WO2008036733A2 - Méthodes de traitement de troubles du transport vésiculaire - Google Patents

Méthodes de traitement de troubles du transport vésiculaire Download PDF

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WO2008036733A2
WO2008036733A2 PCT/US2007/078882 US2007078882W WO2008036733A2 WO 2008036733 A2 WO2008036733 A2 WO 2008036733A2 US 2007078882 W US2007078882 W US 2007078882W WO 2008036733 A2 WO2008036733 A2 WO 2008036733A2
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fluoro
disease
cyclopropanecarboxylic acid
biphenyl
chosen
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PCT/US2007/078882
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WO2008036733A3 (fr
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Christine Klein
Andrew D. Gassman
Leena Bhoite
John Manfredi
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Myriad Genetics, Inc.
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Publication of WO2008036733A2 publication Critical patent/WO2008036733A2/fr
Publication of WO2008036733A3 publication Critical patent/WO2008036733A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • the invention relates to therapeutic compounds and to the use of such compounds for treating diseases and disorders responsive to the modification of vesicle transport.
  • Therapeutic compounds e.g. (R)-2-(2-fluoro-4-biphenyl)propionic acid
  • AD Alzheimer's Disease
  • a ⁇ 42 amyloidogenic peptide
  • the mechanism by which such compounds accomplish this reduction in A ⁇ 42 is uncertain.
  • evidence is accumulating to indicate that compounds can directly inhibit the activity of ⁇ -secretase, the complex responsible for production of A ⁇ 42 (J Clin Invest 112:440, 2003; JBC 279:43419, 2004).
  • AD Alzheimer's disease
  • neurodegenerative diseases share common features related to vesicle transport and vesicle trafficking. For example, focal bead-like swelling in dendrites and axons (neuritic beading) is thought to be a neuropathological sign in neurodegenerative diseases such as Alzheimer's Disease (Exp. Neurol. 156: 100-1 10, 1999), Parkinson's disease (PD) (Acta. Neuropathol. (Berl) 98: 157-164, 1999) and amyotrophic lateral sclerosis (J. Neurol. Sci. 63 :241-250, 1984; Acta. Neuropathol. (Berl) 94:294-299, 1997).
  • PD Parkinson's disease
  • Amyotrophic lateral sclerosis J. Neurol. Sci. 63 :241-250, 1984; Acta. Neuropathol. (Berl) 94:294-299, 1997.
  • impaired axonal transport is common to the clinical profile of a variety of neuropathologies, including amyotrophic lateral sclerosis (ALS), Charcot- Marie-Tooth Disease 2 (CMT2), spinal muscular atrophy (SPA), spinal muscular atrophy (SMA), Parkinson's Disease (PD), and hereditary sensory motor neuropathy (HSMN).
  • ALS amyotrophic lateral sclerosis
  • CMT2 Charcot- Marie-Tooth Disease 2
  • SPA spinal muscular atrophy
  • SMA spinal muscular atrophy
  • PD Parkinson's Disease
  • HSMN hereditary sensory motor neuropathy
  • impaired axonal transport has been shown to be the primary defect responsible for disease symptoms.
  • CMT2 patients has been shown to carry a loss-of-function mutation in the motor domain of a kinesin protein that participates in axonal transport of synaptic vesicle precursors (Cell. 105 :587, 2001).
  • vesicle trafficking is involved.
  • axonal growth defects contribute to the pathophysiology of spinal muscular atrophy (see J Neurobiol. 58:272, 2004), although the role of vesicle trafficking in the growth defects is unclear.
  • compounds of the present invention may be useful in treating diseases and disorders responsive to the modification of vesicle transport.
  • the invention relates to methods of treating diseases and disorders responsive to the modification of vesicle transport.
  • the method comprises administering to a subject in need thereof an effective amount of a compound according to Formulae I- V:
  • Ri is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 (or can be taken together with R 2 to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);
  • R 2 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 , (or can be taken together with R 2 to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);
  • R 3 is chosen from -COOH, -COOR 6 , -CONH 2 , -CONHR 6 , -CONR 6 R 7 , - CONHSO 2 R 6 , tetrazolyl, and a -COOH bioisostere;
  • R 6 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 ;
  • R 7 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 ;
  • M is an integer chosen from O, 1 , 2, and 3;
  • N is an integer chosen from O, 1 , 2, and 3.
