WO2007092436A2 - Composes pour le traitement de troubles inflammatoires, de troubles de demyelinisation et de cancers - Google Patents

Composes pour le traitement de troubles inflammatoires, de troubles de demyelinisation et de cancers Download PDF

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WO2007092436A2
WO2007092436A2 PCT/US2007/003135 US2007003135W WO2007092436A2 WO 2007092436 A2 WO2007092436 A2 WO 2007092436A2 US 2007003135 W US2007003135 W US 2007003135W WO 2007092436 A2 WO2007092436 A2 WO 2007092436A2
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alkyl
optionally substituted
methyl
taken together
independently
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PCT/US2007/003135
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WO2007092436A3 (fr
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Alfred M. Ajami
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Xanthus Pharmaceuticals, Inc.
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Publication of WO2007092436A3 publication Critical patent/WO2007092436A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • R a and R b are not H or optionally substituted alkyl and R y is not optionally substituted N-morpholinyl, optionally substituted N-piperazinyl, or optionally substituted N-pyrazinyl.
  • R x when R is R x , then R a and R b are not H or optionally substituted alkyl and R y is not optionally substituted N-morpholinyl, or optionally substituted N- pyrazinyl.
  • FIG. 7 is a time dependent chart showing mean clinical score (performance score) of the animals suffering from chronic stage Experimental Autoimmune Encephalomyelitis (EAE) at the indicated day post treatment with SymadexTM after 8 weeks of dosing at 20 mg/kg versus vehicle control.
  • EAE Experimental Autoimmune Encephalomyelitis
  • FIG.8B is a bar chart showing the time course of CD-4 cell counts of the animals suffering from chronic stage Experimental Autoimmune Encephalomyelitis (EAE) at the indicated day post treatment with SymadexTM after 4, 6 and 8 weeks of dosing at 20 mg/kg versus vehicle control.
  • EAE Experimental Autoimmune Encephalomyelitis
  • FIG.8D is a bar chart showing the time course of B-cell counts of the animals suffering from chronic stage Experimental Autoimmune Encephalomyelitis (EAE) at the indicated day post treatment with SymadexTM after 4, 6 and 8 weeks of dosing at 20 mg/kg versus vehicle control.
  • EAE Experimental Autoimmune Encephalomyelitis
  • FIG. 13 is a time dependent chart bar chart showing mean performance of the animals suffering from acute stage Collagen Monoclonal Antibody (mAB) Induced Arthritis at the indicated day post treatment with SymadexTM after 3 consecutive daily oral doses at 30 mg/kg.
  • mAB Collagen Monoclonal Antibody
  • R y is a heteroaryl or a non-aromatic heterocycle, each optionally substituted at one or more substitutable carbons with methyl, hydroxyl, or methoxy, and optionally N'-substituted with C1-C4 alkyl or C1-C4 alkyl substituted with -NR c R d , wherein R c and R d are individually H, methyl or ethyl.
  • R a and R b are not H or optionally substituted alkyl and R y is not optionally substituted N-morpholinyl, optionally substituted N-piperazinyl, or optionally substituted N-pyrazinyl.
  • R is selected from groups represented by structural formulas (II) - (VII):
  • R 21 is optionally substituted Cl-ClO alkyl, or an optionally substituted aryl or aralkyl or, R 21 and R 22 taken together with their intervening atoms form a 5-7 membered non-aromatic heterocycle.
  • R 22 is not a part of a heterocycle defined above, the R and R are each independently -H, or optionally substituted C1-C6 alkyl, provided that R 22 and R 23 are not simultaneously hydrogens.
  • R 21 is optionally substituted Cl-ClO alkyl, phenyl or benzyl optionally substituted with a halogen, -NO 2 ..
  • R 22 and R 23 are each independently -H, or a C1-C3 alkyl; or R 21 and R 22 , taken together with their intervening atoms, form a 5 or 6 membered non-aromatic heterocycle and R 23 is -H, or a Cl -C3 alkyl.
  • the remainder of the variables take the values defined above in formula (I).
  • R 101 is H, optionally substituted Cl -C6 alkyl or optionally substituted aryl or aralkyl.
