacokinetic parameters and their mean and standard deviation were provided.
- Example 48 Stability test of rat liver microsomes for representative molecule LS6-45
- Prepare spiking solutions of test and reference compounds 500 ⁇ M spiking solution: add 5 ⁇ L of 10 mM stock to 95 ⁇ L acetonitrile; 1.5 ⁇ M microsome spiking solution (0.75 mg/mL): add 479.75 ⁇ L K/ 1.5 ⁇ L of 500 ⁇ M spiked solution and 18.75 ⁇ L of 20 mg/mL liver microsomes were added to Mg buffer).
- NADPH was then dissolved in K buffer to make a 6 mM, 5 mg/mL NADPH stock.
- liver microsome stability (Table 6) showed that the stable half-life T 1/2 of liver microsomes of the reference molecule Ketanserin was 18.71 minutes, which was consistent with historical data, indicating the reliability of the experiment.
- the half-life T 1/2 of the example molecule LS6-45 is greater than 120 minutes, indicating that this molecule has high liver microsomal stability.
- Example 49 Representative molecule LS6-45 effectively downregulates JAK3-STAT signaling in U937 cells
- FIG 4 The experimental results are shown in Figure 4, in which, Western Blot analysis of JAK3, STAT3, STAT5 proteins and their time/dose-dependent phosphorylation by compound LS6-45, with GAPDH as an internal reference.
- A is the time-dependent treatment of U937 cell line with compound LS6-45 (100 nM)
- B is the dose-dependent treatment of U937 cell line with compound LS6-45 for 10 h (800 nM 1:4 diluted five concentrations).
- Cell cycle detection Take well-growing cells and adjust the density to 8 ⁇ 10 5 cells/mL, and evenly divide them into 6-well plates, with 2 mL per well. The compound was then diluted in a gradient manner, added to the cell suspension, and incubated in an incubator for 24 hours. In this experiment, BD CycletestTM Plus DNA Reagent Kit was used for staining. After 24 h, the cells were collected into a 15 mL centrifuge tube, the 6-well plate was washed twice with PBS, the washes were combined into a 15 mL centrifuge tube, centrifuged at 12,000 rpm for 5 min, and the supernatant was discarded. Add 5 mL of buffer solution to each tube and gently resuspend the cells.
- PI solution C
- PI-stained samples need to be filtered with gauze before being loaded into the machine; it is recommended that the stained samples be placed on ice; the cells should not be over-digested, and the overall operation time should be as little as possible; A thin layer of cells is sufficient.
- Apoptosis detection Take well-growing cells and adjust the density to 8 ⁇ 10 5 cells/mL, and evenly divide them into 6-well plates, with 2 mL per well. Then the compound was serially diluted, added to the cell suspension, and placed in the incubator for 48h. In this experiment, PE-coupled Annexin-V apoptosis detection kit was used for staining. After 48 h, the cells were collected into a 15 mL centrifuge tube, the 6-well plate was washed twice with PBS, the washings were combined into a 15 mL centrifuge tube, centrifuged (1200 rpm ⁇ 5 min), and the supernatant was discarded.
- FIG. 6 shows the changes of cell cycle (A) and cell cycle-related proteins (B) after treating U937 cells with compound LS6-45 for 24 h, and the changes of apoptosis in U937 cells treated with compound LS6-45 for 48 h (C ).
- the results (Fig. 6) showed that U937 had obvious G0/G1 phase arrest after treatment with different concentrations of compound LS6-45, and showed a dose-dependent manner (A in Fig. 6); meanwhile, cell cycle-related proteins (CDK2, CDK4, CDK6, Cyclin B1, Cyclin D3 and Cyclin E1) were also significantly down-regulated after treatment (B in Figure 6). No apoptosis was observed in U937 cells treated with compound LS6-45 (C in Figure 6).