  • the compound is (R)-2-(2-fluoro-4- biphenyl)propionic acid.
  • methods are provided for treating and/or delaying the onset of Alzheimer's Disease, or a sign or symptom thereof, or other neurodegenerative diseases such as cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistca, Parkinson's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth Disease 2, spinal muscular atrophy, spinal muscular atrophy, and hereditary sensory motor neuropathy.
  • methods are provided for treating and/or delaying the onset of other neurodegenerative diseases, or a sign or symptom thereof, such as Neimann-Pick type C disease; multiple sclerosis; Guillain-Barre syndrome; polyQ diseases such as Huntington disease, spinobulbar muscular atrophy, dentatorubral- pallidoluysian atrophy, Kennedy's disease (also know as spinobulbar muscular atrophy [SBMA]), spinocerebellar ataxia 1 , spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17; traumatic brain and spinal cord injury; hereditary spastic paraplegia, spinal muscular atrophy; tauopathies such as progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chro
  • classes of disease whose natural biology are similar to neurodegenerative disorders or require normal axonal transport may be treated.
  • methods are provided for treating and/or delaying the onset of diseases, or a sign or symptom thereof, such as inflammatory myopathies, including polymyositis, dermatopolymyositis, and inclusion body myositis (IBM); and infectious agents and viral diseases such as rabies, prion encephalopathies such as Creutzfeldt-Jakob disease, HSV-I infection, adenovirus infection, vaccinia virus infection, rabies virus infection, African swine fever virus infection, varicella-zoster virus infection including diseases such as chickenpox and shingles; and HIV-I infection.
  • inflammatory myopathies including polymyositis, dermatopolymyositis, and inclusion body myositis (IBM)
  • infectious agents and viral diseases such as rabies, prion encephalopathies such as Creutzfeldt-J
  • compositions and methods for treating diseases and disorders responsive to the modification of vesicle transport, comprising administering to a subject in need thereof an effective amount of a compound according to Formulae I-V in combination with at least one additional therapeutic agent.
  • Figure 1 depicts the effect of (R)-2-(2-fluoro-4-biphenyl)propionic acid on invertase secretion from yeast cells.
  • the invention relates to methods of treating diseases and disorders responsive to the modification of vesicle transport.
  • the method comprises administering to a subject identified to be in need thereof, an effective amount of a compound according to Formulae I-V:
  • Ri is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 (or can be taken together with R 2 to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);
  • R 2 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 , (or can be taken together with R 2 to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);
  • R 3 is chosen from -COOH, -COOR 6 , -CONH 2 , -CONHR 6 , -CONR 6 R 7 , - CONHSO 2 R 6 , tetrazolyl, and a -COOH bioisostere;
  • R 6 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 ;
  • R 7 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and -CH 2 CH 2 CH 2 CH 3 ;
  • M is an integer chosen from O, 1 , 2, and 3; and
  • N is an integer chosen from O, 1 , 2, and 3.
  • Examples of compounds for use in the invention include those as shown above (and below), including enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof.
  • the compounds described in this invention disclosure can be made by an ordinary artisan skilled in the art of organic chemistry synthesis.
  • Exemplary compounds of Formulae I-V include, 2-methyl-2 (2- fluoro-4'-trifluoromethylbiphen-4-yl) propionic acid; 2-methyl-2 (2-fluoro- 4'cyclohexyl biphen-4-yl) propionic acid; l- (2-fluoro-4'-trifluoromethylbiphenyl- 4-yl) cyclopropanecarboxylic acid; l- (4'-cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (4'-benzyloxy-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (2-fluoro-4'-isopropyloxybiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (2-fluoro-3'-trifluoromethoxybiphenyl-4-yl) cyclopropanecarboxy
  • the compound is (R)-2-(2-fluoro-4- biphenyl)propionic acid.
  • (R)-2-(2-fluoro-4- biphenyl)propionic acid refers to the free acid form of (R)-2-(2-fluoro-4- biphenyl)propionic acid and molar equivalents of various salt forms, substantially free of (S)-2-(2-fluoro-4-biphenyl)propionic acid.