  • R 100 is phenyl or benzyl optionally substituted with a halogen, -NO 2 , -NH 2 . -COOH, alkyl, C1-C3 carbalkoxy, C1-C3 alkoxy group, Cl- C3 haloalkyl or C1-C3 haloalkoxy.
  • R !0! is H or C1-C4 alkyl. More preferably, R 101 is H 5 methyl or ethyl. The remainder of the variables take the values defined above in formula (I).
  • R 107 is C1-C6 alkyl, optionally substituted aryl or aralkyl, or a non -aromatic heterocycle, optionally substituted at one or more substirutable carbon atoms with methyl, hydroxyl, or methoxy, and optionally N'-substituted with C1-C4 alkyl or C1-C4 alkyl substituted with -NR c R d .
  • R alone or taken together with R 4 , or alternatively R 5 , and the intervening carbon atoms is a phenol isosteric group.
  • phenol isosteric group means a chemical moiety whose quantum properties result in such electrostatic charge distribution, polarizability, capacity to form hydrogen bonds, hydrophobicity, steric effect and other inductive or mesomeric effects, that the molecule as a whole is endowed with activity as either agonist or antagonist of receptors, enzyme active sites, and protein/enzyme allosteric modulation sites in the context of biological function.
  • alkyl as used herein, unless otherwise indicated, includes straight or branched saturated monovalent hydrocarbon radicals, typically Cl-ClO, preferably C1-C6.
  • alkyl groups include, but are not limited to, methyl, " ethyl, propyl, isopropyl, and t-butyl.
  • cycloalkyl is a non-aromatic saturated carbocyclic moieties.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Suitable substituents for a cycloalkyl. are defined above for an alkyl.
  • aryl refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to phenyl and naphthyl.
  • heteroaryloxy means a “heteroaryl-O-" group, wherein heteroaryl is defined above.
  • non-aromatic heterocyclic rings examples include 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [l,3]-dioxalanyl, [l,3]-dithiolanyl, [1,3]- dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3- morpholinyl, 4-morpholinyl, 2-thiomorphoIinyl, 3-thiomorpholinyl, 4- thiomorpholinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrorolidinyl, 1 -piperazinyl, 2- piperazinyl, 1 -piperidinyl, 2- ⁇ i ⁇ eridinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substi
  • the "activated alkanoic acylating agent" is defined within the references cited.
  • This acetimidate reacts with the amine in compound (S 1.3) and cyclized to the methyl or ethyl or other alkylimidazole, again per the cited articles.
  • Examples of chronic inflammatory demyelinating neuropathies include: chronic Immune Demyelinating Polyneuropathy (CIDP); multifocal CIDP; multifocal motor neuropathy (MMN); anti-MAG Syndrome (Neuropathy with IgM binding to Myelin-Associated Glycoprotein); GALOP Syndrome (Gait disorder Autoantibody Late-age Onset Polyneuropathy); anti-sulfatide antibody syndrome; anti-GM2 gangliosides antibody syndrome; POEMS syndrome (Polyneuropathy Organomegaly Endocrinopathy or Edema M-protein Skin changes); perineuritis; and IgM anti-GDlb ganglioside antibody syndrome.
  • the method comprises administering to a patient a therapeutically effective amount of a compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention is a method of treatment of a patient suffering from a demyelinating condition.
  • a demyelinating condition is a condition that destroys, breaks the integrity of or damages a myelin sheath.
  • myelin sheath refers to an 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.
  • the present invention is a method of reversing paralysis in a subject in need thereof with a demyeliriating disease, comprising administering to the subject a compound in an amount sufficient to inhibit lymphocyte infiltration of immune cells in the spinal cord to promote remyelination of nerve cells in the spinal cord and .thereby treating paralysis in said subject, wherein the compound is of formula formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) are administered orally in the amount of 1-3 mg/kg daily for 10-15 days, repeating every 30-45 days.
  • the compounds of formula (I) are administered several times over a period of up to 40-60 days, up to a cumulative dose of from 10 mg/kg to 45 mg/kg. Administration can be repeated over one or more periods of up to 40-60 days.
