WO2018195471A1 - Inhibiteurs de syk en association avec des agents d'hypométhylation - Google Patents

Inhibiteurs de syk en association avec des agents d'hypométhylation Download PDF

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Publication number
WO2018195471A1
WO2018195471A1 PCT/US2018/028636 US2018028636W WO2018195471A1 WO 2018195471 A1 WO2018195471 A1 WO 2018195471A1 US 2018028636 W US2018028636 W US 2018028636W WO 2018195471 A1 WO2018195471 A1 WO 2018195471A1
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Prior art keywords
pyrazin
methyl
pyrido
oxy
phenyl
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PCT/US2018/028636
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English (en)
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Esteban M. Abella
Antonio Mario Querido Marcondes
Arati V. Rao
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Gilead Sciences, Inc.
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Publication of WO2018195471A1 publication Critical patent/WO2018195471A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present disclosure relates to methods of treatment of diseases and disorders using combinations of hypomethylating agents and compounds that inhibit Spleen Tyrosine Kinase (SYK) activity.
  • SYK Spleen Tyrosine Kinase
  • HMAs hypomethylating agents
  • decitabine azacitidine
  • CMML chronic myelomonocytic leukaemia
  • MDS Myelodysplastic syndromes
  • AML acute myeloid leukemia
  • Lenalidomide is approved by the FDA for the treatment of patients with low or intermediate- 1 risk MDS with 5q-, with or without additional cytogenetic abnormalities.
  • Spleen Tyrosine Kinase is a member of the family of non-receptor tyrosine kinases, and is a regulator of early B-cell development as well as mature B-cell activation, signaling, and survival. SYK has roles in immunoreceptor- and integrin- mediated signaling in a variety of cell types, including B-cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T-cells, natural killer cells, platelets, and osteoclasts. The inhibition of Syk activity can be useful for the treatment of cancers and inflammatory diseases.
  • a hypomethylating agent can be selected from 5-aza-2'-deoxycytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine), or a pharmaceuticall acceptable salt thereof.
  • the myeloproliferative disorder is selected from myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukaemia (CMML).
  • MDS myelodysplastic syndromes
  • AML acute myeloid leukemia
  • CMML chronic myelomonocytic leukaemia
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MPL myeloproliferative leukemia
  • MDS myelodysplastic syndrome
  • MPD myeloproliferative disease
  • CML chronic myeloid leukemia
  • MM multiple myeloma
  • NHL non-Hodgkin's lymphoma
  • MCL mantle cell lymphoma
  • follicular lymphoma Waldenstrom's macroglobulinemia
  • T-cell lymphoma B-cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • pancreatic cancer bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck
  • myeloproliferative disorders comprising the administration of an effective amount of lenalidomide or antithymocyte globulin, and a spleen tyrosine kinase (SYK) inhibitor to a patient in need thereof.
  • the myeloproliferative disorder is selected from MDS, AML and CMML.
  • the patient has received or is a candidate for receiving allogeneic stem cell transplantation wherein one or more hypomethylating agents is administered in combination with one or more SYK inhibitors.
  • the SYK inhibitor is selected from:
  • myelodysplastic syndrome is refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.
  • the myelodysplastic syndrome is Low-risk, Intermediate- 1, Intermediate-2 or High-risk in international prognostic scoring system (IPSS).
  • the myelodysplastic syndrome is primary or secondary to radiotherapy or chemotherapy.
  • the patient has a del(5q), in particular, Del5q31-33 abnormality.
  • the SYK inhibitor is administered prior to administering the hypomethylating agent. In some embodiments, the SYK inhibitor is administered after administering the hypomethylating agent. In some embodiments, the SYK inhibitor is administered concurrently with the hypomethylating agent.
  • the SYK inhibitor is administered prior to administering lenalidomide or antithymocyte globulin. In some embodiments, the SYK inhibitor is administered after administering lenalidomide or antithymocyte globulin. In some embodiments, the SYK inhibitor is administered concurrently with lenalidomide or antithymocyte globulin.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following:
  • "delaying" the development of a disease or condition means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease or condition, and/or subject being treated.
  • a method that "delays" development of a disease or condition is a method that reduces probability of disease or condition development in a given time frame and/or reduces the extent of the disease or condition in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • Disease or condition development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease or condition progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • compositions and methods when used to define compositions and methods, shall mean excluding other elements of any essential significance to the compositions and methods for the intended use, but not excluding elements that do not materially affect the characteristic(s) of the compositions or methods.