  • (R)-2-(2-fluoro-4- biphenyl)propionic acid is the "R” enantiomer of flurbiprofen ((R,S)-2-(2-fluoro- 4-biphenyl)propionic acid).
  • (R)-2-(2-fluoro-4-biphenyl)propionic acid can be obtained from resolving racemic flurbiprofen or through enantioselective or enantiospecific syntheses.
  • the R-isomer of flurbiprofen ((R)-2-(2-fluoro-4- biphenyl)propionic acid ), or a desired enantiomeric excess of (R)-2-(2-fluoro-4- biphenyl)propionic acid, can then be obtained by resolving the racemic flurbiprofen according to well-known methods, and is also commercially available (e.g., Caymen Chemical, Ann Arbor, MI). Methods of resolving (R)-2-(2-fluoro- 4-biphenyl)propionic acid from the racemate are disclosed in U.S. Pat. No. 5,599,969 to Hardy et al.
  • the compound (R)-2-(2-fluoro-4-biphenyl)propionic acid is substantially free of (S)-2-(2-fluoro-4-biphenyl)propionic acid.
  • (R)- 2-(2-fluoro-4-biphenyl)propionic acid may be at least about 90%, at least about 95%, at least about 99%, or at least about 99.9% by weight of the total 2-(2-fluoro- 4-biphenyl)propionic acid (S + R) administered to a patient according to the invention.
  • vesicle transport disease means a disease, disorder, or condition responsive to the modification of vesicle transport, that is, a disease, disorder or condition amenable to treatment by modulating vesicle transport.
  • Vesicle transport diseases include diseases such as certain neuropathologies that are characterized by deranged vesicle transport.
  • Vesicle transport diseases also include diseases such as inflammatory myopathies or viral infections in which vesicle transport may be normal or functioning vesicle transport is required but whose onset, symptoms, or progression can nonetheless be alleviated by altering the movement of vesicles.
  • vesicle transport diseases includes, but is not limited to, Neiman-Pick type C disease; multiple sclerosis; Guillain-Barre syndrome; polyQ diseases such as Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, Kennedy's disease, spinocerebellar ataxia 1 , spinocerebellar ataxia 1 , spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17; traumatic brain and spinal cord injury; hereditary spastic paraplegia; tauopathies such as progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, frontotemporal dementia, and parkinsonism linked to chromosome 17; dementia with Lewy Bodies; Down syndrome; primary lateral sclerosis; optic neuropathies such as Leber, glabramine, and a
  • the invention provides methods for treating or preventing vesicle transport diseases, or a sign or symptom thereof.
  • compounds of the present invention are useful for the prevention and/or treatment of Alzheimer's disease, or a sign or symptom thereof, or other neurodegenerative diseases such as cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistca, Parkinson's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth Disease 2, spinal muscular atrophy, spinal muscular atrophy, and hereditary sensory motor neuropathy, or a sign or symptom thereof.
  • neurodegenerative diseases such as cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistca, Parkinson's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth Disease 2, spinal muscular atrophy, spinal muscular atrophy, and hereditary sensory motor neuropathy, or a sign or symptom thereof.
  • Neimann-Pick type C disease is another disease that may benefit from treatment with compounds of the invention.
  • the primary lesion of NPC appears to be impaired cholesterol trafficking and excessive glycosphingolipid storage.
  • One consequence of this impairment is abnormal vesicle trafficking in neural tissue, which likely contributes to the neurodegeneration characteristic of the disease (Neurobiol Aging 26:373, 2005).
  • a recent study indicates that the abnormal vesicle trafficking contributes to increased deposition of A ⁇ 42 in brain tissue of NPC patients (Am J Pathol. 164:975, 2004), which suggests that A ⁇ peptides may participate in the neurodegeneration.
  • compounds of the invention may be used to treat NPC and/or relieve symptoms of NPC.
  • polyQ diseases or a sign or symptom thereof may be treated with compounds of the invention.
  • PolyQ diseases involve the expansion of CAG repeats encoding glutamine and are known to cause several late-onset progressive neurodegenerative disorders such as Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, Kennedy's disease (also called spinobulbar muscular atrophy [SBMA]), spinocerebellar ataxia 1 , spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17.
