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US20080176879A1 - Pyrimidylaminobenzamide Derivatives For Sytemic Mastocytosis - Google Patents

Pyrimidylaminobenzamide Derivatives For Sytemic Mastocytosis Download PDF

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US20080176879A1
US20080176879A1 US11/911,575 US91157506A US2008176879A1 US 20080176879 A1 US20080176879 A1 US 20080176879A1 US 91157506 A US91157506 A US 91157506A US 2008176879 A1 US2008176879 A1 US 2008176879A1
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lower alkyl
mono
phenyl
treatment
amino
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Leila Alland
Doriano Fabbro
Jurgen Mestan
Paul W. Manley
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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

Definitions

  • the present invention relates to the use of pyrimidylaminobenzamide derivatives for the preparation of a drug for the treatment of systemic mastocyctosis.
  • the present invention also relates to a method of treating systemic mastocyctosis.
  • SM Systemic mastocytosis
  • indolent SM little or no evidence of impaired organ function
  • aggressive SM presence of impaired organ function
  • SM-AHNMD SM associated hematologic non-mast cell disease
  • mast cell leukemia SM associated hematologic non-mast cell disease
  • Clinical presentation in adult SM is heterogenous and includes skin disease (usually urticaria pigmentosa), mast cell mediator-release symptoms (headache, flushing, lightheadedness, syncope, anaphylaxis, etc), and direct or indirect organ damage (bone pain from lytic bone lesions, osteoporosis or bone fractures, hepatosplenomegaly, cytopenia from bone marrow involvement).
  • skin disease usually urticaria pigmentosa
  • mast cell mediator-release symptoms headache, flushing, lightheadedness, syncope, anaphylaxis, etc
  • direct or indirect organ damage bone pain from lytic bone lesions, osteoporosis or bone fractures, hepato
  • mast cell leukemia is a terminal disease with survival measured in months and no effective therapy to date.
  • the natural history of indolent SM is far better with median survival measured in decades and infrequent progression to aggressive SM and SM-AHNMD.
  • Outcome in SM-AHNMD is determined by the associated AHNMD and is significantly worse than SM without AHNMD.
  • increased bone marrow mast cell and eosinophil content elevated serum alkaline phosphatase, anemia, and hepatosplenomegaly have been associated with poor prognosis (Tefferi and Pardanani 2004).
  • Complete histologic and clinical remission has been achieved in patients with SM associated with the FIP1L1-PDGFR ⁇ gene fusion when treated with Gleevec® (Pardanani 2003a, Pardanani 2003b).
  • pyrimidylaminobenzamide derivatives are effective against SM, especially SM associated with the FIP1L1-PDGFR ⁇ gene fusion.
  • the problem to be solved by the present invention is to pyrimidylaminobenzamide derivatives which are useful in the treatment of especially systemic mastocytosis, especially SM associated with the FIP1L1-PDGFR ⁇ gene fusion.
  • the present invention relates to the use of pyrimidylaminobenzamide compounds of formula (I) (hereinafter: “PYRIMIDYLAMINOBENZAMIDE DERIVATIVES”):
  • R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl,
  • R 2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R 3 , cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
  • R 3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
  • R 1 and R 2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl,
  • R 4 represents hydrogen, lower alkyl, or halogen
  • the present invention further relates to use of compounds of formula I to treat or prevent systemic mastocytosis.
  • the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
  • Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • the compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
  • the invention relates also to possible tautomers of the compounds of formula I.
  • Lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl.
  • Preferably lower alkyl is methyl, propyl or tert-butyl.
  • Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl.
  • aryl group is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical.
  • aryl is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, urei
  • Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, which in each case is either unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyl, e.g. by methyl, by halogen-lower alkyl, e.g. trifluoromethyl, or by phenyl; lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy, lower alkyl, e.g. methyl or propyl; halogen-lower alkyl, e.g.