  • Consisting of or its grammatic variants shall mean excluding elements not specifically recited. Embodiments defined by each of these transition terms are within the scope of this disclosure. For example, when a composition is described as comprising ingredients A, B and C, a composition consisting essentially of A, B and C, and a composition consisting of A, B and C are independently within the scope of this disclosure.
  • a pharmaceutically acceptable carrier includes reference to one and more than one pharmaceutically acceptable carriers.
  • the term "about” means within ⁇ 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%), 0.1%), or 0.05%) of a given value or range.
  • about means ⁇ 5% of a given value or range.
  • about means ⁇ 4% of a given value or range.
  • about means ⁇ 3% of a given value or range.
  • about means ⁇ 2% of a given value or range. In another embodiment, about means ⁇ 1%> of a given value or range. In another embodiment, about means ⁇ 0.5% of a given value or range. In another embodiment, about means ⁇ 0.05% of a given value or range.
  • the term "about x" includes the value "x.”
  • administer refers to introducing an agent into a patient.
  • a therapeutic amount can be administered.
  • administering when used in connection with a compound or composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug.
  • Alkyj encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms.
  • C J -C 6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyi, 2-hexyl, 3-hexyl, 3-methyipentyl, and the like.
  • Alkyl en e is another subset of alkyl, referring to the same residues as alkyl, but having two points of attachment.
  • Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms.
  • Co alkylene indicates a covending bond and Ci alkylene is a methylene group.
  • Ci alkylene is a methylene group.
  • alkyl residue having a specific number of carbons all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, ''butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl.
  • “Lower alkyl” refers to alkyl groups having 1 to 4 carbons.
  • Cycloalkyl indicates a saturated hydrocarbon ring group, having the specified number of carbon atoms, usually from 3 to 10 ring carbon atoms.
  • Examples of cy cloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyi, and cyclohexyl as well as bridged and caged saturated ring groups such as norbomane.
  • Alkoxy refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to 6 carbon atoms attached through the oxygen bridge. "Lower alkoxy” refers to alkoxy groups having 1 to 4 carbons.
  • Acyl refers to the groups (alkyl)-C(O)-; (cycloalkyl)-C(Q)-; (aryl)-C(O)-; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyi functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein.
  • Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms.
  • a C 2 acyl group is an acetyl group having the formula
  • a C l-Cealkoxy carbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • Amino refers to the group -NHz.
  • Aryl encompasses 6 to 14-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetra!in; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • aryl includes phenyl fused to a 5 to 7-membered cycloalkyl ring. For such fused ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the cycloalkyl ring.
  • Aryl does not encompass or overlap in any ⁇ way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • halo includes fluoro, chloro, bromo, and iodo, and the term
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • Heteroaryl encompasses 5 to 14-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or In some embodiments, from 1 to 3, heteroatonis chosen from N, O, and S, with the remaining ring atoms being carbon; and bicyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, ring heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7- membered cycloalkyl ring.
  • the point of attachment may be at the
  • heteroaromatic ring or the cycloalkyl ring When the total number of S and O atoms in the heteroaryl group exceeds I, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroary!
  • groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazoiiny], thiadiazoiinyl, tetrazoiyl, thienyl, benzolhiophenyl, furanyl, benzofuranyi, benzoimidazolinyl, indoiinyl, pyridizinyl, triazolyl, quinolinyl, pyrazoiyl, and 5,6,7,8-tetrahydroisoquino3ine. Heteroary! does not encompass or overlap with ary! as defined above. Substitute
  • heteroaryloxy refers to the group -O-heteroaryl.
  • heterocycloalkyl is meant a single aliphatic ring, usually with 3 to 14 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently- selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • Suitable heterocyc!oalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperdyi, and 2,5-piperzinyl. Morpholiny!
