WO2015047124A1 - Nouveaux composés chimiques dérivés de 2,4-diamino-1,3,5-triazine afin de prévenir et traiter des maladies d'humains et d'animaux - Google Patents

Nouveaux composés chimiques dérivés de 2,4-diamino-1,3,5-triazine afin de prévenir et traiter des maladies d'humains et d'animaux Download PDF

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WO2015047124A1
WO2015047124A1 PCT/RU2013/000840 RU2013000840W WO2015047124A1 WO 2015047124 A1 WO2015047124 A1 WO 2015047124A1 RU 2013000840 W RU2013000840 W RU 2013000840W WO 2015047124 A1 WO2015047124 A1 WO 2015047124A1
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amino
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Гермес Григорьевич ЧИЛОВ
Олег Валентинович СТРОГАНОВ
Виктор Сергеевич СТРОЙЛОВ
Федор Николаевич НОВИКОВ
Алексей Александрович ЗЕЙФМАН
Илья Юрьевич ТИТОВ
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Общество с ограниченной ответственностью "Молекулярные Технологии"
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Priority to PCT/RU2013/000840 priority Critical patent/WO2015047124A1/fr
Publication of WO2015047124A1 publication Critical patent/WO2015047124A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention relates to the treatment of allergic, autoimmune, oncological and other diseases with the help of new families of chemical compounds with increased efficiency in inhibiting SYK kinase and its mutant forms, as well as other therapeutically significant kinases, increased selectivity and bioavailability.
  • SYK kinase and its mutant forms as well as other therapeutically significant kinases, increased selectivity and bioavailability.
  • Protein kinases are an important family of proteins involved in the regulation of key cellular processes, the violation of the activity of which can lead to cancer, autoimmune diseases, chronic inflammatory diseases, diseases associated with tissue destruction, etc.
  • Imatinib Imatinib
  • Nilotinib Nilotinib
  • Dasatinitib Dasatinib
  • Sunitinib Soitenib
  • Sorafenib Sorafenib
  • Lapatinib Lapatinib
  • Gefitinib Erlotinib
  • Crizotinib Crizotinib
  • SYK kinase (Spleen tyrosine kinase) is a non-receptor cytoplasmic tyrosine kinase involved in signal transduction by antigenic and Fc receptors, BCR, and other receptors.
  • the most intense SYK kinase is expressed in hematopoietic cells (such as macrophages, mast cells, white blood cells, platelets and red blood cells), to a lesser extent - in epithelial cells, fibroblasts, neuronal cells, hepatocytes, etc. (Yanagi, S., et al., Biochem Biophys Res Commun, 2001, 288, 495-8).
  • SYK kinase activation triggers a cell cascade leading to the synthesis and release of large the number of modulators of inflammation that can cause the development of acute allergic reactions (Valent et al., Intl J Hematol, 2002, 75, 257-362).
  • SYK kinase plays a key role in the immune response, the development of autoimmune (Lee, DM. Et al., Lancet, 2001, 358, 903-1 1) and oncological diseases, such as lymphomas (Young, RM., Et al., Blood, 2009, 113, 2508-16).
  • SYK kinase Inhibition of SYK kinase is a promising strategy for combating various allergic, autoimmune, and oncological diseases caused by aberrant activity of cells expressing SYK kinase.
  • more than one hundred low molecular weight substances capable of inhibiting SYK are known (Xie, HZ, et al., Bioorg Med Chem Lett, 2009, 19, 1944-9).
  • R112, R343 developed on the basis of R1 12 as a form convenient for inhalation
  • R406 and R788, which are at different stages of clinical trials.
  • These structurally similar derivatives of 2,4-diaminopyrimidine were developed by Rigel Pharmaceuticals, Inc.
  • R788 was developed based on R406 to improve oral bioavailability (Bajpai, M., IDrugs, 2009, 12, 174-85). It is worth noting that R788 in the body breaks down, and the active substance, in fact, is R406.
  • R788 is currently undergoing clinical trials in rheumatoid arthritis (phase II) (Weinblatt, M.E., et al., N Engl J Med, 2010, 363, 1303-12) and non-Hodgkin lymphoma (phase II) (Friedberg, JW , et al., Blood, 2010, 115, 2578-85).
  • kinase inhibitors which are phosphoric derivatives containing diamino-triazine groups in a number of alternatives.
  • the compounds have activity against a whole group of kinases.
  • This invention relates to new chemical compounds, inhibitors of kinases, which have increased efficiency in inhibiting SYK kinase and its mutant forms, and are promising for use in the treatment of cancer, autoimmune, inflammatory and other diseases.
  • Y represents CH 2 , CHR ', CR D , C (R') 2 , NR ', 0, S, S (O) or S (0) 2 .
  • X 1, X2, X 3 are independently selected from CH, CR 'or N.
  • R 1 represents an aliphatic group, an aryl group, ethylenedioxyphenyl, methylenedioxyphenyl optionally substituted with one or more identical or different R ′′ groups
  • R ' represents hydrogen, OH, halogen, such as
  • R 21 , R 22 , R 23 , R 24 are independently selected from the groups F, C1,
  • a particular class of compounds of interest include compounds of formula I in which R 1 is aliphatic optionally substituted with one or more identical or different R groups. ”Illustrative examples of this class are the following compounds:
  • a separate class of compounds of interest include compounds of formula I in which R 1 represents an aryl, ethylenedio-diphenyl group optionally substituted with one or more identical or different R groups. ”Illustrative examples of this class are the following compounds:
  • One of the preferred embodiments of the invention are compounds of formula IA-1, in which R 1 represents a phenyl group optionally substituted with one or more identical or azine groups R ′′.
  • n 0,1,2,3, 4 or 5
  • a particularly preferred embodiment of the invention are compounds of formula IA-1 in which R represents an alkoxy group.
  • Illustrative examples of this class are the following compounds:
  • a separate preferred embodiment of the invention are compounds of formula IA-1, in which R is halogen or — CF 3 .
  • R is halogen or — CF 3 .
  • Illustrative examples of this class are
  • One preferred embodiment of the invention are compounds of formula IA-2, in which R 1 represents a 3,4-ethylenedioxyphenyl group optionally substituted with one or more identical or different R groups.
  • n 0,1,2,3 or 4; m— 1, 2 or 3 2.7.
  • Particularly preferred embodiment of the invention are compounds of formula IA-2, in which R 'represents an alkoxy group or halogen or haloalkyl.
  • R ' represents an alkoxy group or halogen or haloalkyl.
  • Illustrative examples of this class are the following compounds:
  • One of the preferred embodiments of the invention are compounds of formula IA-3 in which R 1 represents a 3,4-methylenedioxyphenyl group optionally substituted with one or more identical or azine R ′′ groups.
  • n 0.1 or 2; m— 1,2 or 3
  • Particularly preferred embodiment of the invention are compounds of formula IA-3, in which R "represents an alkoxy group or halogen or haloalkyl.
  • R represents an alkoxy group or halogen or haloalkyl.
  • Illustrative examples of this class are the following compounds:
  • a particular class of compounds of interest include compounds of formula I in which X or X 3 represents an N atom.
  • Illustrative examples of this class are the following compounds:
  • a particular class of compounds of interest include compounds of formula I in which X and X are CH or CR ′.
  • Illustrative examples of this class are the following compounds:
  • a particular class of compounds of interest include compounds of formula I in which Y represents CH2, CHR ′, CR D , C (R ′) 2 group.