  • the administration of the compounds or the combinations of the compounds described herein results in an effective blood level of the compound in the patient of more than or equal to 10 ng/ml.
  • compounds can be administered intravenously in an amount of 20 ⁇ g to about 500 ⁇ g per kilogram body weight of the patient.
  • the term “combination” with reference to pharmaceutically active agents and the term “co-administering” and “co-administration” refer to administering more than one pharmaceutically active agent to a patient during one- treatment cycle and not necessarily simultaneous or in a mixture.
  • Suitable anti -inflammatory agents include corticosteroid such as prednisone, methylprednisolone, dexamethasone Cortisol, cortisone, fludrocortisone, prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, or betamethasone.
  • the compounds of the present invention can be administered in combination with one or more other pharmaceutically active agents that are effective against multiple sclerosis.
  • agents include the interferons (interferon beta 1-a, beta 1-b, and alpha), g ⁇ atiramer acetate or corticosteroids such as methylprednisolone and prednisone as well as chemotherapeutic agents such as mitoxantrone, methotrexate, azathioprine, cladribine cyclophosphamide, cyclosporine and tysabri.
  • compositions of the present invention include: 3-4 diaminopyridine; ABT-874; Actos® (pioglitazone); ALCAR (acetyl-L- carnitine); Alpha lipoic acid; AndroGel® (testosterone gel); combination of trimethoprim and vitamin C; combination of azithromycin and rifampin; minocycline; donezepil HCL; Avandia® (rosiglitazone maleate; combination of IFN beta-la) and acetaminophen, ibuprofen or prednisone; combination of Avonex® (interferon beta- Ia) + CellCept®
  • pharmaceutically active agents that are effective against multiple sclerosis and are suitable to be administered in combination with compounds of the present invention include compounds include: Mylinax, an oral formulation of cladrlbine used in leukaemia treatment, developed by Serono/Ivex; Teriflunomide.
  • methyl donator developed by Transition Therapeutics
  • Laquinlmod an oral formulation of a derivative of linomide, developed by Active Biotecb/Teva
  • deskar pirfenidone ⁇ a TNF -alpha inhibitor developed by Mamac
  • ATL-1102 a second generation antisense inhibitor targeting VLA4, developed by Antisense Therapeutics. . •
  • compounds of formula (A) can be administered in combination with antivascular agents, in particular agents inhibiting the growth " factor receptors, Epidermal Growth Factor Receptor. (EGFR), Vascular Epidermal Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR).
  • antivascular agents in particular agents inhibiting the growth " factor receptors, Epidermal Growth Factor Receptor. (EGFR), Vascular Epidermal Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR).
  • the present invention is a method of treating a subject suffering from, a 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 that can be treated by the compounds of the present invention include: colorectal cancer, non- small cell lung cancer, ovarian, renal, sarcoma, melanoma, head & neck, hepatocellular, thyroid, multidrug-resistant leukemia, lymphoma, and multiple myeloma.
  • 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).
  • Treating refers to partially or totally inhibiting, delaying, or reducing (partially or completely) the progression of cancer including cancer metastasis; inhibiting, delaying or preventing the recurrence of cancer including cancer metastasis in,. for example, a human.
  • sarcomas cancers arising from connective or supporting tissues such as bone or muscle
  • carcinomas cancers arising from the body's glandular cells and epithelial cells, which line body tissues
  • lymphomas cancers of the lymphoid organs such as the lymph nodes, spleen, and thymus, which produce and store infection-fighting cells.
  • ovarian cancer is cancer of the ovaries or fallopian tubes, including cancers of germ cells, stromal cells, and epithelial cells.
  • ovarian cancers include but are not limited to:
  • Epithelial Ovarian Tumors which include but are not limited to, serous adenomas, mucinous adenomas, and Brenner tumors, rumors of low malignant potential (LMP tumors), borderline epithelial ovarian cancer, epithelial ovarian cancers, carcinomas and undifferentiated epithelial ovarian carcinomas;
  • Germ Cell tumors which include but are not limited to, teratoma, dysgerminoma, endode ⁇ al sinus tumor, and choriocarcinoma; and
  • Renal cancer or “kidney cancer”, as used herein, includes but is not limited to, transitional cell cancer (TCC) of the renal pelvis, Wilms Tumour and renal cell cancer.