  • heterocycloalkyl also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide,
  • Heterocycloalkyl also includes bicyclic ring systems wherein neither of the rings is aromatic and wherein at least one of the rings in the bicyclic ring system contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently chosen from oxygen, sulfur, and nitrogen.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl,
  • heterocycloalkyl and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from -R a , -OR b , -0(Ci- C2 alkyl)0- (e.g., methylenedioxy-), -SR b , guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NR ⁇ , halo, cyano, oxo (as a substituent for heterocycloalkyl), nitro, -COR b , -C02R b , -CONR ⁇ , -OCOR b , -OCO2R 11 , -OCONR ⁇ , -NR c COR b , -NRTOiR 8 , -NR c CONR b R c , -SOR a , -SOaR 8
  • R a is chosen from optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R b is chosen from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R c is chosen from hydrogen and optionally substituted C1-C4 alkyl
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl -C1-C4 alkyl-, C1-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-0-C1-C4 alkyl, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NIfc, -N(C1-C 4 alkyl)(Ci-C 4 alkyl), -NH(Ci-C 4 alkyl), -N(Ci-C 4 al
  • substituted acyl refers to the groups (substituted alkyl)-C(O)-;
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., -0-(substituted alkyl)) wherein “substituted aikyi” is as described herein,
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-0- C(O)- wherein the group is attached to the parent staicture through the carbonyl functionality and wherein "substituted aikyi" is as described herein.
  • substituted heteroaryl oxy refers to heteroaryloxy wherein the aryl constituent is substituted (i .e., -0-(substituted heteroaryl)) wherein “substituted heteroaryl” is as described herein.
  • substituted cycioalkyloxy refers to cycloalkyloxy wherein the cvcloalkyl constituent is substituted (i .e., -0-(substituted cycloalkyl)) wherein “substituted cvcloalkyl” is as described herein.
  • substituted amino refers to the group -NHR d or -NR a R d where each R d is independently chosen from; hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl,
  • alkoxycarbonyl, sulfinyl and sulfonyi provided that only one R d may be hydroxyl, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from -R a , -OR b , -0(Ci-C2 alkyl)0- (e.g., methylenedioxy-), -SR b , guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NR b R c , halo, cyano, nitro, -COR b , -CO?.R b , -CONR b
  • substituted amino also refers to N-oxides of the groups -NHR d , and NR d R d each as described above.
  • N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
  • “Pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable vehicles e.g., carriers, adjuvants, and/or other excipients
  • “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • Examples of salts may include hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, mesylate, p-toluenesulfonate, 2- hydroxy ethyl sulfonate, benzoate, salicylate, stearate, and alkanoate (such as acetate, HOOC- (CH2)n-COOH where n is 0-4).
  • alkanoate such as acetate, HOOC- (CH2)n-COOH where n is 0-4
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • solvate refers to a crystal form with either a stoichiometric or non-stoichiometric amount of solvent incorporated into the crystal structure.
  • hydrate refers specifically to a crystal form with either a stoichiometric or non-stoichiometric amount of water incorporated into the crystal structure.
  • co-crystal refers to crystalline structure of a compound and one or more co-crystal formers connected through non-covalent interactions. Co-crystals may additionally be present in anhydrous, solvated or hydrated forms. In some embodiments, there is no hydrogen transfer between the compound and the co-crystal former in the crystalline structure.
  • Prodrugs means any compound which releases an active parent drug in vivo when such prodrug is administered to a patient.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., ⁇ , ⁇ -dimethylaminocarbonyl) of a hydroxy functional group in a compound, and the like.
  • Tautomer means compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom.
  • the tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.
  • keto-enol tautomers such as acetone/propen- 2-ol, imine-enamine tautomers and the like
  • ring-chain tautomers such as glucose/2,3, 4,5,6- pentahydroxy-hexanal and the like
  • Certain compounds may have one or more tautomers and therefore include various isomers. All such isomeric forms of these compounds are expressly included in the present disclosure.
  • “Isomers” mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. “Stereoisomer” and “stereoisomers” refer to compounds that exist in different
  • stereoisomenc forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures.
  • Stereoisomers include enantiomers and diastereomers.
  • Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers.”
  • enantiomers stereoisomers that are not mirror images of one another
  • enantiomers those that are non- superimposable mirror images of each other.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture.” Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
  • therapeutically effective amount refers to an amount that may be effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the effective amount may vary depending on the compound, the disease or condition being treated and its severity, the subject including the age, weight, etc., of the subject to be treated, and the manner of administering, which can readily be determined by one of ordinary skill in the art.
  • the effective amount can include a range of amounts.
  • a pharmaceutically effective amount includes amounts of an agent which are effective when combined with other agents.
  • patient refers to a mammal that is treated with a method as described herein, including but not limited to, a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.
  • the patient is a human.