  • These polyQ disorders commonly exhibit defects in axonal transport ⁇ Neuron. 40: 1 , 2003; Neuron 40:25, 2003; Neuron 40:41 , 2003). Indeed, evidence suggests that perturbations in transport pathways are an early event in polyQ disease ⁇ Arch Neurol. 62:46, 2005).
  • Traumatic brain and spinal cord injury may also be treated with compounds of the invention.
  • Traumatic brain injury (TBI) is marked by rapid and long-term accumulation of proteins, including beta- amyloid precursor protein. TBI is also an epigenetic risk factor for developing neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease (N euromolecular Med. 4:59, 2003). Therefore, compounds of the invention may be used to treat traumatic injury to both the brain and spinal column.
  • Hereditary spastic paraplegia and spinal muscular atrophy are motor neuron diseases that exhibit clear cytoskeletal abnormalities, which suggests the involvement of axonal transport in the pathogenesis of the diseases ⁇ Trends Neurosci. 25 :532, 2002). Indeed, a single missense mutation in a vesicle trafficking protein, VAPB, is reported to result in late-onset spinal muscular atrophy (LOSMA) ⁇ Am J Hum Genet. 75 :822, 2004). Accordingly, hereditary spastic paraplegia and spinal muscular atrophy or a sign or symptom thereof may be treated by compounds of the invention
  • tau Aberrant functions of the microtubule-associated proteins collectively called tau can lead to neurodegenerative disorders like progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) ⁇ Biochim Biophys Acta. 1739:240, 2005; Brain Res Brain Res Rev. 33 :95, 2000).
  • tauopathies is the disruption of axonal transport that accompanies them. Accordingly, compounds of the invention may also be used to treat tauopathies, or a sign or symptom thereof.
  • Dementia with Lewy Bodies is characterized by the presence of cytoplasmic inclusions of alpha-synuclein in the cerebral cortex and in the nuclei of the brain stem Arch Gerontol Geriatr 39: 1 , 2004). Protein aggregates, whether they are aggregates of tau, A ⁇ , prions or other proteins, apparently disrupt vesicle transport.
  • a therapy that relieves symptoms of one disease with protein aggregates e.g. AD
  • compounds of the invention are believed to be effective in treating DLB or a sign or symptom thereof.
  • Inflammatory myopathies or a sign or symptom thereof may also be treated with compounds of the invention.
  • inclusion body myositis IBM
  • IBM inclusion body myositis
  • a ⁇ and tau protein Curr Opin Rheumatol 16:700, 2004.
  • inflammatory myopathies such as polymyositis, dermatopolymyositis, and IBM may be treatable with compounds of the invention. While treatment may not remove the underlying cause of myopathy, it may promote biochemical alterations that compensate for the loss of normal functions.
  • JNCL Juvenile-onset neuronal ceroid lipofuscinosis
  • CLN3 is localized to synaptic vesicles in neurons (Hum MoI Genet 8: 1585, 1999), indicating a function in neuronal endocytosis or exocytosis. Agents that modulate axonal trafficking may therefore be therapeutic for Batten disease.
  • NCLs neuronal ceroid lipofuscinoses
  • Additional diseases exist that exhibit a natural biology requiring normal axonal transport (J Neurobiol. 58:295, 2004). Such diseases, or a sign or symptom thereof, may be treated with compounds of the present invention.
  • rabies virus spreads centripetally to the central nervous system and spreads within the central nervous system by fast axonal transport. Thus, the virus exploits normal axonal transport for its dissemination.
  • prion encephalopathies involve the use of normal vesicle transport pathways.
  • Prions proteinaceous infectious agents composed of an aberrantly folded protein designated PrP(Sc), cause neurodegenerative diseases such as Creutzfeldt- Jakob disease, bovine spongiform encephalitis in cows, and scrapie in sheep and goats. Progression of these diseases may be slowed by interventions that affect intracellular membrane trafficking. Effective interventions could influence intracellular trafficking of prions themselves or trafficking of PrP(Sc).
