WO2011106168A1 - Composés de purine pour le traitement de maladies auto-immunes et démyélinisantes - Google Patents

Composés de purine pour le traitement de maladies auto-immunes et démyélinisantes Download PDF

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WO2011106168A1
WO2011106168A1 PCT/US2011/024404 US2011024404W WO2011106168A1 WO 2011106168 A1 WO2011106168 A1 WO 2011106168A1 US 2011024404 W US2011024404 W US 2011024404W WO 2011106168 A1 WO2011106168 A1 WO 2011106168A1
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purin
indazol
amine
methyl
purine
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PCT/US2011/024404
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English (en)
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Alfred M. Ajami
Kenneth W. Duncan
Xinqin Fang
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Dcam Pharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • 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
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom

Definitions

  • DC dendritic cells
  • macrophages and microglia are the homeostatic regulators of the immune system (Liu et al, Science 324:392-397, 2009; Merad and Manz, Blood 113:3418-3427, 2009). Their functions straddle both the initial priming of the immune response, with its attendant burst of inflammatory signaling, and the chronic effector stages of tissue destruction. They also have the capacity to counteract disease by inducing tolerance and permitting tissue repair (Shklovskaya and de St. Groth, Methods Mol. Biol. 380:25-46, 2007). In effect, DCs and their descendant lineages become therapeutic targets because they are hubs in a dysregulated immune system. DCs have the potential to activate autoreactive lymphocytes and secrete cytokines that further influence the status of those lymphocytes.
  • dendritic cells as the cellular target, i.e. mode of action
  • RTKs as the molecular target, i.e. mechanism of action
  • RTK inhibition have been documented in multiple studies, and can be viewed as setting the paradigms for understanding all such immune system diseases sharing similar cellular and molecular etiologies.
  • Multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease are particularly illustrative in this respect, but the same phenomenology applies to psoriasis, graft- versus-host-disease, and other autoimmune diseases.
  • the present invention is directed to a compound of Structural Formula (I):
  • R and R each independently are hydrogen or -L'-R 0 ;
  • R 4 and R 5 taken together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl Ar 2 , optionally including one or two additional heteroatoms selected from N, S or O;
  • Figure 2C is a plot of dendritic cells proliferation as a function of time in the presence of a representative compound of the present invention as well as controls, where the cells counted are limited to the CD 1 lc+CDl lb+ phenotype.
  • Figure 10 is a plot showing time course of body weight change of DBA/1 mice with in the Collagen -Induced Arthritis (CIA) animal model in the presence of representative compounds of the present invention as well as controls.
  • CIA Collagen -Induced Arthritis
  • Figure 12B is a plot showing Mean Clinical Arthritis Score as a function of time for "Non-enrollment Paws" in the Collagen-Induced Arthritis (CIA) animal model, in the presence of a representative compound of the present invention as well as control and comparator methotrexate.
  • Figure 15 shows a histogram of a quantitative measurement of pannus in a joint of animal in the Collagen-Induced Arthritis (CIA) model in the presence of representative compounds of the present invention as well as controls.
  • CIA Collagen-Induced Arthritis
  • Figure 23 is a histogram showing inflammatory score in C57BL/6 mice in the dextran sodium sulfate (DSS)-induced murine colitis model, in the presence of a representative compound of the present invention as well as controls.
  • DSS dextran sodium sulfate
  • Figure 24 is a histogram showing percent weight loss in C57BL/6 mice in the dextran sodium sulfate (DSS)-induced murine colitis model, in the presence of representative compounds of the present invention as well as control.
  • DSS dextran sodium sulfate
  • Figure 28 shows two histograms, each histogram representing the amount of a representative biomarker (IL-10, IL-27) determined by qPCR of cells from mesenteric lymph nodes (MLN) collected from a mouse in the dextran sodium sulfate (DSS)- induced murine colitis model, at Day 12 in the presence of representative compounds of the present invention as well as control.
  • IL-10 mesenteric lymph nodes
  • DSS dextran sodium sulfate
  • Embodiments of the present invention provide compounds that can modulate kinase activity, modulate dendritic cell maturation and activation, and can treat or alleviate the symptoms of various autoimmune diseases.
  • a 1 is selected from H, hydroxyl, -C(0)NH 2 , or -C(0)NH(C1-C3)alkyl; and A 2 is selected from H, hydroxyl, or a C1-C6 alkyl, provided that A 1 and A 2 are not simultaneously hydrogens.