  • provided herein are methods for treating a
  • myeloproliferative disorder comprising the administration of an effective amount of a hypomethylating agent and a therapeutically effective amount of a spleen tyrosine kinase (SYK) inhibitor to a patient in need thereof.
  • the hypomethylating agent can be selected from 5-aza-2'-deoxycytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine), or a pharmaceutically acceptable salt thereof.
  • MDS myelodysplastic syndromes
  • hypomethylating agent and a therapeutically effective amount of a spleen tyrosine kinase (SYK) inhibitor to a patient in need thereof.
  • the hypomethylating agent can be selected from 5-aza-2'-deoxycytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine), or a pharmaceutically acceptable salt thereof.
  • a method of treating a myeloproliferative disorder comprising administering to a patient in need thereof, a therapeutically effective amount of lenalidomide or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a spleen tyrosine kinase (SYK) inhibitor.
  • SYK spleen tyrosine kinase
  • provided herein are methods for treating
  • myeloproliferative disorders comprising the administration of an effective amount of antithymocyte globulin or a pharmaceutically acceptable salt thereof, and a spleen tyrosine kinase (SYK) inhibitor to a patient in need thereof.
  • SYK spleen tyrosine kinase
  • the myeloproliferative disorder is selected from MDS, A ML and CMML.
  • a method of treating Intermediate- 1 or Low risk myelodysplastic syndrome in a patient in need thereof comprising administering a therapeutically effective amount of a spleen tyrosine kinase inhibitor to said patient.
  • myelodysplastic syndrome is refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.
  • the myelodysplastic syndrome is Low-risk, Intermediate- 1, Intermediate-2 or High risk in international prognostic scoring system (IPSS).
  • the myelodysplastic syndrome is primary or secondary to radiotherapy or chemotherapy.
  • the patient has a del(5q), in particular, Del5q31-33 abnormality.
  • the patient has been previously treated or untreated for MDS.
  • the patient has a de novo MDS.
  • De novo MDS refers to an MDS that has arisen without an obvious or specific cause.
  • the patient has a secondary MDS.
  • Secondary MDS is an MDS that is found to have been caused by specific reasons and includes two general types: the first type is MDS that seems to have arisen from another bone marrow failure disorder or bone marrow cancer.
  • the second type of secondary MDS relates to cancer therapies for other cancers, including chemotherapy and radiation therapy, and is also referred to as treatment-related MDS or therapy-related MDS.
  • the patient has a de novo or secondary MDS of French- American- British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia).
  • myelodysplasia is associated with multilineage dysplasia.
  • myelodysplastic syndrome associated with an isolated del(5q), in particular, Del5q31-33 chromosome abnormality, or
  • SYK inhibitors can be used in the methods described herein.
  • R 1 is phenyl substituted with one or two groups chosen from
  • cycloalkyl optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, and lower alkyl
  • heterocycloalkyl optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, lower alkyl, lower alkyl substituted with hydroxy, optionally substituted amino, and oxo
  • R 6 and R 7 are independently selected from hydrogen, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl, and
  • heterocycloalkyl or R 6 and R 7 together with the nitrogen to which they are bound form a 3- to 7-membered heterocycloalkyl ring optionally substituted with one or two groups chosen from hydroxy, lower alkyl, and lower alkyl substituted with hydroxy,
  • R 6 and R 7 are independently selected from hydrogen, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl, and
  • heterocycloalkyl or R 6 and R 7 together with the nitrogen to which they are bound form a 3- to 7-membered heterocycloalkyl ring optionally substituted with one or two groups chosen from hydroxy, lower alkyl, and lower alkyl substituted with hydroxy, provided that at least one of R 6 and R 7 is not hydrogen,
  • lower alkoxy optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, optionally substituted amino, carboxy, aminocarbonyl, and heterocycloalkyl,
  • lower alkyl optionally substituted with one or two groups chosen from hydroxy, lower alkoxy, halo, trifluoromethyl, optionally substituted amino, and heterocycloalkyl optionally substituted with lower alkyl; or wherein A is chosen from aryl, cycloalkyl and heterocycloalkyl groups, each of which groups having from 5 to 7 ring atoms including the atoms shared with the 6 membered aromatic ring and each of which groups being optionally substituted;
  • R 2 is chosen from optionally substituted aryl and optionally substituted heteroaiyl
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 5 is hydrogen
  • the '811 patent discloses the following SYK inhibitors: N-(3,4- dimethoxyphenyl)-6-(3-methylphenyl)imidazo[l,2-a]pyrazin-8-amine; N-(3,4- dimethoxyphenyl)-6-(3-nitrophenyl)imidazo[l,2-a]pyrazin-8-amine; N-(3,4- dimethoxyphenyl)-6- ⁇ 3-[(ethylamino)methyl]phenyl ⁇ imidazo[l,2-a]pyrazin-8-amine; N- (3,4-dimethoxyphenyl)-6-[3-(trifluoromethyl)phenyl]imidazo[l,2-a]pyrazin-8-amine; N- (3,4-dimethoxyphenyl)-6-(3-methoxyphenyl)imidazo[l,2-a]pyrazin-8-amine; N-(3,4- dimethoxyphenyl)-6-((3,4
  • the SYK inhibitor is Compound 1 having the formula:
  • the SYK inhibitor is a bis-mesylate salt of the above compound.