  • TCC transitional cell cancer
  • Renal cell cancer is also called renal adenocarcinoma or hypernephroma.
  • the cancerous cells are found in the lining of the tubules (the smallestjubes inside the nephrons that help filter the blood and make urine).
  • renal cell cancer There are several types of renal cell cancer including but not limited to clear cell, chromophilic, chromophobic, oncocytic, collecting duct and sarcomatoid.
  • Renal cancer also includes cancers containing more than one of the cell types described above.
  • melanoma is a type of skin cancer that occurs in the cells that color the skin, called melanocytes.
  • Types of melanoma include but are not limited to: Cutaneous melanoma, superficially spreading melanoma, nodular malignant melanoma, lentiginous malignant melanoma, acral lentiginous melanoma, demoplastic malignant melanomas ' , giant melanocyte nevus, amelandtic malignant melanoma, acral lentiginous melanoma unusual melanoma variants, including mucosal malignant melanoma and ocular malignant 'melanoma.
  • Sphercomas include but are not limited to, fibrosarcomas from fibrous body tissues, leiomyosarcomas and rhabdomyosarcomas from muscle tissues, liposarcomas from fat, synovial sarcomas, angiosarcomas from blood vessels, MPNST - malignant peripheral nerve sheath tumours (PNSTs), GIST - gastrointestinal stromal sarcoma, osteosarcoma, myosarcoma, chondrosarcoma, bile duct sarcoma, brain sarcoma, breast sarcoma, soft tissue sarcoma, uterine sarcoma, endocardial sarcoma, stromal sarcomas from supporting tissues (endometrial stromal sarcoma), granuloytic, histiolytic, hemangioendothelial, Kupffer-cell, neurogenic, round-
  • thyroid cancer includes but is not limited to, papillary and/or mixed papillary/follicular, follicular and/or Hurthle cell, lymphoma, medullary, anaplastic and combinations thereof.
  • cancers include but are not limited to squamous cell carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, lymphoma, adenocarcinoma, esthesioneuroblastoma, tumors of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, cancers of the oral cavity (including all the various parts of the mouth: the lips; the lining inside the lips and cheeks (the buccal mucosa); the bottom of the mouth; the front of the tongue; the front part of the top of the mouth (the hard palate); the gums; and the area behind the wisdom teeth (the retromolar trigone)), tumors of the oropharynx, hypopharyngeal tumors, laryngeal cancer and salivary gland cancer (including malignant salivary gland tumor).
  • non-small, cell lung cancer includes, squamous cell . carcinoma, adenocarcinoma and undifferentiated non-small cell lung cancer (undeveloped cancer cells are known as undifferentiated cells) and large cell carcinoma.
  • the present invention is a method of treating a patient suffering from an acute myeloid leukemia characterized by a FLT3 mutation.
  • the compound of formula (I) can be administered in combination with an anti-cancer agent.
  • the compounds used in the present invention can be administered alone or in combination with one or more other pharmaceutically active agents that are effective against the cancer being treated.
  • anti-cancer drugs that can be employed in combination with the compounds described herein include: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynylurac.il; abiraterone; aclar ⁇ bicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; ainidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; ' andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apuri
  • xhemotherapeutic agents that can be employed in combination with the compounds of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones.
  • the compound of formula (I) of this invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base.
  • the base for example, may comprise one or more of petrolatum, • lanolin, polyethylene glycols, bee wax, mineral oil,- diluents such as water and alcohol, and emulsif ⁇ ers and stabilizers.
  • IL-4 serves as a growth and differentiation factor for B cells, mast cells and macrophages and is a switch factor for synthesis of IgE in mice. It also promotes growth of a cloned CD4 + T cell and enhances class II MHC molecule expression and resting B lymphocytes enlargement. In man, CD4 + T lymphocytes also produce IL- 4, but the human variety has not been shown to serve as a B cell or mast cell growth factor. Both murine and human IL-4 induce switching of B lymphocytes to synthesize IgE. Human IL-4 also induces CD23 expression by B lymphocytes and macrophages in man. IL-4 may have some role in cell mediated immunity.