  • R and R each independently are hydrogen or -L -R .
  • R and R 3 each independently are hydrogen, phenyl, pyridyl, or benzyl, the phenyl, pyridyl or benzyl being optionally substituted with one to three substituents independently selected from a halogen, C1-C3 alkyl, -CF 3 , hydroxyl, and a (Cl-C3)alkoxy.
  • R 6 is hydrogen, C1-C4 alkyl, or Ar 1 .
  • R 6 is hydrogen, methyl, ethyl, pyridyl, thiophenyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or furyl, the pyridyl, thiophenyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or furyl group, optionally substituted with one to three substituents independently selected from a halogen, C1-C3 alkyl, -CF 3 , hydroxyl, and a (Cl-C3)alkoxy.
  • a C1-C6 alkyl a C2-C6 alkenyl, a C2-C6 alkynyl, each optionally substituted with a halogen or a 5- or 6-membered aryl or heteroaryl,
  • Q 2 is O, CH 2 , NH, or NR 100
  • R 100 is -C(0)OEt or a C1-C6 alkyl optionally substituted with -CN, -OH, phenyl, or cyclopropyl.
  • the compound of the present invention is represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof.
  • Ar is substituted with one to three substituents R selected from a halogen, C1-C3 alkyl, hydroxyl, and a (Cl-C3)alkoxy, wherein said C1-C3 alkyl is optionally substituted with a halogen, or, alternatively, two groups R taken together with the intervening atoms form a 1,3-dioxole ring or a 2,3-dihydro-l,4-dioxine ring, and values and alternative values for the remainder of the variables are as described for Structural Formula (I).
  • the compound of the present invention is represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof.
  • a and A each independently are a C1-C6 alkoxy, optionally substituted with a halogen or a 5- or 6-membered aryl or heteroaryl; and values and alternative values for the remainder of the variables are as described for Structural Formula (I).
  • the compound of the present invention is represented by Structural Formulas (IA2) or (IB2), or a pharmaceutically acceptable salt thereof.
  • R 4 is H or C 1-6 alkyl
  • R 5 is -L 2 -R 7
  • R 7 is a 5- to 6-membered aryl or heteroaryl Ar 3 ;
  • Ar 3 is selected from pyridyl, thiophenyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and furyl
  • y is 1 ; and values and alternative values for the remainder of the variables are as described for Structural Formula (I).
  • the compound of the present invention is represented by Structural Formulas (IA2) or (IB2), or a pharmaceutically acceptable salt thereof.
  • R 4 is H, y is 2, Ar 3 is phenyl and R K is H or methyl; and the optional substituent R° is, for each occurrence independently, selected from a halogen and a C1-C6 alkoxy group, or, alternatively, two groups R° taken together with the intervening atoms form a 1,3-dioxole ring or a 2,3-dihydro-l,4-dioxine ring; and values and alternative values for the remainder of the variables are as described for Structural Formula (I).
  • the compound of the present invention is represented by Structural Formulas (IA2) or (IB2), or a pharmaceutically acceptable salt thereof.
  • R 5 is L 2 -R 7 ; and values and alternative values for the remainder of the variables are as described for Structural Formula (I).
  • the compound of the present invention is represented by Structural Formulas (IA2) or (IB2), or a pharmaceutically acceptable salt thereof.
  • R 5 is L 2 -R 7 ;
  • R 7 is -NR M R N ;
  • R M and R N taken together with the nitrogen to which they are attached, form a 5- to 7-membered heterocyclyl C , and further wherein C 3 isselected from the group consisting of
  • the compound of the present invention is represented by Structural For pharmaceutically acceptable
  • the compound of the present invention is represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof.
  • R 1 is NR 4 R 5 ;
  • a 1 is hydroxyl, a C1-C6 alkoxy or H; and
  • a 2 is selected from hydroxyl, a C1-C6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, and H;
  • R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl C , selected form the roup consisting of
  • the compound of the present invention is represented by Structural Formula (IC), or a pharmaceutically acceptable salt thereof:
  • alkyl groups examples include methyl (Me), ethyl (Et), propyl (e.g., n-propyl, and isopropyl,), butyl (e.g., n- butyl, isobutyl, s-butyl, t-butyl), pentyl groups (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • a lower alkyl group typically has up to 6 carbon atoms.