  • Illustrative examples of this class are the following compounds:
  • a particular class of compounds of interest include compounds of formula I in which Y represents an NR ′, S, S (O) or S (0) 2 group.
  • Illustrative examples of this class are the following compounds:
  • Particularly preferred embodiment of the invention are compounds of formula IB-1, in which R 21 and R 22 represents alkyl (usually metal) group.
  • Illustrative examples of the class are the following compounds:
  • Formula IB-2
  • a particularly preferred embodiment of the invention are compounds of formula IB-2, in
  • R 1 and R represents halogen (usually fluorine).
  • halogen usually fluorine
  • kinases especially SYK, ZAP-70, JAKl JAK2, JAK3, BTK, TYK1 and LYN kinases, or other kinases of interest, with an IC50 value of 5 ⁇ M or less (obtained by any scientifically based inhibition experiment) kinases), preferably with an IC of 5 o 1 ⁇ M or lower, and optimally with an IC50 of 500 nM or lower; or
  • compositions comprising at least one compound of the invention or a salt, hydrate or other solvate thereof, and at least one pharmacologically acceptable excipient or additive.
  • Such compositions may be administered to an object, in need of suppression of aberrant activity and / or aberrant proliferation of cells of the immune system.
  • compositions may be useful for the treatment of allergic, autoimmune and oncological diseases according to the present invention, which includes the introduction (as monotherapy or in combination with one or more immunosuppressants or anti-cancer agents, one or more agents to alleviate side effects, radiation, and t .p.) a therapeutically effective amount of the subject compound to a human or animal organism in need of suppression aberrantly activity or aberrant proliferation of cells of the immune system.
  • administration is a method of treating or preventing diseases caused by one or more kinases inhibited by one of the disclosed compounds or their pharmacologically acceptable derivatives.
  • administering of a compound of the present invention to an organism includes the delivery to a recipient of a compound of the present invention, a prodrug, or other pharmacologically acceptable derivative of such a compound, using any suitable preparation or route of administration to the body, as described herein.
  • connection is introduced into the patient’s body once or several times a week, for example, daily, every other day, 5 days a week, etc.
  • Oral and intravenous administration is of particular interest.
  • pharmacologically acceptable derivative means any pharmacologically acceptable salt, ester or ester salt of a compound, as well as any other adduct or derivative which, when administered to a patient, is capable of (directly or indirectly) delivering the compound, its metabolite or its product decay (having a molecular weight of more than 300).
  • Pharmacologically acceptable derivatives thus include, in particular, prodrugs.
  • a prodrug is a derivative of a compound, usually with significantly reduced pharmacological activity, that contains an additional chemical group that can be removed in vivo to form the parent pharmacologically active molecule of the compound.
  • the prodrug may be an ester or amide, which decomposes in vivo to form the desired compound.
  • Prodrugs of various compounds, materials and methods for preparing a derivative of the starting compound are well known and can be adapted for the present invention.
  • Particularly advantageous derivatives and prodrugs of the starting compounds are those derivatives and prodrugs that increase the bioavailability of the compound when introduced into the body of a mammal (for example, by increasing absorption in the blood when taken orally), or those that increase delivery to the body of interest relative to the starting compound.
  • Preferred prodrugs include derivatives of the subject compound with increased solubility in water or more actively penetrating the intestinal membrane compared to the parent compound.
  • An important aspect of the invention is a method for the prevention and treatment of human and animal diseases, based on the inhibition of one or more protein kinases, including but not limited to SYK, ZAP-70, JAK1, JAK2, JAK3, BTK, TYK1 and LYN kinases, with a therapeutically effective amount of a composition comprising compound of the invention.
  • protein kinases including but not limited to SYK, ZAP-70, JAK1, JAK2, JAK3, BTK, TYK1 and LYN kinases
  • Treatment can be carried out in combination with one or more other drugs and non-drug therapy, including surgery, radiation (for example, gamma radiation, neutron, electron, proton radiation therapy, brachytherapy, etc.), hormone therapy, biological response modifiers, hyperthermia, cryotherapy, agents to mitigate any adverse effects (e.g., antiemetics), as well as other anti-cancer chemotherapeutic drugs.
  • radiation for example, gamma radiation, neutron, electron, proton radiation therapy, brachytherapy, etc.
  • hormone therapy for example, neutron, electron, proton radiation therapy, brachytherapy, etc.
  • biological response modifiers for example, antigen therapy, etc.
  • hyperthermia for example, antigen therapy, etc.
  • cryotherapy agents to mitigate any adverse effects (e.g., antiemetics), as well as other anti-cancer chemotherapeutic drugs.
  • Other agent (s) can be introduced into the patient's body using either similar or different from those used for the compounds of the present invention, preparation
  • the invention also includes the preparation of compounds according to any one of formulas I, IA-1, IA-2, IA-3, IB-1, IB-2, or any other compounds of the present invention.
  • the invention also includes the use of a compound of the invention or a pharmacologically acceptable derivative thereof in the manufacture of a medicament for the treatment of allergic, autoimmune, oncological diseases, as well as diseases associated with tissue destruction or inflammation.
  • the compounds that make up the essence of the present invention can be used in the manufacture of drugs for the prevention and treatment of diseases associated with aberrant activity of cells of the immune system.
  • Compounds of the essence of the present invention can be used in the production of anti-cancer drugs.
  • the compounds of the present invention can also be used in the manufacture of medicaments to alleviate or prevent various disorders by inhibiting one or more kinases, such as SYK, ZAP-70, JAK1, JAK2, JAK3, BTK, TYK1 and LYN, etc.
  • compositions containing compounds of the present invention including compounds of any of the described classes or subclasses, including any of the formulas described above, inter alia, preferably in a therapeutically effective amount, in combination with at least one therapeutically acceptable carrier, adjuvant or solvent.
  • the compounds of the present invention can also be used as standards and reagents for characterizing various kinases, in particular, but not limited to, SYK, ZAP-70, JAK1, JAK2, JAK3, BTK, TYK1 and LYN kinases, as well as to study the role of such kinases in biological and pathological phenomena; to study the signaling pathways carried out using such kinases, for a comparative assessment of new kinase inhibitors; as well as for the study of various types of cancer in models of cell lines and animals.
  • aliphatic as used herein means both saturated and unsaturated (but not aromatic) straight (i.e. unbranched), branched, cyclic or polycyclic non-aromatic hydrocarbon chain — a residue that may optionally be substituted with one or more functional groups.
  • alkyl, other aliphatic, alkoxy and acyl groups usually contain 1-8 (i.e. Ci-s), and in most cases 1-6 (C.) of adjacent aliphatic carbon atoms.
  • such aliphatic groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methylene, cyclopropyl allyl, n-butyl, ewo 7-butyl, cyclobutyl, cyclobutylmethyl, n-pentyl, 2-cyclopentenyl, cyclopentyl, tert- pent, isopentyl, cyclopentylmethyl, n-hexyl, sec-tex, cyclohexyl, cyclohexylmethyl, propargyl, allyl, homoallyl, homopropargyl, adamantyl derivatives and the like, which may contain one or more substituents.
  • the term "aliphatic" therefore, means the inclusion of alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl fragments.
  • alkyl as used herein means both straight or branched, cyclic or polycyclic alkyl groups. Similar conventions apply to other general terms, such as alkenyl, alkynyl, etc. In addition, “alkyl”, “alkenyl”, “alkynyl” and similar groups can be both substituted or unsubstituted.