  • hydroxy-lower alkyl e.g. hydroxymethyl or 2-hydroxy-2-propyl
  • lower alkoxy-lower alkyl e.g. methoxymethyl or 2-methoxyethyl
  • lower alkoxycarbonyl-lower alkyl e.g. methoxy-carbonylmethyl
  • lower alkynyl such as 1-propynyl
  • esterified carboxy especially lower alkoxycarbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or iso-propoxy carbonyl
  • N-mono-substituted darbamoyl in particular carbamoyl monosubstituted by lower alkyl, e.g.
  • lower alkylamino e.g. methylamino
  • di-lower alkylamino e.g. dimethylamino or diethylamino
  • a cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and further by oxo or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.
  • Substituted alkyl is alkyl as last defined, especially lower alkyl, preferably methyl; where one or more, especially up to three, substituents may be present, primarily from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is especially preferred.
  • Mono- or disubstituted amino is especially amino substituted by one or two radicals selected independently of one another from lower alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; lower alkoxy lower alkyl, such as methoxy ethyl; phenyl-lower alkyl, such as benzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstituted or especially
  • Disubstituted amino is also lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g. piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.
  • lower alkylene-amino e.g. pyrrolidino, 2-oxopyrrolidino or piperidino
  • lower oxaalkylene-amino e.g. morpholino
  • lower azaalkylene-amino e.g. piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.
  • Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
  • Etherified hydroxy is especially C 8 -C 20 alkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic heteroaryl comprising one or two nitrogen atoms, preferably lower alkoxy which is substituted by imidazolyl, such as 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyr
  • Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.
  • Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
  • Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl.
  • N-Mono- or N,N-disubstituted carbamoyl is especially substituted by one or two substituents independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or aza-lower alkylene optionally substituted at the terminal nitrogen atom.
  • a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted, refers to a heterocyclic moiety that is unsaturated in the ring binding the heteroaryl radical to the rest of the molecule in formula I and is preferably a ring, where in the binding ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring preferably has 5 to 12, more preferably 5 or 6 ring atoms; and which may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy.
  • the mono- or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinnolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo[d]pyrazolyl, thienyl and furanyl.
  • the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl, benzo[d]pyrazolyl, thienyl, and furanyl.
  • imidazolyl such as 1H-imidazol-1-yl
  • benzimidazolyl such as 1-benzimidazolyl
  • indazolyl especially 5-indazolyl
  • pyridyl
  • the pyridyl radical is substituted by hydroxy in ortho position to the nitrogen atom and hence exists at least partially in the form of the corresponding tautomer which is pyridin-(1H)2-one.
  • the pyrimidinyl radical is substituted by hydroxy both in position 2 and 4 and hence exists in several tautomeric forms, e.g. as pyrimidine-(1H,3H)2,4-dione.
  • Heterocyclyl is especially a five, six or seven-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1,3-dioxolan-2-yl
  • Salts are especially the pharmaceutically acceptable salts of compounds of formula I.
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-dis
  • salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
  • bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
  • a compound of formula I may also form internal salts.
  • salts for isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
  • pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • PYRIMIDYLAMINOBENZAMIDE DERIVATIVES possesses therapeutic properties, which render it particularly useful as an inhibitor of PDGFR ⁇ (platelet derived growth factor ⁇ , also abbreviated as PDGRA) and especially for the treatment and prophylaxis of FIP1L1-PDGFR ⁇ -induced diseases such as systemic mastocytosis.
  • PDGFR ⁇ platelet derived growth factor ⁇ , also abbreviated as PDGRA
  • FIP1L1-PDGFR ⁇ -induced diseases such as systemic mastocytosis.
  • FIP1L1-PDGFR ⁇ is the designation of the fusion product of the genes FIP1L1 (FIP1 like 1) with PDGFR ⁇ .
  • the present invention thus concerns the use of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES for the preparation of a drug for the treatment of FIP1L1-PDGFR ⁇ -induced systemic mastocytosis, or other diseases associated with FIPL1-PDGFR ⁇ or similar mutations that activate PDGFR ⁇ .