  • IL-IO inhibits cytokine synthesis by T H I cells, blocks antigen presentation, and inhibits the formation of interferon ⁇ .
  • IL-10 inhibits the macophage's ability to present antigen and to form IL-I, IL-6 and TNF- ⁇ .
  • IL-10 also participates in IgE regulation. Although IL-10 suppresses cell-mediated immunity, it stimulates B lymphocytes, IL-2 and IL-4 T lymphocyte responsiveness in vitro, and murine mast cells exposed to IL-3 and IL-4.
  • IL-10 may find therapeutic utility by suppressing T lymphocyte autoimmunity in multiple sclerosis and type I diabetes mellitus as well as in facilitating allograft survival.
  • T-lymphocyte cells isolated from thymus of balb/c mice weighing 17 ⁇ 1 g were used.
  • Test compound and/or vehicle is incubated with the cells (4 x 10 6 /ml) in the presence of 3 ⁇ g/mL Concanavalin A (Con A) in AIM-V medium pH 7.4 at 37 0 C for 24 hours.
  • Concanavalin A Con A
  • [ 3 H]Thyrmdine (120 nM) was then added for an additional overnight incubation period. Thymidine incorporation was assessed by liquid scintillation counting.
  • Treatments of EAE come in many structural forms: treatment can be prophylactic or preventative, whereby the therapeutic composition is administered before immunization; treatment can be initiated during the first week of induction; and treatment can be interventious, initiated after clinical symptoms are extent (acute or chronic).
  • Prevention protocols are very common in the literature, treatment after disease is rarer, and treatment after weeks of disease are the most infrequent.
  • the experiments reported herein are in the last classification in which animals in the chronic- progressive (CP) phase with extensive demyelinated plaques are treated.
  • CP- EAE induced by whole CNS in complete Freund's adjuvant is a florid disease with extensive inflammatory and demyelinated changes.
  • CP- EAE induced by whole CNS in complete Freund's adjuvant is a florid disease with extensive inflammatory and demyelinated changes.
  • As a general philosophy we believe that successful intervention at later times can better predict effectiveness in the human condition. This is particular relevant to the case of prevention studies, which concentrates on the peripheral immune system,
  • H-E hematoxylin-eosin
  • SCR solochrome-R-cyanin
  • FIG. 4 The longitudinal course of recovery from disease is further illustrated in FIG.” 4.
  • the vehicle controls showed a steady course of disease.
  • Treated animals, in both the 20 and 40 mg/kg cohorts entered the study presenting disease of greater severity than controls, a coincidental circumstance attributed to the phenomenology of randomization prior to assignment of a treating group.
  • treatment began on day forty and progressed for a total of four doses.
  • both treated cohorts showed significant disease improvement to levels significantly below control, despite having entered the study at a disease level well above control.
  • Statistical significance even with 3 and 4 animal small cohorts showed p values supporting the hypothesis that treatment afforded a statistically different outcome over control. These were determined by non-parametric comparisons by the Mann- Whitney or Wilcoxon rank-sum test for difference in medians. The significance values were 0.001 and 0.004 for the 40 and 20 mg/kg cohorts, respectively.
  • Demyelination is a key pathological feature of the MS lesion..Not only does this alter electrical response of the axon, current thought suggests that prolonged demyelination can result in permanent axonal damage and death. Thus neuro- degeneration is also a key component of the MS pathological milieu.
  • SymadexTM has proved to be effective in permitting endogenous remyelination even after a period of disease progression that reached 97% spinal chord demyelination in this chronic - progressive model. • It appears to permit this CNS recovery by reducing the inflammation in existing lesions.
  • Example 2 The only significant protocol deviation from the method of Example 2 was that the pool of immunized animals was culled of animals presenting with a ' disease severity greater than 2 and randomized so that the' mean disease severity of each cohort was matched in the severity score range of 1 to 1.5. This measure was invoked in order to avoid the chance circumstance, observed in Example 2, that animal selected for treatment should start treatment with a more severe presentation than the corresponding vehicle controls.