  • alkyl refers to groups typically having from one to eight, preferably from one to six carbon atoms.
  • “alkyl” may mean methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, cyclobutyl, tert-butsh, cyclobutyl, pentyl, cyclopentyl, tert-pentyl, isopentyl, hexyl, isohexyl, cyclohexyl etc.
  • substituted alkyl groups include, but are not limited to, the following groups: fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, 2-phenylethyl, substituted 2-phenylethyl, etc.
  • the term Ci. 6 alkyl means alkyl containing from 1 to 6 carbon atoms and includes C 1? C 2 , C3, C 4 , C5, and C are b- alkyl groups.
  • alkoxy refers to alkyl groups corresponding to the definition given above, and which are attached to the molecule via a bridging oxygen atom.
  • alkoxy means —O-alkyl, where the alkyl group contains from 1 to 8 carbon atoms in the form of a linear (unbranched) or branched chain or in the form of a cycle.
  • alkoxy groups include, but are not limited to, the following groups: methoxy, ethoxy, n-propoxy, n-butoxy, mpem-butoxy, allyloxy, cyclobutoxy, etc.
  • haloalkyl includes branched and linear saturated hydrocarbon chains in which one or more hydrogen atoms are replaced by halogen.
  • haloalkyl groups include, but are not limited to, the following groups: difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, 1, 1,1,3,3,3-hexafluoro-2-methylpropan-2-yl, and the like.
  • alkenyl refers to groups usually having from two to eight, more often from two to six carbon atoms.
  • alkenyl may mean ⁇ -2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-5-enyl, 2,3- dimethylbut-2-enyl and the like.
  • alkynyl also refers to groups usually having from two to eight, more often from two to six carbon atoms, including, but not limited to, the following groups: ⁇ -2-ynyl, but-2-ynyl, but-3-ynyl , pent-2-ynyl, 3-methyl pent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc.
  • cycloalkyl refers to groups having from three to 12, usually from three to ten carbon atoms in a mono-, di- or polycyclic (ie ring) structure.
  • cycloalkyls include, but are not limited to, the following radicals: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like, which, as with other aliphatic or heteroaliphatic or heterocyclic substituents, may be substituted.
  • cycloalkyl and “carbocycle” are equivalent.
  • aryl used alone or as part of a larger moiety, such as “arylalkyl,” “aroxy,” or “aryloxyalkyl,” means groups containing an aromatic ring and having six to fourteen carbon atoms in such a ring, such as phenyl , 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl.
  • Aryl cycles may contain one or more substitutes.
  • aryl may be used interchangeably with the term “aryl ring”.
  • Aryl also includes polycyclic aromatic systems in which the aromatic cycle combines one or more cycles.
  • aryl cyclic groups include, but are not limited to, phenyl, hydroxyphenyl, galgenophenyl, alkoxyphenyl, dialkoxyphenyl, trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthracenyl, phenanthrocenyl, and the like, as well as 1-naphthyl, 2- naphthyl, 1-anthracyl and 2-anthracyl.
  • aryl includes groups in which the aromatic ring is connected to one or more non-aromatic rings or heterocycles, such as indanyl, phenanthridinyl or tetrahydronaphthyl, 3,4-ethylenedioxyphenyl, in which the radical atom or junction belongs to the aromatic ring.
  • a stable or chemically feasible compound is a compound whose lifetime is sufficient for its synthesis and analytical detection.
  • Preferred compounds of this The inventions are quite stable and do not decompose at temperatures up to 40 ° C in the absence of moisture or other chemically active conditions for at least one week.
  • Certain compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds, unless otherwise indicated.
  • a particular optical isomer can be obtained by resolving the racemic mixture in accordance with a standard procedure, for example, by preparing diastereoisomeric salts by treatment with an optically active acid or base followed by separation of the mixture of diastereomers by crystallization, followed by the isolation of optically active bases or acids from these salts.
  • suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluolvic and camphorsulfonic acid.
  • Another technique for separating optical isomers is to use a chiral chromatographic column.
  • another separation method involves the synthesis of covalent diastereomeric molecules by reacting the compounds of the invention with an optically pure acid in an activated form or an optically pure base.
  • the resulting diastereomers can be separated by conventional methods, for example, chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.
  • optically active compounds of this invention can be prepared using optically active starting materials.
  • Such isomers may be in the form of a free acid, free base, ester or SALT.
  • the compounds of the invention may exist in a radioisotope-labeled form, i.e. these compounds may contain one or more atoms, whose atomic mass or mass number differs from the atomic mass or mass number most common in nature.
  • Napirimer, radioisotopes of hydrogen, carbon, phosphorus, chlorine include 3 N, 14 C, 32 P, S, and O, respectively.
  • Compounds of the present invention that contain such radioisotopes and / or other radioisotopes of other atoms are within the scope of the present invention.
  • Deuterieva, i.e. 2 N, tritium, i.e. 3 N and carbon, i.e. 14 C radioisotopes are particularly preferred due to the ease of preparation and detection.
  • Radioisotope-labeled compounds of the present invention can be obtained using methods well known to specialists in this field. Labeled compounds can be prepared using the procedures described herein by simply replacing unlabelled reagents with the corresponding labeled reagents.
  • the compounds of the present invention can be prepared using various well-known synthetic procedures, including the synthetic procedures described below.
  • the synthesis of chemical compounds that are the subject of the present invention can be carried out from commercially available starting reagents or starting reagents that can be obtained by the methods described in (Weigand - Hilgetag. Experimental Methods in Organic Chemistry. Ed. by Prof. N. N. Suvorov. M, Chemistry, 1968, “Syntheses of Heterocyclic Compounds”, issue 1-16 Yerevan 1956-1987; “Syntheses of Organic Preparations” chL-12 M. 1949-1964; “Syntheses of Organic Compounds with Isotopes of Hydrogen” Merrey A., William D. L.
  • the compounds described in this invention can be used to treat diseases in the pathogenesis of which protein kinases are involved.
  • the compounds described in this invention are capable of inhibiting tyrosine kinases SYK, ZAP-70, JAK1, JAK2, JAK3, BTK, TYK1 and LYN.
  • a number of compounds constituting the present invention suppress the aberrant activity of cells of the immune system in vitro experiments and have in vitro antiproliferative activity against cancer cell lines, such as, for example, Daudi, NAMALVA, RZNZ, P3HR-1, Raji .
  • Such compounds are of interest for the treatment of autoimmune, allergic and oncological diseases, and in particular for the treatment of diseases resistant to other methods of therapy.
  • autoimmune diseases e.g. Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis, malignant anemia, autoimmune, autoimmune, autoimmune, Goodpasture syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia graves disease, primary biliary cirrhosis of the liver, chronic aggressive hepatitis, ulcerative colitis t, membrane glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, Reiter’s syndrome, polymyositis, dermatomyositis, systemic scleroderma, nodular polyarthritis, multiple sclerosis, etc.) and oncological diseases (for example, conjunctivitis, rhinitis, asthma, atopic dermatitis, food allergies, etc.), autoimmune diseases (e.g. Hashimoto's thyroiditis, autoimmune hemolytic
  • SYK kinase (Spleen tyrosine kinase) is a non-receptor cytoplasmic tyrosine kinase involved in signal transduction by antigenic and Fc receptors, BCR, and other receptors. Most intensely, SYK kinase is expressed in hematopoietic cells (such as macrophages, mast cells, white blood cells, platelets and erythrocytes), to a lesser extent - in epithelial cells, fibroblasts, neuronal cells, hepatocytes, etc. (Yanagi, S., et al., Biochem Biophys Res Commun, 2001, 288, 495-8).