  • SM Systemic Mastocytosis
  • indolent SM includes indolent SM, aggressive SM, and SM associated hematologic non-mast cell disease and mast cell leukemia.
  • the instant invention relates to the use of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES for the preparation of a pharmaceutical composition for use in treating allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis, more particularly for treating allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis with resistance to imatinib.
  • allergic rhinitis means any allergic reaction of the nasal mucosa. Such allegic reaction may occur, e.g., perennially, e.g. vernal conjunctivitis, or seasonally, e.g., hay fever.
  • allergic dermatitis means especially atopic dermatitis, allergic contact dermatitis and eczematous dermatitis, but comprises, e.g., also seborrhoeic dermatitis, Lichen planus, urticaria and acne.
  • Atopic dermatitis as defined herein is a chronic inflammatory skin disorder seen in individuals with a hereditary predisposition to a lowered cutaneous threshold to pruritus. It is principally characterized by extreme itching, leading to scratching and rubbing that in turns results in the typical lesons of eczema.
  • Allergic contact dermatitis as defined herein is a form of dermatitis that is due to the allergic sensitization to various substances that produce inflammatory reactions in the skin of those who have acquired hypersensitivity to the allergen as a result of previous exposure to it.
  • drug allergy or food allergy refers to an allergic reaction produced by a drug or ingested antigens, such as, for example, strawberries, milk or eggs.
  • bronchopulmonary aspergillosis relates to an infection of the lungs with Aspergillus.
  • mastocytosis as used herein, relates to systemic mastocytosis, for example mastocytoma, and also to canine mast cell neoplasms.
  • Mastocytosis is a myeloproliferative disorder with limited treatment options and generally a poor prognosis.
  • the pathogenesis of mastocytosis has been attributed to constitutive activation of the receptor tyrosine kinase KIT.
  • the deregulated tyrosine kinase activity of KIT is due to a mutation within the codon 816 of the protein (D816V) which also confers resistance to imatinib or imatinib mesylate, the latter being marketed as Gleevec® in the United States or Glivec® elsewhere, in vitro and in vivo.
  • mast cells play an important role as the primary effector cells in the allergic disorders mentioned herein. Antigen-specific IgE-mediated degranulation of mast cells leads to the subsequent release of chemical mediators and multiple cytokines and to leukotriene synthesis. Furthermore, mast cells are involved in the pathogenesis of multiple sclerosis.
  • mast cell neoplasms occur in both humans and animals. In dogs, mast cell neoplasms are called mastocytomas, and the disease is common, representing 7%-21% of canine tumors.
  • human mastocytosis which is usually transient or indolent
  • canine mast cell neoplasia which behaves unpredictably and is often aggressive and metastatic. For instance, human solitary mastocytomas do not often metastasize; in contrast, 50% of canine mastocytomas behave in a malignant fashion, as estimated by Hottendorf & Nielsen (1969) after review of 46 published reports of tumors in 938 dogs.
  • Cancer in the pet population is a spontaneous disease. Pet owners, motivated by prolonging the quality of their animals' life, frequently seek out the specialized care and treatment of veterinary oncologists at private referral veterinary hospitals and veterinary teaching hospitals across the country. Therapeutic modalities of veterinary cancer patients are similar to humans, including surgery, chemotherapy, radiation therapy, and biotherapy. It has been estimated that there are 42 million dogs and approximately 20 million cats in the United States. Using crude estimates of cancer incidence, there are roughly 4 million new cancer diagnoses made in dogs and a similar number in cats made each year.
  • Cutaneous mast cell tumors in dogs are a common problem. Most mast cell tumors are benign and are cured with simple resection; however, if recurrent or metastatic to distant sites therapeutic options are limited. Treatment options for recurrent lesions can include external beam radiation therapy. For distant metastases or disseminated disease the use of Lomustine® and vinblastine containing chemotherapy protocols have demonstrated some benefit. Sites for metastases for mast cell tumors include skin, regional lymph nodes, spleen, liver, and bone marrow.