- mice 5 to 7 days after inoculation (U937 tumor grows very fast, observe once every 3 days), when the tumor grows to 100-200mm 3 in size, it is administered in groups, and animals that are too large or too small are excluded. Mice were randomly divided into administration group and solvent group, with 6 mice in each group. 50mg/kg, 25mg/kg and 12.5mg/kg doses of the drug were administered twice a day (bid), and 10mg/kg of the drug was intraperitoneally injected once (qd), and the control group was given an equal volume of solvent.
- the dosing cycle was 10 days, daily administration, and the animal body weight was weighed every 2 days to measure the tumor volume (the initial tumor volume and body weight were recorded on the day of grouping).
- the next day after the administration the animals were weighed and the tumor volume was measured, and the animals were sacrificed to dissect the tumor and weighed. Tumors were fixed with neutral formalin for pathological observation. Animal blood samples could be collected for routine blood analysis and major organs of animals were collected for pathological analysis according to experimental needs. At the end of the study, all animals were euthanized and tumors, livers, kidneys and lungs from nude mice were removed for further analysis.
Abstract
Description
LS6-45 | iv(5mg/kg) | po(15mg/kg) |
动物数量 | 3 | 3 |
C max(ng/mL) | 911.33±139.73 | 238.28±13.68 |
AUC (0-∞)(h*ng/mL) | 536.99±9.89 | 333.50±45.52 |
CL(mL/min/kg) | 155.22±2.83 | |
F(%) | 20.66±2.83 |
Claims (23)
- 具有式(Ⅰ)所示结构的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物:其中,R 1选自:H、卤素、氰基、一个或多个R 11取代或未取代的C 1-C 6烷基、一个或多个R 11取代或未取代的C 3-C 6环烷基、一个或多个R 11取代或未取代的C 1-C 6烷氧基、一个或多个R 11取代或未取代的C 3-C 6环烷氧基、甲酰胺基;R 2选自:H、卤素、-(CH 2) mNR 3R 4、-(CH 2) mCR 3R 4R 5或-(CH 2) mOCR 3R 4R 5;其中,各m分别独立地为0、1、2或3;各R 3和各R 4分别独立地选自:H、一个或者多个R 12取代的C 1-C 6烷基,或者R 3、R 4和与其相连的N或C一同形成一个或者多个R 12取代的环原子中含有0、1、2或3个杂原子的3-12元单环、稠环、桥环或螺环;R 5选自:H、氰基或C 1-C 3烷基;各R 12分别独立地选自:H、卤素、羟基、氨基、C 1-C 3烷基、-C(=O)NHR 13取代的C 1-C 3烷基、羟基取代的C 1-C 3烷基、C 3-C 6环烷基取代的C 1-C 3烷基、C 3-C 8杂环基取代的C 1-C 3烷基、C 1-C 3烷氧基、-NHR 13、-N(R 13) 2、-C(=O)R 13、R 13取代或未取代的含有0、1、2或3个杂原子的4-8元单环、稠环、桥环或螺环;R 13为C 1-C 3烷基;所述杂原子为O、S和/或N;W、X、Y、Z各自独立地为N或-CR 6;其中,R 6选自:氢、卤素、一个或多个R 