  • hematopoietic cells such as macrophages, mast cells, white blood cells, platelets and erythrocytes
  • SYK kinase Activation of the SYK kinase triggers a cellular cascade leading to the synthesis and release of a large number of inflammatory modulators that can cause the development of acute allergic reactions (Valent et al., Intl J Hematol, 2002, 75, 257-362).
  • SYK kinase plays a key role in the immune response, the development of autoimmune (Lee, DM. Et al., Lancet, 2001, 358, 903-1 1) and cancer, such as lymphoma (Young, RM., Et al., Blood, 2009, 1 13, 2508-16).
  • Inhibition of SYK kinase is a promising strategy for combating various allergic, autoimmune, and oncological diseases caused by aberrant activity of cells expressing SYK kinase.
  • the use of the SYK inhibitor as a monotherapy drug or in combination with current chemotherapy agents against various oncological, autoimmune and allergic diseases will allow achieving a significant and long-term remission, or the SYK inhibitor can be used as a means of maintenance therapy, designed to prevent possible relapse in patients in need of such treatment.
  • the subject of this invention includes the administration to a subject in need of appropriate treatment of a therapeutically effective amount of a compound of this invention.
  • “Therapeutically effective amount” refers to the amount of a compound that is necessary for detectably killing cancer cells or inhibiting their growth or spread rate throughout the body, the size or number of tumors, or other characteristics of the cancer. The exact amount required can vary from subject to subject depending on the type, age and general condition of the patient, the severity of the disease, the characteristics of the anticancer agent, the method of administration of the drug, combined treatment with other drugs, etc.
  • the substance, or pharmaceutical composition containing the substance can be introduced into the patient's body in any quantity and by any route of administration effective to suppress aberrant activity and / or suppressing aberrant proliferation of cells of the immune system.
  • Single doses of the drug compounds constituting the subject of the present invention are preferably formulated in a form convenient for administration to a patient.
  • the expression "single dose” in terms of the present invention means a portion of the drug suitable for treating a patient. According to existing practice, the total daily dose of the compounds and compositions described in the present invention, is prescribed by the attending physician, relying on a thorough medical opinion.
  • the specific therapeutically effective dosage level for each particular patient or organism depends on a number of factors, including the type of disorder, the severity of the disease, the activity of the particular drug used, the characteristics of the pharmaceutical composition, age, body weight, general health, gender and diet of the patient, method and schedule of administration , metabolic rate and / or excretion of the compound, duration of treatment, medications used in combination or in conjunction with the administration of the compound of the invention I, and like factors well known in medicine.
  • compositions that make up the essence of the invention can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (using skin patches, powders, ointments or drops), sublingually, buccally, in the form of a spray for mouth or nose, etc.
  • the compound is administered to a patient in need of such treatment in a daily dosage of from about 50 to 2000 mg per patient.
  • the introduction can be carried out both once and several times a day, week (or any other time interval), or from time to time.
  • the compound may be administered to the patient once or several times a day on a weekly basis (for example, every Monday) for an indefinite time or for several weeks (for example, 4-10 weeks).
  • the compound may be introduced into the body.
  • the patient daily for a certain period of days (for example, 2-10 days), and then a period without taking the substance (for example, 1-30 days) follows.
  • a cycle can be repeated indefinitely or for a predetermined number of cycles, for example 4-10 cycles.
  • the compound of the present invention can be administered into the patient’s body daily for 5 days, followed by a break of 2 days, and so on, repeating the cycle an undetermined number of times, or for 4-10 cycles.
  • the amount of compound that will be effective in treating or preventing a particular disorder or condition depends, in particular, on well-known factors that influence the effective dosage of drugs.
  • in vitro or in vivo measurements can optionally be used to determine the optimal dose range.
  • a rough way to determine the effective dose is to extrapolate the dose-response curves, which will depend on the in vitro or animal testing model.
  • the exact dosage level determined by the attending physician depends on well-known factors, including the method of administration of the drug, as well as the age, body weight, gender and general health of the patient; the nature, severity and clinical condition of the disease; use (or non-use) of concomitant therapy as well as the nature and extent of genetic changes in the patient’s cells.
  • the effective dosage of a compound of this invention may vary depending on the particular compound used, the route of administration of the drug to the body, the conditions and severity of such administration; the state of the disease, as well as a different number of physical factors associated with the patient undergoing treatment. In most cases, a satisfactory result can be achieved by administering to the patient a compound in a daily dosage of from about 0.05 mg / kg to 500 mg / kg, usually between 0.1 and 150 mg / kg.
  • the estimated daily dosage is expected to vary depending on the method of administration to the patient. Thus, the dosage level for parenteral administration often ranges from 10 to 20% of the oral dosage level.
  • the compound of the present invention is used as part of a combination therapy regimen, a dose of each of the components of the combination therapy is administered during the required treatment period.
  • the compounds that make up the combination therapy can be administered to the patient at a time in the form of dosages containing all components, and in the form of individual dosages of the components; in addition, the combination compounds may be administered to the patient at different times during the treatment period, or one of them may be administered as a preliminary therapy for the other.
  • the compounds of this invention may exist in free form during processing, or, if desired, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. A detailed description of the properties of such salts is given by Berge SM, et al., In "Pharmaceutical Salts” J. Pharmaceutical Science, 66: 1-19 (1977), incorporated herein by reference.
  • Salts may be prepared in situ by isolation or purification. compounds of the invention, and can also be obtained separately, by reacting the free acid or free base of the compounds of the invention with a suitable base or acid, respectively.
  • suitable base or acid examples include amino salts formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic, methanesulfonic or malonic acids, or obtained other methods used in this field, for example, using ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, heptofluorosulfonate, glycetate gluconate , heptane, hexanate, hydroiodide, 2-hydroxy ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectin, pectin 3-phenyl propionate, phosphate, picrate, pivalate, propionate,
  • Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium and others.
  • pharmaceutically acceptable salts may contain, if desired, non-toxic cations of ammonium, quaternary ammonium and amine obtained using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
  • ester means an in vivo hydrolyzable ester that readily decomposes in the human body to the parent compounds or their salts.
  • a suitable ester group includes, for example, derivatives of pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic, alkenic, cycloalkanoic and alkanedienic acids, in which each alkyl or alkenyl component usually has no more than 8 carbon atoms. Examples of specific esters include derivatives of formates, acetates, propionates, butyrates, acrylates and ethyl succinates.
  • esters can also be formed by a hydroxyl group or a carboxylic acid group of a compound of the invention.
  • pharmaceutically acceptable prodrug form in the context of this invention, means such prodrugs from among the compounds that make up the essence of this invention, which are suitable for use by humans and animals without undue toxicity, irritation, allergic reactions, etc., correspond to a reasonable balance of benefits and risk.
  • prodrugs means compounds that are transformed in vivo to form the parent compound of the above formula, for example, by hydrolysis in blood (See T. Higuchi and V. Stella, Drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987).
  • compositions which contain one of the compounds described herein (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers or excipients. These compositions may also contain one or more additional therapeutic agents. Alternatively, a compound of the invention may be administered to a patient in need of appropriate therapy in combination with one or more other therapeutic regimens (e.g., in conjunction with other kinase inhibitors, antibodies that block TNP binding to TNFR, methotrexate, etc.) .