  • the KIT receptor's involvement in the pathogenesis of mastocytosis is suggested by the observation that several mutations resulting in constitutive activation of KIT have been detected in a number of mast cell lines. For instance, a point mutation in human c-KIT, causing substitution of Val for Asp816 in the phosphotransferase domain and receptor autoactivation, occurs in a long-term human mast cell leukemia line (HMC-1) and in the corresponding codon in two rodent mast cell lines. Moreover, this activating mutation has been identified in situ in some cases of human mastocytosis. Two other activating mutations have been found in the intracellular juxtamembrane region of KIT, ie. the Val560Gly substitution in the human HMC-1 mast cell line, and a seven amino acid deletion (Thr573-His579) in a rodent mast cell line called FMA3.
  • the present invention more particularly concerns the use of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES for the preparation of a drug for the treatment of systemic mastocytosis.
  • the instant invention provides a method for treating systemic mastocytosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES, or pharmaceutically acceptable salts or prodrugs thereof.
  • the instant invention provides a method for treating mammals, especially humans, suffering from systemic mastocytosis comprising administering to a mammal in need of such treatment an FIP1L1-PDGFR ⁇ inhibiting amount of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide (Compound (II)) or a pharmaceutically acceptable salt thereof.
  • treatment includes both prophylactic or preventative treatment as well as curative or disease suppressive treatment, including treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as ill patients. This term further includes the treatment for the delay of progression of the disease.
  • curative means efficacy in treating ongoing episodes involving systemic mastocytosis.
  • prophylactic means the prevention of the onset or recurrence of diseases involving systemic mastocytosis.
  • delay of progression means administration of the active compound to patients being in a pre-stage or in an early phase of the disease to be treated, in which patients for example a pre-form of the corresponding disease is diagnosed or which patients are in a condition, e.g. during a medical treatment or a condition resulting from an accident, under which it is likely that a corresponding disease will develop.
  • This effect can especially be clinically relevant for patients with systemic mastocytosis.
  • the precise dosage of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES to be employed for inhibiting systemic mastocytosis depends upon several factors including the host, the nature and the severity of the condition being treated, the mode of administration.
  • the compound of formula I can be administered by any route including orally, parenterally, e.g., intraperitoneally, intravenously, intramuscularly, subcutaneously, intratumorally, or rectally, or enterally.
  • the compound of formula I is administered orally, preferably at a daily dosage of 1-300 mg/kg body weight or, for most larger primates, a daily dosage of 50-5000, preferably 500-3000 mg.
  • a preferred oral daily dosage is 1-75 mg/kg body weight or, for most larger primates, a daily dosage of 10-2000 mg, administered as a single dose or divided into multiple doses, such as twice daily dosing.
  • a small dose is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
  • the upper limit of dosage is that imposed by side effects and can be determined by trial for the host being treated.
  • Compounds of formula I may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants and administered enterally, e.g. orally, in the form of tablets, capsules, caplets, etc. or parenterally, e.g., intraperitoneally or intravenously, in the form of sterile injectable solutions or suspensions.
  • enteral and parenteral compositions may be prepared by conventional means.
  • the PYRIMIDYLAMINOBENZAMIDE DERIVATIVES can be used alone or combined with at least one other pharmaceutically active compound for use in these pathologies.
  • These active compounds can be combined in the same pharmaceutical preparation or in the form of combined preparations “kit of parts” in the sense that the combination partners can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e., simultaneously or at different time points.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • Non-limiting examples of compounds which can be cited for use in combination with PYRIMIDYLAMINOBENZAMIDE DERIVATIVES are cytotoxic chemotherapy drugs, such as cytosine arabinoside, daunorubicin, doxorubicin, cyclophosphamide, VP-16, or imatinib etc. Further, PYRIMIDYLAMINOBENZAMIDE DERIVATIVES could be combined with other inhibitors of signal transduction or other oncogene-targeted drugs with the expectation that significant synergy would result.