  • prions may use exosomes, which are endosome-derived membrane vesicles released into the extracellular environment upon fusion of multivesicular endosomes with the cell surface.
  • exosomes secreted by infected cells could serve as vehicles for delivery of prions to surrounding cells.
  • prions could exploit a normal route of cell-to-cell communication for their propagation within a host.
  • compounds of the invention may be used to treat viral diseases in which the virus life cycle involves vesicle transport.
  • microtubules are essential for HSV-I (J Cell Biol 136: 1007, 1997) and adenovirus (J Cell Biol 144:657, 1999) to reach the nucleus of infected cells.
  • Vaccinia virus exploits first the microtubule network for its intracellular movement (EMBO J 12:3932, 2000) and then the actin cytoskeleton to enhance its cell-to-cell spread (Nat Cell Biol 3 :992, 2001).
  • African swine fever virus uses microtubules for movement in cells (J Virol 2001 , 75 :9819). HIV-I particles migrate along microtubules (J Cell Biol 2002, 159:441), and distinct classes of retroelements may use the dynein-dynactin complex motor on the MT network to make their way to or from the nucleus, through the cytoplasm. "Varicella-zoster virus, the cause of chickenpox and shingles, also requires the vesicular transport machinery of the host cell for replication (J Virol. 68:6372, 1994). Disruption of vesicular transport within an infected cell should therefore attenuate both intercellular spread of the virus and emergence of once-latent virus following its activation.”
  • Additional diseases that may be treated with the compound of the invention also include:
  • Optic neuropathies Histological evidence suggests impaired axonal transport of mitochondria in Leber's hereditary optic neuropathy (LHON) and in Cuban epidemic of optic neuropathy (CEON). Since mitochondria are transported along microtubules by mechanisms similar to microtubule-directed transport of vesicles, the pyrrole derivatives of the present invention could potentially be used to treat these diseases, or reduce or reverse their symptoms.
  • Diabetic neuropathy In addition to the involvement of impaired axonal transport, or impaired vesicle trafficking, in the pathoetiology of the neurodegenerative diseases and disorders outlined above, diabetic neuropathy is also characterized by impaired axonal transport. (See McLean, Neurochem Res. 22:951-956 (1997) and Schoemaker, Diabetes Care. 17: 1362 (1994).) In certain rodent models of diabetes expression deficits occur in nerve growth factor (NGF), and in its high-affinity receptor, trkA.
  • NNF nerve growth factor
  • trkA high-affinity receptor
  • CGRP calcitonin gene-related peptide
  • any individual having, or suspected of having ALS; PD; CMT2; SMA; HSMN; LOSMA; poly Q diseases including Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, Kennedy's disease (SBMA), spinocerebellar ataxia 1 , spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17; traumatic brain and spinal cord injury; HSP; MS; Guillain-Barre syndrome; PLS; taupathies including supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP- 17); DLB; NPC; optic neuropathies including LHON and CEON; or DN can be treated using the compositions and methods
  • compositions and methods for treating diseases and disorders responsive to the modification of vesicle transport, or symptoms thereof, comprising administering to a subject identified to be in need thereof an effective amount of a compound according to Formulae I-V in combination with at least one additional therapeutic agent.
  • the additional therapeutic agent will be one that is useful for treating the disorder of interest.
  • Exemplary additional therapeutic agents do not diminish the effects of the primary agent(s) and/or potentiate the effect of the primary agent(s).
  • an additional therapeutic agent in combination with a compound of Formulae I-V can result in less of any of the Formulae I-V compounds and/or less of the additional agent being needed to achieve therapeutic efficacy. In some instances, use of less of an agent can be advantageous in that it provides a reduction in undesirable side effects.
  • the compound to be administered in combination with an additional therapeutic agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.
  • the compounds of Formulae I-V and the additional therapeutic agents may be administered separately or together in a single composition.
  • the compounds of Formulae I-V and the additional therapeutic agents may be administered at the same time or may be administered at different times of the day.
  • the compounds for use in the methods of the invention and compositions of the invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the compounds may be administered to animals, e.g., mammals, orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated. In one example, approximately 0.01 to approximately 10 mg/kg of body weight is orally administered. For intramuscular injection, the dose is generally approximately one-half of the oral dose.