  • the SYK inhibitor is a SYK inhibitor disclosed in U.S. Patent No. 8,455,493, U.S. Patent Publication Nos. 20150038504, 20150038505,
  • the SYK inhibitor is a compound selected from:
  • the SYK inhibitor is a compound having the formula:
  • Fostamatinib R-406 or a pharmaceutically acceptable salt thereof.
  • Cyclobutanol l-[4-[5-[[(2S)-4-(methylsulfonyl)-2-morpholinyl]methoxy]pyrido[3,4- b]pyrazin-7-yl]phenyl]-;
  • Ethanone l-[(2S)-2-[[[7-[4-(l-amino-2- methylpropyl)phenyl]pyrido[3,4-b]pyrazin-5-yl]oxy]methyl]-4-morpholinyl]-;
  • Benzeneethanol p,p-dimethyl-4-[5-[[(2S)-4-(methylsulfonyl)-2- morpholinyl]methoxy]pyrido[3,4-b]pyrazin-7-yl]-;
  • Benzenemethanol a-(l-methylethyl)-4- [5-[[(2S)-4-(methylsulfonyl)-2-morpholinyl]methoxy]pyrido[3,4-b]pyrazin-7-yl]-;
  • Benzenemethanol a-(l,l-dimethylethyl)-4-[5-[[(2S)-4-(methylsulfonyl)-2- morpholinyl]methoxy]pyrido[3,4-b]pyrazin-7-yl]-; Cyclobutanecarbonitrile, l-[4-[5-[[(2S)-
  • Pyrido[3,4-b]pyrazine 5-[[(2S)-4-(methylsulfonyl)-2-morpholinyl]methoxy]-7-[l- (tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-yl]-; Pyrido[3,4-b]pyrazine, 7-(4-methylphenyl)- 5-[[(2S)-4-(methylsulfonyl)-2-morpholinyl]methoxy]-; Pyrido[3,4-b]pyrazine, 7-(4- chlorophenyl)-5-[[(2S)-4-(methylsulfonyl)-2-morpholinyl]methoxy]-; Pyrido[3,4- b]pyrazine, 7-(l-methyl-lH-indol-5-yl)-5-[[(2S)-4-(methylsulfonyl)-2- morpholinyljmethoxy
  • the SYK inhibitor, hypomethylating agent, lenalidomide or antithymocyte globulin may be administered using any suitable methods known in the art.
  • the compounds may be administered bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrasternally, intravenously,
  • a SYK inhibitor may be administered with a
  • hypomethylating agent lenalidomide or antithymocyte globulin in a fixed dose
  • compositions or in separate pharmaceutical compositions, each of which can independently be administered bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperitoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, or vaginally.
  • parenterally intramuscularly, intraperitoneally intrasternally, intravenously, subcutaneously
  • rectally topically, transdermally, or vaginally.
  • pharmaceutical compositions that contain one or more of the compounds of any of the formulae disclosed herein or a pharmaceutically acceptable salt, isomers, prodrug, or solvate thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • diluents including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • the pharmaceutical composition is administered orally.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • the pharmaceutical composition is in the form of tablets.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound of any of the formulae described herein or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof, can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods of the present application employs transdermal delivery devices ("patches").
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of any of the above formulae or a pharmaceutically acceptable salt, prodrug, or solvate thereof.