11取代或未取代的C 1-C 3烷基、一个或多个R 11取代或未取代的C 1-C 3烷氧基、-NH-CN、-NHC(O)-CR 7=CR 8R 9、-NHS(O) 2-CR 7=CR 8R 9;R 7、R 8和R 9分别独立地选自:H、氰基、一个或多个R 11取代或未取代的C 1-C 6烷基;n为0或1;L为O或S;为一个或多个R 10取代的4-12元饱和或部分饱和的环原子中含有0、1、2或3个杂原子的单环、桥环、螺环或者稠环;其中,各R 10分别独立地选自:氢、卤素、羟基、一个或多个R 11取代或未取代的C 1-C 3烷基、一个或多个R 11取代或未取代的C 1-C 3烷氧基,所述杂原子为O、S和/或N;R 11选自:卤素、羟基、氨基、C 1-C 3烷基、C 1-C 3烷氧基、-NHR 13、-N(R 13) 2、-C(=O)R 13。
- 根据权利要求1-11任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物,其特征在于,R 2选自:H、卤素、-(CH 2) mNR 3R 4、-(CH 2) mCR 3R 4R 5;其中,各m分别独立地为0、1、2或3;各R 3和各R 4分别独立地选自:H、一个或者多个R 12取代的C 1-C 3烷基,或者R 3、R 4和与其相连的N或C一同形成一个或者多个R 12取代的环原子中含有0、1、2或3个杂原子的5-11元单环、稠环、桥环或螺环;R 5选自:H、氰基或C 1-C 3烷基;各R 12分别独立地选自:H、羟基、乙酰基、R 13取代或未取代的4-8元杂环基、卤素、羟基、氨基、C 1-C 3烷基、C 1-C 3烷氧基、-NHR 13、-N(R 13) 2;R 13为C 1-C 3烷基。
- 根据权利要求12所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物,其特征在于,R 2选自:H、卤素、-(CH 2) mNR 3R 4、-(CH 2) mCR 3R 4R 5;其中,各m分别独立地为0或1;各R 3和各R 4分别独立地选自:H、C 1-C 3烷基、羟基取代的C 1-C 3烷基、-NHR 13取代的C 1-C 3烷基、-N(R 13) 2取代的C 1-C 3烷基,或者R 3、R 4和与其相连的N或C一同形成一个或者多个R 12取代的环原子中含有0、1、2或3个杂原子的5-11元单环、桥环或螺环;R 5选自:H、氰基或C 1-C 3烷基;各R 12分别独立地选自:H、羟基、乙酰基、R 13取代的哌嗪基、C 1-C 3烷基、-NHR 13、-N(R 13) 2; R 13为C 1-C 3烷基。
- 根据权利要求1-11任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物,其特征在于,R 1选自:H、卤素、氰基、甲酰胺基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基。
- 根据权利要求15所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物,其特征在于,R 1选自:H、卤素、C 1-C 3烷基、C 1-C 3烷氧基。
- 根据权利要求1-11任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物,其特征在于,R 1选自:H、卤素、甲基、氰基、甲酰胺基、三氟甲基、二氟甲基、甲氧基、环丙基、三氟甲氧基。
- 权利要求1-19任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物在制备JAK3抑制剂中的应用。
- 权利要求1-19任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物在制备预防和/或***和/或炎症性疾病的药物中的应用。
- 根据权利要求21所述的应用,其特征在于,所述肿瘤为血液瘤和实体瘤,所述血液瘤为多发性骨髓瘤、B淋巴瘤、骨髓纤维化、真性红细胞增多症、原发性血小板增多症、慢性髓系白血病、急性髓性白血病、急性淋巴细胞性白血病、慢性粒细胞白血病、组织细胞淋巴瘤、急性巨核细胞白血病、幼淋巴细胞白血病、T淋巴细胞白血病、T淋巴母细胞性淋巴瘤;所述实体瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、鼻咽癌、胶质瘤;所述炎症性疾病为类风湿性关节炎、特应性皮炎、接触性皮炎、牛皮癣、银屑病、溃疡性结肠炎、克罗恩病、湿疹、盘状红斑狼疮、全身性红斑狼疮、斑秃、移植物抗宿主病、强直性脊柱炎、弥漫性皮肤***性硬化、皮肌炎。
- 一种防治肿瘤和/或炎症性疾病的药用组合物,其特征在于,由活性成分和药学上可接受的载体或者辅料制备得到,所述活性成分包括权利要求1-19任一项所述的2-氨基嘧啶类化合物或者其药学上可接受的盐、同位素衍生物、溶剂化物,或者其立体异构体、几何异构体、互变异构体,或者其前药分子、代谢产物。
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