  • other therapeutic regimens e.g., in conjunction with other kinase inhibitors, antibodies that block TNP binding to TNFR, methotrexate, etc.
  • compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants, etc., suitable for a particular dosage form.
  • pharmaceutically acceptable carriers may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants, etc.
  • compositions are within the scope of this invention.
  • Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; malt, gelatin; talcum powder; excipients such as: cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers.
  • composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate
  • dyes such as sodium lauryl sulfate and magnesium stearate
  • release fluids such as sodium lauryl sulfate and magnesium stearate
  • film-forming agents such as sodium lauryl sulfate and magnesium stearate
  • sweeteners such as sodium lauryl sulfate and magnesium stearate
  • flavors and fragrances such as sodium lauryl sulfate and magnesium stearate
  • preservatives and antioxidants such as sodium lauryl sulfate and magnesium stearate
  • the subject of this invention are also dosage forms - a class of pharmaceutical compositions whose composition is optimized for a particular route of administration to the body in a therapeutically effective dose.
  • the medicinal compositions of this invention can be administered orally, topically, rectally, intraocularly, pulmonally, for example, as an inhalation spray, or intravascularly, intranasally, intraperitoneally, subcutaneously, intramuscularly, intrasternally, as well as by infusion, in the recommended dosages.
  • the pharmacologically active compounds that make up the essence of this invention can be processed in accordance with generally accepted methods of pharmaceutical production to obtain the appropriate dosage forms for administration to a patient, including humans and other mammals.
  • the dosage form When administered orally, the dosage form may be, for example, in the form of a tablet, capsule, suspension or liquid.
  • the dosage form is preferably made in the form of a unit dose containing a certain amount of the active ingredient.
  • Such a unit dose is tablets or capsules, which may contain from 1 to 2000 mg of the active ingredient, preferably from 1 to 500 mg, usually 5 to 200 mg.
  • a suitable daily dose for a human or other mammal depends on the condition of the patient and other factors.
  • the active compounds constituting the essence of the invention are usually combined with one or more adjuvants, excipients or carriers suitable for the chosen route of administration.
  • the compound can be mixed with lactose, sucrose, starch powder, cellulose ethers and alkanoic acids, alkyl cellulose ethers, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration to the patient.
  • Such capsules or tablets may have the property of controlled release of the active compound, provided that the active compound is dispersed in hydroxypropylmethyl cellulose.
  • Dosage forms suitable for topical use include liquid or semi-liquid preparations suitable for penetration through the skin (for example, ointments, lotions, rubbing, creams or pastes), as well as drops suitable for administration through the eye, nose or ear.
  • a typical dosage of the active compound of this invention is in the range of from 0.1 to 150 mg, administered daily from one to four times, preferably once or twice a day.
  • the content of the active ingredient in the dosage form can be from 0.001 to 10 mass. %, for example, from 1% to 2% by weight of the drug.
  • the mass fraction of the active ingredient may also be up to 10 mass. %, preferably not more than 5 mass. %, and even more preferably from 0.1 to 1% by weight of the drug.
  • the active ingredient can be used with any paraffin or water-soluble base.
  • a cream may be prepared.
  • the aqueous phase of the cream base may include, for example, from 30 mass. % polyhydric alcohols such as propylene glycol, butyl-1,3-diol, mannitol, sorbitol, glycerin, polyethylene glycol or mixtures thereof.
  • a topical preparation may also include compounds that facilitate absorption or penetration of the active ingredient through the skin or other areas. Examples of such compounds for enhancing penetration through the skin are dimethyl sulfoxide and the like.
  • the compounds of the invention can also be administered to a patient using transdermal devices.
  • the transdermal administration is carried out using a sticker or patch with a reservoir and a porous membrane, or with a solid phase carrier.
  • the active ingredient is delivered continuously from the container or microcapsules through the membrane into the permeable to the active agent layer, which is in contact with the skin or mucous membrane of the patient. If the active agent is absorbed into the skin, a controlled and predetermined amount of the active agent is administered to the patient.
  • the encapsulating material may serve as a membrane.
  • the oil phase of the emulsion included in this invention can be created from known ingredients in a known manner.
  • the oil phase may consist only of an emulsifier, or may contain a mixture of at least one emulsifier with fat or oil, or both at the same time.
  • hydrophilic emulsifier used in conjunction with a lipophilic emulsifier that acts as a stabilizer. It is also desirable to use both fat and oil at the same time.
  • the emulsifier (s), with or without stabilizer (s) form the so-called emulsion wax, and the wax together with fat and oil forms the so-called emulsifying ointment base, which makes up the oil phase of the cream.
  • Emulsifiers and emulsion stabilizers suitable for use in pharmacological formulations based on the compounds of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glycerol distearate, alone or together with wax or other materials known in pharmacology.
  • the selection of suitable oils or fats for an optimal composition is based on the desired cosmetic properties.
  • the cream should preferably be non-greasy, non-staining and easy to rinse, in a consistency that avoids leakage from a tube or other container.
  • Straight or branched chain mono- or di-basic alkyl esters such as diisoadipate, isoacetyl stearate, diesters of propylene glycol and coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a branched chain ester mixture.
  • These substances can be used alone or in combination, depending on the required properties.
  • lipids with a high melting point can be used, as well as white soft paraffin and / or liquid paraffin or other mineral oils.
  • Formulations suitable for topical ophthalmic use also include eye drops in which the active ingredients are dissolved or suspended in a suitable vehicle, especially an aqueous solvent.
  • a suitable vehicle especially an aqueous solvent.
  • the selected concentration of the active ingredient is from 0.5 to 20%, preferably from 0.5 to 10%, in particular about 1.5 mass. %
  • Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions.
  • Such solutions or suspensions may be prepared from sterile powders or granules using one or more carriers or solvents listed for use in oral formulations, or other suitable dispersing or wetting or suspending agents.
  • the compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn, cottonseed, peanut, sesame oil, benzyl alcohol, sodium chloride, and other buffer solutions.
  • the active ingredient may also be administered to the patient by injection into compositions with suitable carriers, including saline, dextrose solution, a solubilizing solvent (e.g. propylene glycol), or a micellar solubilizer (e.g. Tween 80).
  • suitable carriers including saline, dextrose solution, a solubilizing solvent (e.g. propylene glycol), or a micellar solubilizer (e.g. Tween 80).
  • suitable carriers including saline, dextrose solution, a solubilizing solvent (e.g. propylene glycol), or a micellar solubilizer (e.g. Tween 80).
  • suitable carriers including saline, dextrose solution, a solubilizing solvent (e.g. propylene glycol), or a micellar solubilizer (e.g. Tween 80).
  • sterile oils are often used as solvents or suspending agents.
  • the dosage form may be an aerosol (including powder) and administered via an inhaler.
  • Suppositories for rectal administration of the drug can be performed by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycol, solid at ordinary temperature but liquid at rectal temperature, so that the excipient melts in the rectum and releases the drug.
  • a suitable non-irritating excipient such as cocoa butter and polyethylene glycol
  • the dosage form may be subjected to conventional pharmaceutical operations, such as sterilization, and / or may contain conventional additives, such as preservatives, stabilizers, humectants, emulsifiers, buffers, etc. Tablets and pills may additionally be enteric coated.
  • Such compositions may also contain adjuvants, such as humectants, sweeteners, flavorings, deodorizing agents.