  • a pharmaceutical excipient When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable
  • compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • the SYK inhibitor is administered prior to administering the hypomethylating agent. In some embodiments, the SYK inhibitor is administered after administering the hypomethylating agent. In some embodiments, the SYK inhibitor is administered concurrently with the hypomethylating agent.
  • the SYK inhibitor is administered prior to administering lenalidomide or antithymocyte globulin. In some embodiments, the SYK inhibitor is administered after administering lenalidomide or antithymocyte globulin. In some embodiments, the SYK inhibitor is administered concurrently with lenalidomide or antithymocyte globulin.
  • a dosage may be expressed as a number of milligrams of a compound of the formula per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.01 and 200 mg/kg may be appropriate. In some embodiments, about 0.01 and 150 mg/kg may be appropriate. In other embodiments a dosage of between 0.05 and 100 mg/kg may be appropriate.
  • Normalizing according to the subject's body weight can be useful, for example, when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the daily dosage may also be described as a total amount of a compound of the formulae administered per dose or per day.
  • Daily dosage of a compound may be between about 1 mg and 2,000 mg, between about 1,000 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 1 to 500 mg/day, between about 100 to 150 mg/day, between about 1 to 100 mg/day, between about between about 1 to 50 mg/day, between about 50 to 100 mg/day, between about 100 to 125 mg/day, between about 100 to 150 mg/day, between about 100 to 175 mg/day, between about 100 to 200 mg/day, between about 100 to 225 mg/day, between about 100 to 250 mg/day, between about 100 to 350 mg/day, between about 100 to 400 mg/day, between about 100 to 450 mg/day, or between about 100 to 500 mg/day.
  • the total daily dosage for a human subject may be between 1 mg and 1,000 mg/day, between about 1 to 100 mg/day, between about 1 to 50 mg/day, between about 50 to 100 mg/day, between 50 to 300 mg/day, between 50 to 200 mg/day, between 75 to 200 mg/day, between 75 to 150 mg/day, between 100 to 200 mg/day, between about 200 to 300 mg/day, between about 300 to 400 mg/day, between about 400 to 500 mg/day, between about 100 to 150 mg/day, between about 150 to 200 mg/day, between about 200 to 250 mg/day, between about 75 to 150 mg/day, or between about 150 to 300 mg/day.
  • the daily dosage of a SYK inhibitor may be between about 1 mg and 2,000 mg, between about 1,000 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 1 to 500 mg/day, between about 100 to 150 mg/day, between about 1 to 100 mg/day, between about between about 1 to 50 mg/day, between about 50 to 100 mg/day, between about 100 to 125 mg/day, between about 100 to 150 mg/day, between about 100 to 175 mg/day, between about 100 to 200 mg/day, between about 100 to 225 mg/day, between about 100 to 250 mg/day, between about 100 to 350 mg/day, between about 100 to 400 mg/day, between about 100 to 450 mg/day, or between about 100 to 500 mg/day.
  • the daily dosage of a SYK inhibitor is about 400 mg/day.
  • the daily dosage of a SYK inhibitor is about 800 mg/day.
  • the daily dosage of a hypomethylating agent may be between about 1 mg and 2,000 mg, between about 1,000 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 1 to 500 mg/day, between about 1 to 100 mg/day, between about 1 to 90 mg/day, between about between about 1 to 80 mg/day, between about 1 to 70 mg/day, between about 1 to 60 mg/day, between about 1 to 50 mg/day, between about 1 to 40 mg/day, between about 1 to 30 mg/day, between about 1 to 20 mg/day, or between about 1 to 10 mg/day.
  • the daily dosage of decitabine may be between about 1 mg/day and 20 mg/day, such as about 20 mg/day.
  • the daily dosage of azacitidine for example, may be between about 10 and 100 mg/day, such as about 75 mg/day.
  • the daily dosage of lenalidomide may be between about 1 mg and 100 mg, between about 1 to 50 mg/day, between about 1 to 30 mg/day, between about 1 to 25 mg/day, or between about 2 to 25 mg/day.
  • the daily dosage of lenalidomide may be between about 1 mg/day and 20 mg/day, such as about 25, about 10, about 5 or about 2.5 mg/day.
  • lenalidomide is administered daily.
  • lenalidomide is administered on Days 1-21 of repeated 28-day cycles.
  • lenalidomide is administered orally at about 25 mg once daily orally on Days 1-21 of repeated 28-day cycles.