  • an alkyl group has 1 to 6 carbon atoms, and is referred to as a "Ci -6 alkyl group", “C1-C6 alkyl group”, or (Cl-C6)alkyl group.
  • C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), and butyl groups (e.g., n-butyl, isobutyl, s-butyl, t-butyl).
  • a branched alkyl group has at least 3 carbon atoms (e.g., an isopropyl group) and up to 6 carbon atoms, e.g.
  • Substituents on alkyl groups include hydroxyl, oxo, amino, cyano, (Cl-C3)alkylamino, di(Cl-C3)alkylamino, halogen (typically, F, CI, and Br), (Cl-C3)alkoxy, (C3-C6)cycloalkyl, a 5- to 6- membered aryl or heteroaryl, -C(0)OR G2 or -C(0)NR H1 R J1 , wherein R G2 is hydrogen or (Cl-C4)alkyl, and R H1 and R J1 each independently are hydrogen or a (Cl-C3)alkyl.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like.
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene).
  • a branched alkenyl group has at least 3 carbon atoms, and in various embodiments, has up to 6 carbon atoms, e.g. it is a C 3- 6 alkenyl or (C3-C6)alkenyl group.
  • heteroatom refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium.
  • non-aromatic heterocyclic group or “heterocyclyl” refers to a non-aromatic cycle having 5-7 ring atoms (unless the number of “ring atoms” or “members” is specifically provided), among which 1 to 3 ring atoms (unless specifically provided) are heteroatoms independently selected from oxygen (O), nitrogen (N) and sulfur (S) (unless specifically provided), and that optionally contains one or more, e.g., two, double or triple bonds.
  • R F is hydroxyl, cyano, a C1-C3 alkyl, a C3-C6 cycloalkyl, amino, a (Cl-C3)alkylamino, a di(Cl-C3)alkylamino, a C1-C3 alkoxy, a 5- to 6- membered heteroaryl or phenyl, -C(0)OR G2 or -C(0)NR H1 R J1 ;
  • R G , R G1 , and R G2 are each independently hydrogen or a C1-C4 alkyl; and
  • R H , R J , R HI , R J1 each independently hydrogen or a C1-C4 alkyl; and R H , R J , R HI , R J1 each
  • Heterocyclyl groups (and, particularly, C 3 ) can further be substituted with a group R 100 selected from a CI- C6 alkyl, a C3-C6 cycloalkyl, phenyl, cyano, hydroxyl and -C(0)OR lul , wherein R 1U1 is methyl or ethyl.
  • heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Generally, heteroaryl rings do not contain 0-0, S-S, or S-0 bonds. However, one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene S, S -dioxide).
  • heteroaryl rings include, but are not limited to, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, tetrazole, pyrazole, imidazole, isothiazole, thiazole, thiadiazole, isoxazole, oxazole, and oxadiazole.
  • the heteroaryl ring may be attached at C-2, C-3, or C-4; that is, be pyridin-2-yl, pyridine-3-yl, or pyridine-4-yl.
  • heteroaryl groups may be C-attached or N-attached (where such is possible).
  • a group derived from pyrrole may be pyrrol-l-yl (N-attached) or pyrrol-3-yl (C-attached).
  • Heteroaryl and aryl groups can further be substituted with one to three substituents R°, wherein each R° is independently selected from:
  • said C1-C6 alkoxy group is optionally substituted with a 5- or 6- membered aryl or heteroaryl, said 5- or 6-membered aryl or heteroaryl further optionally substituted with a halogen, hydroxyl or a C1-C6 alkoxy, or, alternatively,
  • a “protecting group” refers to modification of a functional group that reduces the reactivity of the functional group in an unwanted reaction.
  • protecting groups for amines include, but are not limited to, tert-butyloxycarbonyl (t-BOC), benzyl (Bn), and carbobenzyloxy (Cbz) groups.
  • C 1-6 alkyl is specifically intended to individually disclose Q, C 2 , C 3 , C 4 , C 5 , C 6 , Ci-C6, Q-C5, Cj-C 4 , C1-C3, C C2, C 2 -C 6 , C 2 -Cs, C 2 -C 4 , C 2 -C 3 , C 3 - C 6 , C3-C5, C 3 -C , C 4 -C 6 , C -C 5 , and C 5 -C 6 alkyl.
  • the term "5-9 membered heteroaryl group” is specifically intended to individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7, 5-6, 6-9, 6- 8, 6-7, 7-9, 7-8, and 8- 9 ring atoms.