  • a suitable intramuscular dose would be approximately 0.0025 to approximately 25 mg/kg of body weight, and from approximately 0.01 to approximately 5 mg/kg of body weight.
  • an overactive bladder or urinary incontinence therapeutic agent is also administered, it is administered in an amount that is effective to achieve its intended purpose.
  • the amounts of such overactive bladder or urinary incontinence therapeutic agents effective for treating such disorders are well known to those skilled in the art.
  • Exemplary daily dosages of compounds of Formulae I-V are from about 1 mg to about 2000 mg, from about 1 mg to about 1600 mg, from about 1 mg to about 800 mg, and from 1 mg to about 600 mg.
  • Additional exemplary daily dosages of compounds of Formulae I-V are at least 2000 mg/day, at least 1600 mg/day, at least 800 mg/day, at least 600 mg/day, at least 400 mg/day, at least 300 mg/day, at least 250 mg/day, at least about 200 mg/day, at least about 150 mg/day, and at least about 100 mg/day.
  • a daily dose of 1600 mg (R)-2-(2-fluoro-4- biphenyl)propionic acid (given as two 400 mg (R)-2-(2-fluoro-4- biphenyl)propionic acid tablets, BID) is administered to a patient.
  • a daily dose of 800 mg (R)-2-(2-fluoro-4-biphenyl)propionic acid (given as two 400 mg (R)-2-(2-fluoro-4-biphenyl)propionic acid tablets, BID) is administered to a patient.
  • the compound in a topical formulation, may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
  • the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations that may be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations that may be used pharmaceutically.
  • the preparations particularly those preparations which may be administered orally and that may be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations that may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, may contain from approximately 0.01 to 99 percent, from approximately 0.25 to 75 percent of active compound(s), together with the excipient.
  • nontoxic pharmaceutically acceptable salts of the compounds of the present invention are included within the scope of the present invention.
  • Acid addition salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
  • Basic salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, ⁇ f-methyl-glucamine and the like.
  • compositions of the invention may be administered to any animal, which may experience the beneficial effects of the compounds of the invention.
  • animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present invention are manufactured in a manner, which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular: fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates e.g. tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch paste, using, e.g., maize starch, wheat starch, rice starch, potato
  • disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxy- propymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which may be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active compounds in the form of: granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • suitable liquids such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which may be used rectally include, e.g., suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, e.g., natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, e.g., liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, e.g., water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400), or cremophor, or cyclodextrins.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the topical compositions of this invention may be formulated as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12).
  • the preferred carriers are those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.
  • Creams may be formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture of the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed.
  • An oil such as almond oil
  • a typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
  • a vegetable oil such as almond oil
  • a typical example of such an ointment is one which includes approximately 30 % almond oil and approximately 70 % white soft paraffin by weight.
  • This Example tests the sensitivity to (R)-2-(2-fluoro-4- biphenyl)propionic acid of yeast strains that are heterozygous for either of two secretory genes, SEClO/seclO and SEC3/sec3. Both SEClO and SEC3 are essential genes and their proteins products are components of a multiprotein complex, the exocyst, which mediates the targeting and tethering of post-Golgi secretory vesicles for subsequent membrane fusion (Int Rev Cytol. 233 :243, 2004).
  • This Example determines the effect of (R)-2-(2-fluoro-4- biphenyl)propionic acid on secretion of the enzyme invertase from wild-type yeast. Agents that interfere with the movement of secretory vesicles are expected to reduce secretion of invertase.
  • Yeast strain MY148 (genotype MATa/ ⁇ his3 ⁇ l/his3 ⁇ l leu2 ⁇ 0/leu2 ⁇ 0 metl 5 ⁇ 0/MET ⁇ 15 lys2 ⁇ 0/LYS ⁇ 2 ura3 ⁇ 0/ura3 ⁇ 0) was grown overnight in synthetic complete medium containing 2% glucose (SD medium) to repress expression of invertase. After sub-culturing, the cells were grown for an additional 2 hours in SD medium supplemented with 0, 50, 100, 200, or 300 mM (R)-2-(2-fluoro-4-biphenyl)propionic acid.