  • AU treated animals showed statistically significant improvement in disease. That is, their symptoms of paralysis attributable to the demyelinating progression of inflammatory cell assault on nerve chord parenchyma, were reduced close to baseline, pre-disease levels. These results are evident by mere inspection of the disease course plots and also proved to be highly significant by non-parametric, rank-order statistical analysis.
  • the therapeutic response shows a graded temporal response against control. Sick animals become progressively healthier in proportion to the weekly duration of response, while . control animals progress irreversibly towards complete neurological dysfunction, whose root cause is irreversible demyelination.
  • the cumulative pharmacodynamic effect of drug treatment is durable, because treated animals remain in stable condition, commensurate with their degree of treatment, while untreated controls sustain an accelerating progression in. disease. This is a particularly noteworthy observation in light of the effects obtained with the ' most promising recent therapy for progressive MS, namely the ⁇ 4 integrin antagonists like Tysabri and its small molecule ligand equivalents, as described by Piraino PiS. et al, J.
  • Symadex does not exert its action via the activation and recruitment of inflammatory cells.
  • the histopathology of • spinal chord from animals sacrificed at periodic interval throughout the time course of disease recovery show accumulation, rather than diminution, of inflammatory cells in blood vessels and perivascular cuffs, as noted in Example 2. Yet, these cells are apparently blocked from transmigrating beyond the basement membrane of parenchyma, suggesting a block via mechanisms that could involve: cell adhesion, motility, and extracellular matrix remodeling.
  • Experiment 2 was applied to a cohort of animals and controls, which were allowed to reach ' the chronic phase of disease at.30 days post immunization. Six animals with a disease score of 1 were selected and half were treated -with 20 mg/kg SymadexTM administered intraperitoneally. Two dose were given 72 hours apart to 3 animals. Three animals served as vehicle controls.
  • the SymadexTM treatment on a 72 hour schedule reversed the progression of disease and restored baseline clinical scores with just 2 doses, while disease progression continued in the control cohort.
  • the difference is statistically significant by a p value of 0.002 by the rank-sum test.
  • Example 5 SymadexTM Alleviates the Symptoms of Experimental Autoimmune Encephalomyelitis (EAE), an Animal Model of Acute Multiple Sclerosis Upon Daily Dosing Over the Initial Course of Disease Induction.
  • EAE Experimental Autoimmune Encephalomyelitis
  • the EAE model in the guinea pig is biphasic.
  • the typical clinical pattern of neurological impairment begins with acute signs of disease day 9 post immunization.
  • Clinical onset results in weight loss, hind limb weakness and an abnormal righting reflex.
  • the severity of these symptoms peaks over 6-7 additional days followed by a short duration transient and partial resolution by day until day- 20, when the disease course changes to a steady progressive decline, from which there is no clinical recovery.
  • Example 4 As an important extension to the utility of Symadex, its therapeutic effect at this earlier stage of disease presentation was examined. The experiment was further designed to build on the results of Example 4, which suggested that more frequent dosing affords more rapid and unidirectional symptom resolution. Since the acute phase of EAE also mimics active, but not necessarily progressive disease, as would be expected to be the case in human subjects with remitting-relapsing multiple sclerosis, the experiment was further designed to test the efficacy in comparison to mitoxantrone. This later drug, as indicated earlier, is an approved therapeutic agent and had served as the starting point for the chemical evolution of what became the SymadexTM molecule minus the toxicophoies known to be causative agents for cardiotoxicity.
  • the mitoxantrone .dose was selected to reflect a typical high dose given to rats or mice by daily dosing in the prior art, but allonietrically scaled to the guinea pig-
  • the cohorts treated with either SymadexTM or mitoxantrone present a consistently different trend than the vehicle controls.
  • the onset of disease is followed by a steady increase in clinical score until day 15, followed by the characteristic short term reversion and a second climb towards higher disease severity by day 20.
  • mitoxantrone and Symadex the initial rise in neurological impairment is arrested, and all animals continued on a course of recovery towards basal levels throughout the dosing period.
  • FIG. 11 shows the weight gain profile, a sensitive indicator of general health status in guinea pigs. Acute EAE disease onset triggers a rapid weight loss from which there develops a steady recovery after day-15. Control animals and SymadexTM treated animals regain the ability to add weight every day, which is the norm for guinea pigs when healthy and prior to the onset of severe, chronic disease.