  • Representative compounds of Formula (I) in accordance with embodiments of the present invention include, but are not limited to, the compounds presented in Table 1 below. Table 1
  • step d acetic anhydride and triethylorthoformate
  • Invitrogen, Inc. (Carlsbad, CA, USA). Animal models for various diseases, including autoimmune diseases, are known in the art, and include, for example, Collagen- Induced Arthritis (CIA) and Collagen Antibody-Induced Arthritis (CAIA) for rheumatoid arthritis (RA), Experimental Autoimmune Encephalomyelitis (EAE) for multiple sclerosis (MS), dextran sodium sulfate (DSS)-induced murine colitis for inflammatory bowel disease (IBD) and 2,4,6-trinitrobenzene sulfonic acid (TNBS)- induced murine colitis for Crohn's Disease, Ova-Induced- Asthma for chronic obstructive pulmonary disease (COPD) or asthma, and granuloma and air pouch models for inflammation, among others.
  • CIA Collagen- Induced Arthritis
  • CAIA Collagen Antibody-Induced Arthritis
  • EAE Experimental Autoi
  • RTKs such as Flt3, CSF-1R, ACVR1 (ALK2), GSG2 (Haspin), LRRK2, LRRK2 G2019S, MELK, MUSK, NLK, NTRK1 (TRKA), NTRK3 (TRKC), PDGFRA D842V, PDGFRA V561D, PIK3CA/PIK3R1 (pi 10 alpha/p85 alpha), PTK6 (Brk), and RIPK2, and ROS1.
  • RTKs such as Flt3, CSF-1R, ACVR1 (ALK2), GSG2 (Haspin), LRRK2, LRRK2 G2019S, MELK, MUSK, NLK, NTRK1 (TRKA), NTRK3 (TRKC), PDGFRA D842V, PDGFRA V561D, PIK3CA/PIK3R1 (pi 10 alpha/p85 alpha), PTK6 (Brk), and RIPK2, and ROS1.
  • Flt3 has been linked to the negative regulation of IL-10, a principal regulator of the immunogenic-tolerogenic balance toward tolerogenic Th2 and T-reg biology, wherein silencing Flt3 downregulates T-cell reactivity and T-reg signaling by upregulation of IL-10 (see, Astier et al, J.Immunology, 184:685 -693, 2010).
  • IL-10 has a role in many diseases such as IBD, MS, and asthma, among others.
  • IL-10-deficiency in mice leads to the development of colitis while IL- 10 treatments have been shown effective in inhibiting the development of type I diabetes and EAE.
  • IL-10 may reduce Thl7 and macrophages that cause joint and bone erosion, while having only a limited impact on reducing joint inflammation.
  • Compounds of the present invention can be used to modulate production of IL- 10.
  • compounds of Formula (I) can modulate the activity of the following kinases: Flt3, CSF-IR, ACVRl (ALK2), GSG2 (Haspin), LRRK2, LRRK2 G2019S, MELK, MUSK, NLK, NTRKl (TRKA), NTRK3 (TRKC), PDGFRA D842V, PDGFRA V561D, PIK3CA/PIK3R1 (pi 10 alpha/p85 alpha), PTK6 (Brk), ROS1, and RIPK2.
  • a variety of pathological conditions, states, disorders or diseases, including autoimmune diseases, can be treated by modulating the activity of one or more of these kinases.
  • Compounds of Formula (I) can be used in the treatment of disorders mediated by one or more kinase selected from Flt3, CSF-IR, ACVRl (ALK2), GSG2 (Haspin), LRRK2, LRRK2 G2019S, MELK, MUSK, NLK, NTRKl (TRKA), NTRK3 (TRKC), PDGFRA D842V, PDGFRA V561D, PIK3CA/PIK3R1 (pi 10 alpha/p85 alpha), PTK6 (Brk), ROS1, and RIPK2.
  • kinase selected from Flt3, CSF-IR, ACVRl (ALK2), GSG2 (Haspin), LRRK2, LRRK2 G2019S, MELK, MUSK, NLK, NTRKl (TRKA), NTR
  • ROS1 has been shown to be activated in gliobastomas and astrocytomas.
  • disorders mediated by one or more of these kinases are disorders in which one or more symptoms can be inhibited, alleviated, reduced or whose onset can be delayed by completely or partially inhibiting the protein kinase.