  • the dosage form of the present invention may contain a compound of the formula described here or a pharmaceutically acceptable salt thereof, and an additional preparation, for example, selected from the following: kinase inhibitor, antidepressant, antitumor drug, antiviral drug, anti-inflammatory drug, antifungal drug or compound against vascular hyperproliferation, and any pharmaceutically acceptable carrier, adjuvant or solvent.
  • an additional preparation for example, selected from the following: kinase inhibitor, antidepressant, antitumor drug, antiviral drug, anti-inflammatory drug, antifungal drug or compound against vascular hyperproliferation, and any pharmaceutically acceptable carrier, adjuvant or solvent.
  • pharmaceutically acceptable carrier or adjuvant means a carrier or adjuvant that can be introduced into the patient’s body together with the compound that is the essence of this invention, and which does not destroy the pharmacological activity of this compound, and is non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • Pharmaceutically acceptable carriers, adjuvants and solvents that can be used in the pharmaceutical composition of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-alpha-tocopherol polyethylene glycol succinate surfactants in pharmaceutical forms, such as Twins, or other similar polymer delivery matrices, whey proteins, such as human serum albumin, buffer such as phosphonates, glycine, sorbic acid, potassium sorbate, partial mixtures of vegetable saturated fatty acid glycerides, water, salts or electrolytes such as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium silicate , polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, wax, polyethylene-polyoxypropylene block copoly
  • Cyclodextrins such as i-, P- and y-cyclodextrin or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins or other soluble derivatives, can also be used successfully to enhance the delivery of a compound of the formula described herein.
  • compositions of the present invention can be administered orally to a patient in any available dosage form, including, but not limited to, capsules, tablets, emulsions, aqueous suspensions, dispersions and solutions.
  • commonly used carriers include lactose and corn starch.
  • lubricating agents such as magnesium stearate are usually added.
  • diluents used include lactose and dry corn starch.
  • the active ingredient may be suspended or dissolved in the oil phase in combination with an emulsifying or suspending agent.
  • Dosage forms of the present invention may contain sweeteners and / or flavorings and / or colorants. Dosage forms of the present invention may contain formulations prepared using liposome or microencapsulation methods, methods for preparing nanoforms of the preparation, and other examples known in the pharmaceutical art.
  • the compounds of this invention can be administered as an individual active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention, or one or more other agents.
  • the therapeutic agents can be different dosage forms that are administered simultaneously or sequentially at different times, or the therapeutic agents can be combined into a single dosage form.
  • combination therapy in relation to the compounds of this invention in combination with other pharmaceutical agents, means the simultaneous or sequential administration of all agents, which in one way or another will provide a beneficial effect of the combination of drugs.
  • Co-administration includes, in particular, co-delivery, for example, in one tablet, capsule, injection or in another form having a fixed ratio of active substances, as well as simultaneous delivery in several separate dosage forms for each compound, respectively.
  • the administration of the compounds of this invention can be carried out in combination with additional treatment methods known to specialists in the prevention and treatment of allergic, autoimmune, oncological and other diseases, including radiation therapy, the use of immunodepressants, cytotoxic and cytotoxic drugs and drugs to suppress symptoms or side effects of one of the drugs.
  • the dosage form is a fixed dose, such a combination uses the compounds of this invention in an acceptable dosage range.
  • the substances of this invention can also be introduced into the patient's body sequentially with other antitumor, cytotoxic or immunity suppressing agents, in the case when the combination of these drugs is not possible.
  • the invention is not limited to the sequence of administration; the compounds of this invention can be administered to a patient together, before or after administration of another antitumor or cytotoxic drug.
  • kits for convenient and effective therapy.
  • a pharmaceutical kit or kit includes one or more containers filled with one or more of the pharmaceutical compositions described herein.
  • Such kits are particularly convenient for the delivery of solid forms for oral administration, such as tablets or capsules.
  • Such a kit usually contains a certain number of unit doses, and may also include cards with doses arranged in the order of their intended use.
  • a reminder can also be provided, for example, in the form of numbers, letters or other markings, or a calendar indicating a treatment schedule with marked days for a dose.
  • a placebo dose, calcium supplement, in the same or other form may be included in the pharmaceutical kit provided.
  • a notice in the form may be attached, established by the government agency that regulates the manufacture, use or marketing of pharmaceutical products, which reflects the agency’s permits for the manufacture, use or marketing of the drug for human use.
  • reaction mixture was stirred for one hour at -78 ° C, then for another hour at -50 ° C and maintaining the desired temperature, 9.8 g (0.06 mol) of 2,6-difluoro-3-chloromethylpyridine was added, the reaction mixture was stirred for another 2 hours at -50 - -40 ° C, after which I leave it overnight, poured into 1 liter of cold water and acidified to pH ⁇ 4, extracted with ethyl acetate (3x300ml). The combined organic phases are washed with water until neutral, then with brine and dried over MgS0 4 , the solvent is removed, the residue is dried and chromatographed (hexane ether).
  • the reaction mixture was stirred at 18 ° C for 30 minutes until gas evolution ceased, and a solution of 77.6 g (0.45 mol) of diethyl chlorophosphate in 200 ml of ether was added, maintaining the temperature at about 0 ° C, after which the reaction mixture was stirred for another 4 hours at 18 ° C, after which 15 ml of a saturated aqueous solution of ammonium chloride are added dropwise while maintaining a temperature of about 0 ° C and stirred while maintaining a predetermined temperature until gas evolution ceases (about 20 minutes), the organic layer is separated, washed with a saturated aqueous solution of Inso3 (1x100 ml), then ice water (2x100 ml) and dried over MgSC> 4. The solvent is removed in vacuo at a temperature not exceeding 10 ° C. Receive: 92.1 g (92%) of the product, which was immediately used in the next stage.
  • the reaction mixture is stirred at a predetermined temperature for 8 hours, allowed to warm to room temperature and 100 ml of a saturated aqueous solution of ammonium chloride are added and stirred while maintaining the temperature until gas evolution ceases.
  • the precipitate was filtered off, washed with ether (3x100 ml), the filtrate was washed with 20% aqueous ammonia (3x100 ml), and then with water (3x200 ml), dried over Na 2 Sd) 4, the ether was removed, and the residue was distilled in vacuo (76-79 ° C / 50 torr). Receive: 4.0 g (89%) of the product.
  • n n 0.29 g (0.92 mmol) 6 - [(4-chloro-1,3,5-triazin-2-yl) amino] -2,2-difluoro-2-benzo [8] [1,4] -oxazin-3 (4) -one is dissolved in 5 ml of anhydrous degassed DMF, 0.25 g (1.85 mmol) of 3,4-methylenedioxyaniline are added and stirred in an argon atmosphere at 110 ° C. for 6 hours.
  • Sitnes 7 - ((4- (cyclopropylamino) - 1,3,5-triazin-2-yl) amino) -3,3-dimethyl-3,4-dihydro-1, 8-naphtharridin-2 (1 #) - it is carried out in accordance with Scheme I.
  • the commercially available 7-amino-3,3-dimethyl-3,4-dihydro-1, 8-naphtharidin-2 (1 //) is used - it is synthesized in accordance with Scheme VI
  • Sitnes 7 '- ((4 - ((3,3-difluorocyclobutyl) amino) -1, 3,5-triazin-2-yl) amino) spiro [cyclopropane-1, 3'-pyrido [3,4-b] [1, 4] oxazine] -2 '(H) -one is carried out in accordance with scheme I.
  • Sitnes 7 '- ((4 - ((3,3-difluorocyclobutyl) amino) -1, 3,5-triazin-2-yl) amino) spiro [cyclopropan-1, 3'-pyrido [3,4-b] [1,4] oxazine] -2 '(GY) -one is carried out in accordance with scheme I.