  • the invention further pertains the combination of a PYRIMIDYLAMINOBENZAMIDE DERIVATIVE as described hereinbefore with imatinib for the treatment of the diseases and conditions described hereinbefore.
  • the administration of such a combination may be affected at the same time, for instance in the form of a fixed, combined pharmaceutical composition or preparation, or sequentially or timely staggered.
  • the administration of a PYRIMIDYLAMINOBENZAMIDE DERIVATIVE in a dosage form as described hereinbefore and of imatinib in its marketed form of GLEEVEC® in the US/GLIVEC® in Europe and with the dosages envisaged for these dosage forms is currently preferred.
  • the treatment of systemic mastocytosis with the above combination may be a so-called first line treatment, i.e. the treatment of a freshly diagnosed disease without any preceeding chemotherapy or the like, or it may also be a so-called second line treatment, i.e. the treatment of the disease after a preceeding treatment with imatrinib or a PYRIMIDYLAMINOBENZAMIDE DERIVATIVE, depending on the severity or stage of the disease as well as the over all condition of the patient etc.
  • first line treatment i.e. the treatment of a freshly diagnosed disease without any preceeding chemotherapy or the like
  • second line treatment i.e. the treatment of the disease after a preceeding treatment with imatrinib or a PYRIMIDYLAMINOBENZAMIDE DERIVATIVE, depending on the severity or stage of the disease as well as the over all condition of the patient etc.
  • the effects of compounds on viability and proliferation of the cells is determined using the luminescent ATP Detection assay kit ATPLiteTM from Perkin Elmer Life Sciences (Cat. No: 6016947) according to the instructions of the suppliers.
  • This assay system is based on the production of light (luminescence) caused by the reaction of ATP with added luciferase and D-luciferin.
  • RPMI 1640 Invitromex, Cat.No.: L0501
  • 10% fetal calf serum Amimed, Cat.No.: 2-01F86-I
  • 2 mM L-glutamine Gabco
  • Cells without compound are used as a control and medium without cells is used to determine the assay background signal. After 70 h incubation (37° C., 5% CO 2 ), the cells are lysed by addition of 50 ⁇ L per well mammalian cell lysis solution (provided with the kit) and 5 min shaking in an orbital plate shaker at 700 rpm. Subsequently, 50 ⁇ L substrate solution (luciferase and D-luciferin) is added and after 5 min shaking and 10 min dark-adaptation of the plates, light emission is measured with a Packard TopCount.
  • substrate solution luciferase and D-luciferin
  • the compound activity is determined as total growth inhibition (TGI) of the cell cultures and is calculated as follows: After subtraction of the background signal the signal obtained for the control cells is taken as 100%. The effect of the compound is expressed as percent reduction of the control signal.
  • TGI50 values are determined from the dose response curves by graphical extrapolation.
  • GIST882 is a human gastrointestinal stromal tumor (GIST) cell line expressing an activating KIT mutation (exon 13, K-642-E) (Tuveson D A, Willis N A, Jacks T, Griffin J D, Singer S, Fletcher C D, Fletcher J A, Demetri G D, ST 1571 inactivation of the gastrointestinal stromal tumor c - KIT oncoprotein: biological and clinical implications, Oncogene, Aug. 16 , 2001; 20(36):5054-8).
  • the GIST882 cells are cultivated in RPMI 1640 (Invitromex, Cat. No: L0501), supplemented with 15% FCS, and 2 mM glutamine (Gibco).
  • GIST882 cells are seeded into black 96-well tissue culture plates (Packard) at a density of 10000 cells per well in 50 ⁇ L complete medium and incubated for one day in order to allow for attachment of the cells. Serial two-fold dilutions of 2 ⁇ concentrated compound is added (50 ⁇ L per well) in duplicates (final volume: 100 ⁇ L per well). Cells without compound are used as a control and medium without cells is used to determine the assay background signal. After 70 h incubation (37° C., 5% CO 2 ), the cells are lysed by addition of 50 ⁇ L per well mammalian cell lysis solution (provided with the kit) and 5 min shaking in an orbital plate shaker at 700 rpm. Subsequently, 50 ⁇ L substrate solution (luciferase and D-luciferin) is added and after 5 min shaking and 10 min dark-adaptation of the plates, light emission was measured with a Packard TopCount.