  • the RTK is Flt3 or CSF-IR
  • compounds of the present invention are useful in the treatment of a Flt3-mediated disorder or a CSF-1R- mediated disorder.
  • Flt3 -mediated disorder and “CSF-lR-mediated disorder” refer to disorders in which one or more symptoms can be inhibited, alleviated, reduced or whose onset can be delayed by completely or partially inhibiting the protein kinase Flt3 or the protein kinase CSF-IR, respectively.
  • Flt3-mediated disorders and conditions include autoimmune disorders such as ankylosing spondylitis, arthritis, aplastic anemia, Behcet's disease, type 1 diabetes mellitus, graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia, Wegener's granulomatosis, hyper IgE syndrome, idiopathic thrombocytopenia purpura, rheumatoid arthritis, Crohn's disease, multiple sclerosis, Myasthenia gravis, psoriasis, and lupus, transverse myelitis, and amyotrophic lateral sclerosis; neurodegenerative diseases such as infantile spinal muscular atrophy and juvenile spinal muscular atrophy, Creutzfeldt- Jakob disease; and subacute sclerosing panencephalitis; and cancers such as leukemia including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocy
  • CSF-lR-mediated disorders and conditions include autoimmune disorders such as sarcoidosis, asthma, psoriasis, diabetes, Sjogren's syndrom, and uveitis;
  • cardiovascular disease involving chronic inflammation (e.g. atherosclerosis ); cancers such as osteolytic sarcoma, myeloma, breast cancer, tumor metastasis to bone, uterine cancer, stomach cancer, and hairy cell leukemia; diseases with an inflammatory component including glomerulonephritis, prosthesis failure, congestive obstructive pulmonary disease, pancreatitis, HIV infection, tumor related angiogenesis, age- related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain, osteoporosis, Paget's disease, and prosthesis failure.
  • diseases with an inflammatory component including glomerulonephritis, prosthesis failure, congestive obstructive pulmonary disease, pancreatitis, HIV infection, tumor related angiogenesis, age- related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, skeletal pain caused by tumor met
  • the present invention is a method of treating a patient suffering from an autoimmune disease by administering to a patient suffering from such disorders a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • IBD inflammatory bowel disease
  • IBD Crohn's disease and ulcerative colitis
  • UC primarily affects the mucosal lining of the large intestine and rectum, while Crohn's disease may involve any part of the GI tract.
  • Extraintestinal manifestations are often associated with IBD, and include inflammatory conditions such as peripheral arthritis, ankylosing spondylitis, sacroiliitis, uveitis, and primary sclerosing cholangitis, among others.
  • treatment of IBD and symptoms thereof includes treatment of both intestinal and extraintestinal aspects.
  • preferred compounds useful for the treatment of a patient with IBD, UC, or Crohn's disease, or symptoms thereof are represented by Structural Formula(IAl), (IA2), (IB1) or (IB2).
  • compounds represented by Structural Formula (IA1) and (IB2) useful for the treatment of a patient with IBD, UC, or Crohn's disease , or symptoms thereof are Compounds 12, 36, 47, 129.
  • compounds of Formula (I) useful for the treatment of a patient with RA or psoriatic arthritis , or symptoms thereof have structure (IA1), (IA2), (IB2) or (IB1).
  • compounds of Formula (I) useful for the treatment of a patient with RA or psoriatic arthritis , or symptoms thereof are Compounds 5, 36, 12, 47, 50, 54, 100, and 129.
  • MS Multiple sclerosis
  • MS is characterized by patches of demyelination in the brain and spinal cord, and is an example of a demyelinating condition.
  • a demyelinating condition is a condition that destroys, breaks the integrity of or damages a myelin sheath, the insulating layer surrounding vertebrate peripheral neurons that increases the speed of conduction and formed by Schwann cells in the peripheral or by oligodendrocytes in the central nervous system.
  • demyelinating autoimmune conditions include Chronic Immune Demyelinating Polyneuropathy (CIDP); multifocal CIDP; inflammatory demylinating
  • compounds useful for the treatment of a patient with MS or demyelinating autoimmune conditions have structure (IA1) or (IB1).
  • compounds of Formula (IA1) and (IB1) useful for the treatment of a patient with MS or demyelinating autoimmune conditions are
  • compounds of Formula (I) can be used in the treatment of cancer.