  • mitoxantrone may have alleviated the acute clinical symptoms of EAE at a lower relative dose but it also impairs weight gain, a sign of generalized toxicological response to a drug that is a potent and broad spectrum cytotoxic.
  • Comparison of the weight gain profiles between vehicle controls and SymadexTM did not show statistical significance by the Mann- Whitney rank-sum test, whereas the difference between SymadexTM and mitoxantrone reached statistical significance with a p value of 0.034. .
  • RA Rheumatoid Arthritis
  • DMARDS disease modifying antirheumatic drugs
  • TNF- ⁇ tumor necrosis factor ⁇
  • MTX methotrexate
  • CIA Collagen-induced Arthritis
  • rodents rat and mouse
  • nonhuman primates by immunization with type II collagen, the major constituent protein of articular cartilage.
  • CIA manifests as swelling and erythema in the limbs of the mouse.
  • This model of autoimmunity shares several clinical and pathological features with rheumatoid arthritis (RA) and has become the most widely studied model of RA.
  • CIA in the mouse model was first described by Courtenay et al. in 1980 (Courtnay, J.S., Dallman, MJ., Dayman, A.D., Martin A. s and Mosedale, B.
  • mice Groups of 3 BALB/c strain mice, 6-7 weeks of age, were used for the induction of arthritis by monoclonal antibodies (mABs) raised against type II collagen, plus Iipopolysaccharide (LPS).
  • mABs monoclonal antibodies
  • LPS Iipopolysaccharide
  • volumes of both hind paws were measured using a plethysmometer with water cell (12 mm diameter) on Days 0, 5, 7, 10, 14 and 17. Percent inhibition of increase in volume induced by mABs + LPS was calculated by the following formula:
  • Methotrexate a benchmark therapeutic agent, has been shown to yield diminishing benefit in antibody induced models, which are intrinsically less dependent on T-cell activation than on their trafficking and migratory properties.
  • the work of Lange et al. can be cited in this context ⁇ Annals of Rheumatoid Disease 64:599-605, 2005).
  • SymadexTM appears fully active in this model.
  • the results presented in this example are especially relevant to the treatment of human subjects, because the therapeutic effect was obtained by oral administration. In the era of injectable biologies, such as blocking antibodies, the addition of an effective, non-immunosuppressive therapy via the oral route is particularly desirable.
  • Example 7 Symadex " TM downresulates otherwise overexpressed target mechanisms of inflammatory eel! adhesion, cell-surface signaling, and cell proliferation
  • NM_000029 clade A alpha-1 antiproteinase, antitrypsin, member 8
  • CD58 NM_001779 CD58 antigen (lymphocyte function-associated antigen 3)
  • ITSN1 NM_003024 intersectin 1 (SH3 domain protein) potassium inwardly-rectifying channel, subfamily J,
  • KCNJ15 NM_002243 member 15 • potassium voltage-gated channel, KQT-like subfamily,
  • lymphotoxin beta (TNF superfamily, member 3)
  • NCF1 neutrophil cytosolic factor 1 (47kDa, chronic •
  • neutrophil cytosolic factor 2 (65kDa, chronic BI 021745 granulomatous disease, autosomal 1) neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic BI 021745 granulomatous disease, autosomal 1) neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kDa, chronic neutrophil cytosolic factor 2 (65kD
  • VAMP vesicle-associated membrane protein
  • DAVID Database for Annotation, Visualization and Integrated Discovery, from the National Institute of Allergy and Infectious Disease, http://appsl.niaid.nih.gov/david/; the sister program EASE (Expression Analysis Systematic Explorer) at the same site; and the GeneCards bioinformatics project (http://genome- www.stanford.edu/genecards/index.shtml).
  • the down regulated genes ACTA2, ACVRLl, BGN, DSC3, ENG, FBANl 3 FBLNl, HMMR, IGTA2B, ITGA2B, ITGA9, ITGAE, LIMS2, LTB, MAPT, MSLN, NMI, PCDH7, PECAMl, PRDMl, SEMA7A, VAPA all participate in the regulation of these processes via direct modulation of adhesion factors, like integrins and cadherins, or by disrupting the growth factor signals that promote their expression and the assembly of accessory proteins that further facilitate the adhesion process.