  • Sitnes 6 '- ((4-cyclopentylamino-1,3,5-triazin-2-yl) amino) spiro [cyclopropan-1, 2'-pyrazino [2,3-b] [1,4] oxazine] -3 '(4'Y) -one is carried out in accordance with scheme I.
  • the biological activity of the compounds of the present invention has been studied by various methods. For example, the inhibition of kinase activity by these compounds was investigated. Some compounds showed significant inhibitory activity at nanomolar concentrations with respect to SYK kinase. Also, some compounds showed significant antiproliferative activity on cells of non-Hodgkin lymphoma Daudi, NAMALVA, RNZZ, P3HR-1, Raji (sensitive to inhibition of SYK kinase) at concentrations of 10-10000 nM. In addition, a number of conjunctions which are the subject of the present invention showed high activity in cell models of rheumatoid arthritis.
  • Syk kinase inhibitors The efficacy of Syk kinase inhibitors was investigated by determining inhibiting the production of cytokines by differentiated monocytes and it was shown that the chemical compounds of the present invention showed inhibitory ability with respect to the production of cytokines by differentiated monocytes (THP-1 cell line) with EC 50 values of 0.1-100 ⁇ M.
  • the ability to inhibit kinases of interest for the treatment of allergic, autoimmune, oncological, chronic inflammatory and other diseases The list of kinases whose inhibition was studied in accordance with the described procedure included, but is not fundamentally limited, ALK, JAK2, BRAF, MET, TIE-2, FLT3, ABL, LCK, LYN, SRC, FYN, SYK, ZAP70, ITK kinases , TEC, BTK, EGFR, ERB2, PDGFRa, PDGFRb, KFR, IGF-1R, FLT1, TEK, ACT, ROS, EPFIA1, as well as their mutant forms, including those that confer resistance to existing methods of treatment of autoimmune, inflammatory and cancer diseases .
  • kinases in the form of a kinase domain or a full-sized protein coupled with glutathione-8-transferase (GST) or poly-histidine fragments, were expressed in insect-infected baculovirus cells (e.g., Sf21) or in E. Coli cells. After isolation from the cells, the proteins were purified to almost complete homogeneity using affinity chromatography according to known methods (Lehr, RV et. Al., Gene, 1996, 169, 275-9; Gish, G. et. Al., Protein Eng, 1995, 8, 609-14). In some cases, kinases were co-expressed or mixed with purified or partially purified regulatory polypeptides prior to measuring activity.
  • the activity and inhibition of kinases was determined in accordance with known protocols (Braunwaler, AF et. Al., Anal Biochem, 1996, 234, 23-6).
  • a measure of the enzymatic activity was the transfer rate of labeled 33 RS> 4 from ATP to a synthetic substrate poly (C1i, Tug) 4: 1 attached to the bioactive surface of the microtiter substrate.
  • the substrate was washed with 0.5% phosphoric acid, liquid scintillant was added, and the amount of phosphate transferred was determined on the basis of counting the number of scintillations on a liquid scintillation detector.
  • IC50 corresponded to a concentration of a substance that reduces by 50% the amount of 33 P transferred to the substrate bound to the substrate.
  • the compounds described in this invention have nanomolar or micromolar values of 1C 50 for various kinases, including SYK, ZAP-70, JAK1, JAK2, JAK3, BTK, TYK1 and LYN. Also, the compounds described in this invention are selective, and at concentrations up to 1000 nM, kinases such as ABL, AKT2, AURA, AURC, AXL, CDK2, CTK, FAK, IGFIR, IR, IRR, ITK, mTOR, MUSK, PKA, PKC0, RON, SRC, TYR03 do not significantly inhibit.
  • kinases such as ABL, AKT2, AURA, AURC, AXL, CDK2, CTK, FAK, IGFIR, IR, IRR, ITK, mTOR, MUSK, PKA, PKC0, RON, SRC, TYR03 do not significantly inhibit.
  • the compounds of this invention suppress the aberrant activity and proliferation of cells of the immune system and, thus, can be used to treat inflammatory, autoimmune, oncological and other diseases.
  • Syk kinase is a non-receptor tyrosine kinase and is involved in signal transduction by antigenic and Fc receptors.
  • Various in vitro models, and in particular, models based on stimulation of FcyR receptors located on the surface of macrophages, can be used to evaluate the effectiveness of Syk kinase inhibitors.
  • the following is an example of determining the activity of a compound in cell models of autoimmune diseases.
  • a technique was used based on stimulation of macrophages with IgG immunoglobulin and subsequent determination of the intensity of cytokine release.
  • a technique for determining the inhibition of the FcyR signaling pathway of macrophage receptors obtained by monocyte differentiation is described in (Braselmann, S., et al., J Pharmacol Exp Ther, 2006. 319, 998-1008) and patent (WO 2004 / 014382A1).
  • the THP-1 cell line is incubated in RPMI 1640 culture medium (5% C0 2 humidified atmosphere, 37 ° C). To induce differentiation of THP-1 into macrophages, cells are exposed to IFN- ⁇ for 6 days.
  • 96-well plates are coated with combined human IgG and incubated overnight at 4 ° C, or for 1 hour at 37 ° C.
  • part of the wells are coated with antibody fragments F (ab ') 2 as a negative control. Unbound antibodies are removed using sodium phosphate buffer.
  • a solution of the test compound is added to each well to a final concentration of 0.01 - 50 ⁇ M and differentiated macrophage cells in the culture medium. Each concentration of drugs is examined in 3 parallels. Cells are incubated at 37 ° C, after which the concentration of TNFa is determined in the supernatant.
  • experiments to determine cell proliferation and the number of viable cells give a detectable signal proportional to the number of metabolically active cells.
  • the antitumor activity of the compounds can be determined using any characteristic reflecting a decrease in the metabolic activity of cells after exposure to the compound.
  • methods are used in which the integrity of the membrane (for example, the analysis of the elimination of trypan blue) and the synthesis of DNA (for example, the determination of the incorporation of BrdU or H-thymidine) act as a cell viability.
  • Some methods for determining cell proliferation use reagents that are converted to detectable compounds during cell proliferation.
  • Preferred reagents for this determination are tetrazolium salts, including, for example, MTT (3- (4,5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide), MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium), XTT (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -2H-tetrazolium-5-carboxanilide), INT (2- (4-iodophenyl) -3- (4-nitrophenyl) -5-phenyl tetrazolium), NBT (2H-Tetrazolium, 2,2'- (3,3'-dimethoxy [1, 1 '-bipheny
  • preferred methods for determining cell proliferation include incubating cells in a growth medium selected with or without the test substance. Growth conditions for various prokaryotic and eukaryotic cells are described in detail (Ausubel et al. Current Protocols in Molecular Biology. Wiley and Sons. 1999; Bonifacio et al. Current Protocols in Cell Biology. Wiley and Sons. 1999). To determine cell proliferation, after incubation is added to them tetrazolium salt and then the amount of formazan formed is determined. The amount of formazan derivatives formed is determined by the optical density of the treated cells.