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Abstract

L'invention porte sur des méthodes de traitement de maladies et troubles liés à des modifications du transport vésiculaire, consistant à administrer à des patients le nécessitant une dose efficace de composés de formules (I-V) définies dans la description.
PCT/US2007/078882 2006-09-19 2007-09-19 Méthodes de traitement de troubles du transport vésiculaire WO2008036733A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009083115A1 (fr) * 2007-12-21 2009-07-09 Paz Arzneimittel-Entwicklungsgesellschaft Mbh Médicament, sa fabrication et son utilisation pour le traitement de neuropathies douloureuses
WO2011151330A1 (fr) 2010-06-04 2011-12-08 Chiesi Farmaceutici S.P.A. Dérivés de l'acide 1-(2-fluorobiphényl-4-yl)-cyclopropanecarboxylique destinés au traitement de maladies à prions
GB2485169A (en) * 2010-11-03 2012-05-09 Univ Jw Goethe Frankfurt Main (R)-flurbiprofen for use in the treatment of multiple sclerosis
US8673978B2 (en) 2010-04-01 2014-03-18 Chiesi Farmaceutici S.P.A. Polymorphs and salts
CN112107599A (zh) * 2020-08-14 2020-12-22 深圳市中科广瑞生物技术有限公司 干细胞外泌体在制备用于治疗膀胱过度活动综合症的药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064771A2 (fr) * 2003-01-14 2004-08-05 Merck & Co., Inc. Derives de nsaid a disubstitution geminale servant d'agents reducteurs de abeta 42

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064771A2 (fr) * 2003-01-14 2004-08-05 Merck & Co., Inc. Derives de nsaid a disubstitution geminale servant d'agents reducteurs de abeta 42

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009083115A1 (fr) * 2007-12-21 2009-07-09 Paz Arzneimittel-Entwicklungsgesellschaft Mbh Médicament, sa fabrication et son utilisation pour le traitement de neuropathies douloureuses
US8673978B2 (en) 2010-04-01 2014-03-18 Chiesi Farmaceutici S.P.A. Polymorphs and salts
WO2011151330A1 (fr) 2010-06-04 2011-12-08 Chiesi Farmaceutici S.P.A. Dérivés de l'acide 1-(2-fluorobiphényl-4-yl)-cyclopropanecarboxylique destinés au traitement de maladies à prions
CN102905701A (zh) * 2010-06-04 2013-01-30 奇斯药制品公司 用于治疗朊病毒病的1-(2-氟联苯-4-基)-环丙烷羧酸衍生物
GB2485169A (en) * 2010-11-03 2012-05-09 Univ Jw Goethe Frankfurt Main (R)-flurbiprofen for use in the treatment of multiple sclerosis
WO2012059541A1 (fr) * 2010-11-03 2012-05-10 Johann Wolfgang Goethe-Universität, Frankfurt Am Main Nouveau traitement de la sclérose en plaques (ms)
CN103209692A (zh) * 2010-11-03 2013-07-17 弗兰霍菲尔运输应用研究公司 多发性硬化(ms)的新疗法
US20130309199A1 (en) * 2010-11-03 2013-11-21 Irmgard Tegeder Novel Treatment of Multiple Sclerosis (MS)
JP2014505015A (ja) * 2010-11-03 2014-02-27 フラウンホファー‐ゲゼルシャフト・ツア・フェルデルング・デア・アンゲヴァンテン・フォルシュング・エー・ファウ 多発性硬化症（ｍｓ）の新規の治療
KR101877587B1 (ko) * 2010-11-03 2018-07-11 프라운호퍼-게젤샤프트 추르 푀르데룽 데어 안제반텐 포르슝 에 파우 다발성 경화증(ms)의 새로운 치료
CN112107599A (zh) * 2020-08-14 2020-12-22 深圳市中科广瑞生物技术有限公司 干细胞外泌体在制备用于治疗膀胱过度活动综合症的药物中的应用
CN112107599B (zh) * 2020-08-14 2022-06-21 深圳市弘际生物科技有限责任公司 干细胞外泌体在制备用于治疗膀胱过度活动综合症的药物中的应用

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