  • substrate solution luciferase and D-lucifer
  • the compound activity is determined as total growth inhibition (TGI) of the cell cultures and is calculated as follows: After subtraction of the background signal the signal obtained for the control cells is taken as 100%. The effect of the compound is expressed as percent reduction of the control signal.
  • TGI50 values are determined from the dose response curves by graphical extrapolation.
  • Compound (II) inhibits the proliferation of GIST882 cells with a mean IC50 value of ⁇ 200 nM.
  • Adherent cells are grown in 96-well flat-bottom tissue culture plates close to confluency. Cells growing in suspension are seeded at 100000-150000 cells per well.
  • cells are washed once with PBS following cell lysis with 100 to 150 ⁇ L lysis buffer (50 mM Tris/HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodium ortho-vanadate, 1 mM PMSF, 50 ⁇ g/mL aprotinin and 80 ⁇ g/mL leupeptin).
  • Cell lysates are used immediately or stored at ⁇ 20° C.50 ⁇ L of the lysates are transferred to black ELISA plates (NUNC-Maxisorp, Cat.
  • Nr.437111 that are previously coated with a monoclonal anti-CD117 antibody obtained from Diaclone (#854.510.000) is used.
  • the antibody is diluted in PBS and incubated with the plates overnight at 4° C. (50 ⁇ L/well).
  • Phosphorylation of the captured Kit is detected using a commercial anti-P-Tyr Ab, labeled with alkaline phosphatase (AP), PY20 AP from Zymed, at a final concentration range between 1:3000 and 1:10000 (0.1 to 0.33 ⁇ g/ml).
  • AP alkaline phosphatase
  • PY20 AP alkaline phosphatase
  • chemiluminescent AP substrate CDPStar RTU with Emerald II from Applied Biosystems (Cat. No.: T2388C) are added and incubated for 45 min at RT in the dark.
  • the plates are sealed with Packard TopSealTM-A plate sealers (Cat. No. 6005185) and luminescence is quantified by measuring counts per second (CPS) with a Packard Top Count Microplate Scintillation Counter (Top Count).
  • the difference between the ELISA-readout (CPS) obtained with the lysates of the untreated cells and the readout for the assay-background (all components, but without cell lysate) is calculated and taken as 100% reflecting the constitutively phosphorylated Kit protein present in these cells.
  • the activity of the compound on the Kit kinase activity is expressed as percent reduction of the Kit phosphorylation.
  • the values for the IC50 and IC90 are determined from the dose response curves by graphical extrapolation.
  • a Phase II, open-label study was designed to evaluate the safety and efficacy of Compound (II) administered orally 400 mg twice daily.
  • SM patients meeting specific disease criteria and with a clinical indication for treatment were enrolled. The results are based on preliminary data for the first 23 pts in this study. Results: The median age was 49 (range 33-78) yrs and the median time from diagnosis of SM was 27 (range 1 to 292) months. For those with data available, 13/17 pts had a c-kit D816V mutation in bone marrow cells. The median exposure to Compound (II) was 144 days. Treatment is ongoing for 18 (78%) pts; 5 (22%) discontinued, 3 (13%) for adverse events and 2 (9%) withdrew consent.

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WO2016104474A1 (fr) 2014-12-26 2016-06-30 花王株式会社 Procédé de production d'un composé de dicétone cyclique
WO2019241504A1 (fr) 2018-06-15 2019-12-19 Handa Pharmaceuticals, Llc Sels d'inhibiteurs de kinases et compositions associées
KR102535842B1 (ko) 2020-07-31 2023-05-23 (주)파로스아이바이오 2,3,5-치환된 싸이오펜 화합물의 비만세포증 예방, 개선 또는 치료 용도

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