  • cancer refers to the uncontrolled growth of abnormal cells that have mutated from normal tissues.
  • a cancerous tumor (malignancy) is of potentially unlimited growth and expands locally by invasion and systemically by metastasis.
  • cancers examples include: breast cancer, colorectal cancer, non-small cell lung cancer, ovarian, renal, sarcoma, melanoma, head & neck, hepatocellular, thyroid, leukemia, lymphoma, multiple myeloma, esophageal, large bowel, pancreatic, mesothelioma, carcinoma (e.g. adenocarcinoma, including esophageal adenocarcinoma), sarcoma (e.g.
  • the patient can be treated for certain leukemias, including Flt3 -mediated leukemias such as acute myeloid leukemia characterized by one or more Flt3 mutations.
  • Flt3 -mediated leukemias such as acute myeloid leukemia characterized by one or more Flt3 mutations.
  • Treating a subject suffering from cancer includes achieving, partially or substantially, one or more of the following: arresting the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and ameliorating or improving a clinical symptom or indicator associated with a cancer (such as tissue or serum components).
  • the patient can be treated for bone metastases.
  • Bone is one of the most common metastatic sites for cancers, such as breast, lung and prostate cancers.
  • metastatic tumour cells in bone enhance bone resorption (osteolysis) by inducing and activating osteoclasts.
  • This in turn releases growth factors, such as TGF- ⁇ and IGF-1 from the bone matrix that promote tumour growth.
  • Osteoclasts are multinucleated cells formed by fusion of Flt3 -positive monocyte-macrophage cells, which can also differentiate to dendritic cells and macrophages. Therefore suppression of hyperactive osteoclasts (OCL), and thus osteolysis, may be effective against bone metastasis.
  • OCL hyperactive osteoclasts
  • Treating bone metastases refers to reducing (partially or completely) the size of the bone metastases, slowing the growth of the metastases relative to the absence of treatment and reducing the extent of further spread of the cancer, and also includes pain reduction, decreased incidents of fractures, relief of spinal cord compression, control of hypercalcaemia, and/or restoration of normal blood cell counts.
  • the method includes administering to a mammal a pharmaceutical composition that comprises a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition that comprises a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier.
  • mammal refers to any warm blooded species, such as a human.
  • the compound of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment of such
  • an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to treat the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable.
  • Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials.
  • the compounds can be formulated in conventional manner, for example, in a manner similar to that used for known anti-inflammatory agents.
  • Oral formulations containing an active compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • the carrier can be a finely divided solid, which is an admixture with a finely divided active compound.
  • an active compound can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets can contain up to about 99% or greater of the active compound.
  • Surface modifying agents can include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the active compound(s).
  • the oral formulation can also consist of administering an active compound in water or fruit juice, containing appropriate solubilizers or emulisifiers as needed.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • An active compound described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intrathecal, intramuscular,
  • compositions for oral administration can be in either liquid or solid form.
  • the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the active compound.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be a capsule or tablet itself, or it can comprise the appropriate number of any such compositions in package form.
  • Such unit dosage form may contain from about 1 mg/kg of active compound to about 500 mg/kg of active compound, and can be given in a single dose or in two or more doses.
  • Such doses can be administered in any manner useful in directing the active compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • Such administrations can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g., rectal and vaginal).
  • the compounds of the present teachings can be formulated, for example, into an aqueous or partially aqueous solution.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.
  • Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g., rectal and vaginal). Topical formulations that deliver active compound(s) through the epidermis can be useful for localized treatment of inflammation and arthritis.
  • Transdermal administration can be accomplished through the use of a transdermal patch containing an active compound and a carrier that can be inert to the active compound, can be non-toxic to the skin, and can allow delivery of the active compound for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active compound can also be suitable.
  • occlusive devices can be used to release the active compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active compound with or without a carrier, or a matrix containing the active compound.
  • Other occlusive devices are known in the literature.
  • Compounds described herein can be administered into a body cavity, (e.g., rectally or vaginally) in the form of a conventional suppository.
  • Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, can also be used.
  • a compound can be desirable to combine a compound with other agents effective in the treatment of the target disease.
  • other active compounds i.e., other active ingredients or agents
  • active compounds of the present teachings can be administered with active compounds of the present teachings.
  • the other agents can be administered at the same time or at different times than the compounds disclosed herein.
  • Drugs useful in the treatment of IBD include 5-ASA compounds,
  • 5-ASA compounds include sulfasalazine and mesalamine.