  • Cancer cell lines for example, Daudi, NAMALVA, RZNZ, P3HR-1, Raji (non-Hodgkin's lymphoma), COLO 205, DLD-1, HCT-15, HT29 (colon cancer) can be used to determine the antiproliferative activity of the compounds; HEP G2 (hepatoma); K-562 (leukemia); A549, NCI-H249, NCI-H2228, NCI-H3122 (lung cancer); Karpas-299, SU-DHL-1 (lymphoma); MCF7, MDA-MB-231 (breast cancer); SAOS-2 (osteosarcoma); OVCAR-3 (ovarian cancer); PANC-1 (pancreatic cancer); DU-145, PC-3 (prostate cancer); ACHN, CAKI-1 (kidney cancer); MG-63 (sarcoma).
  • HEP G2 hepatoma
  • K-562 leukemia
  • mammalian cells are preferably used to determine the antiproliferative activity of the compounds
  • lower eukaryotic cells such as yeast
  • cell lines of humans, rats, mice, rabbits, lower monkeys, hamsters and guinea pigs since cell lines from these organisms are the most well studied and fully characterized.
  • the following is an example of determining the activity of a compound in cell models of cancer. In this experiment, we used a technique for measuring the cytotoxicity of compounds based on measuring the activity of cell dehydrogenases by optical density, was repeatedly described in the scientific literature and is practically the standard for determining cytotoxicity.
  • the biochemical process underlying the method consists in the reduction of yellow 3- (4,5-dimethylthiazol-2-yl) -2,5-tetrazolium bromide (MTT) into insoluble purple-blue intracellular crystals of MTT-formazan (MTT-f) under the action of dehydrogenases localized in mitochondria.
  • MTT-f MTT-formazan
  • the conversion rate of MTT to MTT-f reflects the general level of dehydrogenase activity of the studied cells and is modulated by the activity of conjugated enzyme systems, for example, the respiratory chain of electron transfer, etc.
  • the activity of dehydrogenases decreases at the latest stages of cell death, therefore, the method is suitable for screening cytotoxicity of both toxic and low toxic compounds.
  • Illustrative examples of compounds having activity in vitro to inhibit aberrant proliferation of non-Hodgkin lymphoma cells.
  • the compounds of this invention suppress the aberrant activity and proliferation of cells of the immune system and, thus, can be used to treat inflammatory, autoimmune, oncological and other diseases.
  • In vivo models for determining the effectiveness of chemical compounds in the treatment of various autoimmune diseases are well known and can be used to compare the characteristics of the compounds described in this invention.
  • the following is an example of determining the activity of a compound in an in vivo rat adjuvant arthritis model (chronic immune inflammation).
  • Chronic immune inflammation in rats preferably using Lewis rats 6-7 weeks old
  • PAF Freund's complete adjuvant
  • a secondary immunological response edema on the left paw
  • the measurement of the volume of the paw and the introduction of the test substances begin from 14 days (after involvement in the inflammatory process of the contralateral paw).
  • test compounds are administered intragastrically twice a day for 11 days at concentrations of 30, 60 and 100 milligrams per kilogram of animal weight.
  • the first evaluation of the effect of substances is carried out 24 hours after the first intragastric administration, the last measurements of the paw volume are carried out on the 25th day of the experiment (24 hours after the last injection of substances) and on the 27th day (2 days after the termination of administration).
  • the effect of the therapeutic effect of the test compounds is evaluated by the degree of suppression of the inflammatory reaction and by preventing bone destruction in comparison with the control group not receiving treatment.
  • the following scale was used to assess bone damage in each animal: 1. Pathological installation of the nail phalanges; 2. The presence of soft tissue edema; 3. The presence of a friendly limb lesion; 4.
  • mice and rats The compounds of the invention showing antiproliferative activity in cell experiments were then tested in vivo in mammals.
  • rodents such as mice and rats.
  • Non-Hodgen lymphoma cell lines (Raji, NAMALVA, Daudi, RZNZ, RZNZ-1) in the amount of 5 * 10 6 cells in serum free medium were injected subcutaneously in the right flank of nude nude mice (NCr) 3-4 weeks old. After the tumor reached a volume of ⁇ 200 mm, the mice were divided into 2 groups: control and therapeutic.
  • V LxW2xO, 5 where L is the length of the tumor in mm, W is the width in mm.
  • % T / C the average volume ratio for the therapeutic / control groups
  • the substances described in this invention can be used for the prevention and treatment of human diseases in the form of the following formulations (under the "Substance” refers to the active ingredient):
  • composition for injection III (1 mg / ml, buffer with pH 6)
  • Citric Acid 0.38% w / v
  • these formulations can be prepared in accordance with standard pharmaceutical procedures.
  • Tablets (1) to (3) can be enteric coated using, for example, cellulose acetate phthalate.
  • Aerosol formulations (8) - (ll) can be used in combination with standard dispensers; as a suspending agent, instead of sorbitan trioleate and soya lecithin, sorbitan monooleate, sorbitan semi-oleate, polysorbate 80, polyglycerol oleate or oleic acid can be used.
  • the invention is applicable in the treatment of allergic, autoimmune, oncological and other diseases.

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Abstract

L'invention se rapporte au traitement de maladies allergiques, auto-immunes, oncologiques et autres à l'aide de nouvelles familles d'agents chimiques ayant une efficacité accrue lors de l'inhibition de SYK-kinase et de ses formes mutantes, ainsi que d'autres kinase thérapeutiquement importantes, ainsi qu'une meilleure sélectivité et une meilleure biodisponibilité.
PCT/RU2013/000840 2013-09-26 2013-09-26 Nouveaux composés chimiques dérivés de 2,4-diamino-1,3,5-triazine afin de prévenir et traiter des maladies d'humains et d'animaux WO2015047124A1 (fr)

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CN109526221A (zh) * 2016-05-13 2019-03-26 分子技术有限公司 用于人类使用的2,2-二甲基-6-((4-((3,4,5-三甲氧基苯基)氨基)-1,3,5-三嗪-2-基)氨基)-2H-吡啶并[3,2-b][1,4]噁嗪-3(4H)-酮的新型晶体盐形式
CN109912622A (zh) * 2019-03-20 2019-06-21 中国药科大学 一种福他替尼关键中间体的制备方法及其中间体和利用中间体制备福他替尼的方法
JP2019123709A (ja) * 2018-01-12 2019-07-25 Ｊｘｔｇエネルギー株式会社 硫黄系化合物、該硫黄系化合物を含有する潤滑油添加剤、及び該硫黄系化合物を含有する潤滑油組成物
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors

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CN109526221B (zh) * 2016-05-13 2022-06-21 分子技术有限公司 一种激酶抑制剂的晶体盐形式
CN109526221A (zh) * 2016-05-13 2019-03-26 分子技术有限公司 用于人类使用的2,2-二甲基-6-((4-((3,4,5-三甲氧基苯基)氨基)-1,3,5-三嗪-2-基)氨基)-2H-吡啶并[3,2-b][1,4]噁嗪-3(4H)-酮的新型晶体盐形式
JP2019123709A (ja) * 2018-01-12 2019-07-25 Ｊｘｔｇエネルギー株式会社 硫黄系化合物、該硫黄系化合物を含有する潤滑油添加剤、及び該硫黄系化合物を含有する潤滑油組成物
JP7213694B2 (ja) 2018-01-12 2023-01-27 Ｅｎｅｏｓ株式会社 硫黄系化合物、該硫黄系化合物を含有する潤滑油添加剤、及び該硫黄系化合物を含有する潤滑油組成物
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
CN109912622A (zh) * 2019-03-20 2019-06-21 中国药科大学 一种福他替尼关键中间体的制备方法及其中间体和利用中间体制备福他替尼的方法
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors

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