  • lenalidomide is administered
  • lenalidomide administered orally at about 10 mg once daily. In some embodiments, lenalidomide is administered orally at about 5 mg once daily. In some embodiments, lenalidomide is administered orally at about 2.5 mg once daily.
  • the daily dosage of antithymocyte globulin may be between about 1 mg and 2,000 mg, between about 1,000 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 1 to 500 mg/day, between about 10 to 400 mg/day, or between about 50 to 300 mg/day. In some embodiments, the daily dosage of antithymocyte globulin may be between about 0.1 to 10 mg/kg of body weight, between about 0.5 to 5 mg/kg of body weight, or between about 1 to 2 mg/kg of body weight.
  • the daily dosage of antithymocyte globulin may be about 0.5 mg/kg of body weight, about 1 mg/kg of body weight, about 1.5 mg/kg of body weight, about 2 mg/kg of body weight, about 2.5 mg/kg of body weight, or about 3 mg/kg of body weight.
  • antithymocyte globulin is administered consecutively for about 3 to 20 days.
  • antithymocyte globulin is administered consecutively for about 4 to 14 days.
  • antithymocyte globulin is administered consecutively for about 4 to 7 days.
  • antithymocyte globulin is administered intravenous at about 1.5 mg/kg of body weight daily for 4 to 7 days.
  • antithymocyte globulin is administered intravenous at about 1.5 mg/kg of body weight daily for 7 to 14 days.
  • the compounds of the present application or the compositions thereof may be administered once, twice, three, or four or more times daily, using any suitable mode described above.
  • the dose of a SYK inhibitor, or a pharmaceutically acceptable salt thereof is administered once daily.
  • the dose of a SYK inhibitor, or a pharmaceutically acceptable salt thereof is administered twice daily.
  • the dose of a hypomethaling agent, lenalidomide or antithymocyte globulin is administered once daily.
  • the dose of a hypomethaling agent, lenalidomide or antithymocyte globulin is administered twice daily.
  • a patient undergoing treatment with a SYK inhibitor and a hyopmethylating agent is further administered with one or more additional drugs selected from corticosteroids, glucocorticoids, mineralocorticoids, hydrocortisone, dexamethasone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone, fludrocortisone acetate, deoxycorticosterone, deoxycorticosterone acetate, or aldosterone.
  • additional drugs selected from corticosteroids, glucocorticoids, mineralocorticoids, hydrocortisone, dexamethasone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone,
  • the patient undergoing treatment with a method described herein is not being treated with a Bcl-2 inhibitor. In some embodiments, the patient undergoing treatment with a method described herein is not being treated with a vinca alkaloid.
  • SYK inhibitor as described herein
  • a hypomethylating agent lenalidomide or antithymocyte globulin, as described herein, in the treatment of a medical condition such as those described herein.
  • compositions comprising a SYK inhibitor, as described herein, and compositions comprising a
  • hypomethylating agent lenalidomide or antithymocyte globulin, as described herein, can be prepared and placed in an appropriate container, and labeled for treatment of an indicated condition. Accordingly, provided is also an article of manufacture, such as a container comprising a unit dosage form of a SYK inhibitor and a unit dosage form of a
  • the article of manufacture is a container comprising (i) a unit dosage form of a SYK inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients; and (ii) a unit dosage form of a hypomethylating agent, lenalidomide or antithymocyte globulin, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
  • kits comprising unit dosage forms of a SYK inhibitor, as described herein, and compositions comprising a hypomethylating agent, lenalidomide or antithymocyte globulin, as described herein, and a package insert containing instructions for use of the composition in treatment of a medical condition.
  • the kits comprises (i) a unit dosage form of the SYK inhibitor, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients; and (ii) a unit dosage form of a hypomethylating agent, lenalidomide or antithymocyte globulin, as described herein, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
  • the instructions for use in the kit may be for treating a cancer, including, for example, a hematologic malignancy, as further described herein.

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Abstract

L'invention concerne des méthodes et des compositions pour traiter des maladies et des troubles myéloprolifératifs. Dans certains modes de réalisation, la méthode consiste à administrer à un patient qui en a besoin une quantité efficace d'un inhibiteur de tyrosine kinase de rate et d'un agent d'hypométhylation, de lénalidomide ou de globuline antithymocyte.
PCT/US2018/028636 2017-04-21 2018-04-20 Inhibiteurs de syk en association avec des agents d'hypométhylation WO2018195471A1 (fr)

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