  • Antibiotics include metronidazole and ciprofloxacin.
  • compounds of Formula (I) are used in combination with anti-inflammatory agents for the treatment of an autoimmune disease such as IBD, Crohn's disease, UC, or RA.
  • compositions of the present teachings also can consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
  • Compounds 1-142 can be prepared using the appropriate starting materials in accordance with the following examples. Selected compounds are shown in Table 3 below. It is understood by those skilled in the art of organic synthesis that the substitution patterns of the starting materials determines the substitution patterns of the products, and the skilled practitioner will be able to exercise routine judgment for the selection of suitable starting materials in order to prepare specific products, the order of synthetic steps, and the need for protecting groups for remote functionalities.
  • reaction mixture was filtered through celite and the filtrate concentrated under vacuum. The residue was treated with a small amount of water and the solid filtered off. Whilst moist, the solid was re-crystallized from water, the solid filtered off and dried under vacuum overnight to yield the desired product
  • the title compound was prepared according to the methods in Tanji, K.I. et al., Chem. Pharm. Bull. 35:4972-4976, 1987: 5-Amino-2,4-dichloropyrimidine (9.3 g, 57.1 mmol) and 5-aminoindazole (7.5 g, 57.1 mmol) were combined and dissolved in a mixture of ethanol (30 mL), water (200 mL) and concentrated HC1 (3.0 mL). The reaction mixture was then heated to 90 °C for 20 hours at which point no starting materials remained by t.l.c.
  • the reaction mixture was cooled and the precipitate filtered off washed with water (50 mL), saturated sodium bicarbonate solution (100 mL) and again with water (2 x 100 mL). The solid was dried under vacuum for 20 hours (10. 6g, 40.7 mmol, 71%).
  • the resulting solid was filtered off and washed with water (100 mL), saturated sodium bicarbonate solution (60 mL) and water (100 mL) before drying in a vacuum oven at 40 °C overnight.
  • the solid was shown by HPLC to be at least 95% pure and not purified further (10.6 g, 39.2 mmol, 94% yield).
  • Representative compounds of Formula (I) are screened for activity in several standard pharmacological test procedures. Based on the activity shown in the standard pharmacological test procedures, the compounds of the present teachings can be useful for treating chronic inflammatory and autoimmune diseases.
  • Symadex is used for comparison.
  • "Symadex” and “C-1311” are both names for 5-(2-(diethylamino)ethylamino)-8- hydroxy-6H-imidazo[4,5,l-de]acridin-6-one.
  • the use of Symadex as a Flt3 inhibitor and immune system modulator has been described previously by Ajami, A.M., Boss, M.A. and Paterson, J. in US Patent Appl. 2006/0189546A1.
  • EXAMPLE 1 DETERMINATION OF PROTEIN TYROSINE KINASE ACTIVITY TARGETING IN VITRO.
  • Compounds that are active in inhibition or modulation of Flt3 activity can be used to treat inflammatory and autoimmune diseases.
  • IC 50 the 50% inhibitory concentration
  • DR dose response
  • the most common approach exemplified by the Z-Lyte® assay is based on treating each specific kinase with a unique substrate and optical reporter system in the presence of ATP at apparent Km for each kinase, typically ranging from 5 to 500 ⁇ .
  • the biochemical assay employs a fluorescence-based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non- phosphorylated peptides to proteolytic cleavage.
  • the kinase transfers the gamma-phosphate of ATP to a single tyrosine, serine or threonine residue in a synthetic FRET-peptide.
  • a site-specific protease recognizes and cleaves non-phosphorylated FRET-peptides.
  • Phosphorylation of FRET-peptides suppresses cleavage by the Development Reagent. Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor (i.e., fluorescein) fluorophores on the FRET-peptide, whereas uncleaved, phosphorylated FRET- peptides maintain FRET.
  • a ratiometric method which calculates the ratio (the Emission Ratio) of donor emission to acceptor emission after excitation of the donor fluorophore at 400 nm, is used to quantitate reaction progress versus a baseline response obtained in controls.

Abstract

La présente invention concerne un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci. Des valeurs et des valeurs préférées des variables A1, A2 et R1 sont définies dans la description.
PCT/US2011/024404 2010-02-24 2011-02-10 Composés de purine pour le traitement de maladies auto-immunes et démyélinisantes WO2011106168A1 (fr)

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