  • adhesion factors like integrins and cadherins
  • Neuromodulation via paracrine and autocrine • controls is also evident in the dqwnregulation of systems that further respond to neuroinflammatory insult, including, for example, neurotransmitter transporters associated with damaging, runaway glutamate signaling.
  • the downregu ' lated genes in this latter category are exemplified by ADCYAPl, GABRA3, GGH, KCNQ3, SLCl A2 (and its SLC family solute carrier homologs), and SULT4A1. This latter gene showed close to 300 fold down-regulation. It is a gene associated with heparan sulfation.
  • Sulfated heparans constitute the "molecular velcro" that permits integrins to bind to laminins and thereby provide the linkage that permits invasive inflammatory cells to transmigrate through basal membranes into CNS parenchyma. Down regulation of a such a process would be expected to keep inflammatory cells within the confines of vascular cuffs, as has been observed to be the case in the histopathological evaluation on the SymadexTM treatment effect noted in Examples 2-8.

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Abstract

La présente invention concerne des composés de formule (I) et un procédé de traitement de patient souffrant de troubles inflammatoires et/ou de troubles de démyélinisation, y compris l'administration audit patient d'une quantité thérapeutiquement effective d'un composé de formule (I) ou d'un sel dérivé pharmaceutiquement acceptable. Des définitions des variables sont fournies ici.
PCT/US2007/003135 2006-02-08 2007-02-07 Composes pour le traitement de troubles inflammatoires, de troubles de demyelinisation et de cancers WO2007092436A2 (fr)

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WO2007143096A2 (fr) * 2006-06-02 2007-12-13 Xanthus Pharmaceuticals, Inc. Composés destinés au traitement du cancer
WO2008016665A2 (fr) * 2006-08-02 2008-02-07 Xanthus Pharmaceuticals, Inc. Composés et méthodes de traitement de troubles médiés par flt3
WO2008016660A2 (fr) * 2006-08-02 2008-02-07 Xanthus Pharmaceuticals, Inc. Composés de traitement de la leucémie
WO2009017795A1 (fr) * 2007-08-02 2009-02-05 Xanthus Pharmaceuticals, Inc. Composés d'indazole pour le traitement de troubles inflammatoires, de troubles démyélinisants et de cancers
WO2016174674A1 (fr) * 2015-04-27 2016-11-03 The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center Molécules de ciblage egr1 dans le traitement de maladies inflammatoires et hyperprolifératives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007143096A2 (fr) * 2006-06-02 2007-12-13 Xanthus Pharmaceuticals, Inc. Composés destinés au traitement du cancer
WO2007143096A3 (fr) * 2006-06-02 2008-03-27 Xanthus Pharmaceuticals Inc Composés destinés au traitement du cancer
WO2008016665A2 (fr) * 2006-08-02 2008-02-07 Xanthus Pharmaceuticals, Inc. Composés et méthodes de traitement de troubles médiés par flt3
WO2008016660A2 (fr) * 2006-08-02 2008-02-07 Xanthus Pharmaceuticals, Inc. Composés de traitement de la leucémie
WO2008016665A3 (fr) * 2006-08-02 2008-04-17 Xanthus Pharmaceuticals Inc Composés et méthodes de traitement de troubles médiés par flt3
WO2008016660A3 (fr) * 2006-08-02 2008-04-24 Xanthus Pharmaceuticals Inc Composés de traitement de la leucémie
WO2009017795A1 (fr) * 2007-08-02 2009-02-05 Xanthus Pharmaceuticals, Inc. Composés d'indazole pour le traitement de troubles inflammatoires, de troubles démyélinisants et de cancers
WO2016174674A1 (fr) * 2015-04-27 2016-11-03 The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center Molécules de ciblage egr1 dans le traitement de maladies inflammatoires et hyperprolifératives
AU2016255725B2 (en) * 2015-04-27 2021-09-23 The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center EGR1 targeting molecules for the treatment of inflammatory and hyperproliferative conditions

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