WO2002053159A1 - Analogues de tacrolimus neurotrophiques - Google Patents

Analogues de tacrolimus neurotrophiques Download PDF

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Publication number
WO2002053159A1
WO2002053159A1 PCT/US2001/050419 US0150419W WO02053159A1 WO 2002053159 A1 WO2002053159 A1 WO 2002053159A1 US 0150419 W US0150419 W US 0150419W WO 02053159 A1 WO02053159 A1 WO 02053159A1
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Prior art keywords
compound
injury
nerve
spinal cord
disease
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PCT/US2001/050419
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English (en)
Inventor
Nobuya Matsuoka
Takayuki Yamaji
Bruce Gold
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to AU2002231277A priority Critical patent/AU2002231277B2/en
Priority to CA002433384A priority patent/CA2433384A1/fr
Priority to KR1020037008787A priority patent/KR100794204B1/ko
Priority to EP01991558A priority patent/EP1353671A4/fr
Priority to JP2002554109A priority patent/JP2004527472A/ja
Priority to BR0116762-6A priority patent/BR0116762A/pt
Priority to IL15666401A priority patent/IL156664A0/xx
Priority to MXPA03005941A priority patent/MXPA03005941A/es
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to NZ527209A priority patent/NZ527209A/en
Priority to HU0302521A priority patent/HUP0302521A3/hu
Priority to US10/451,361 priority patent/US20040077676A1/en
Publication of WO2002053159A1 publication Critical patent/WO2002053159A1/fr
Priority to NO20032913A priority patent/NO20032913D0/no
Priority to ZA2003/05806A priority patent/ZA200305806B/en

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention relates to a tacrolimus derivative having a high level of neurotrophic activity and a low level of immunosuppressive activity.
  • Certain macrolide compounds e.g. tacrolimus and related compounds, are known to help prevent or treat cerebral ischemia (WO94/14443).
  • Certain non-immunosuppressive compounds i.e., geldanamycin and its analogs, are shown to disrupt the steroid receptor complex and promote nerve growth (WO99/21552).
  • the present inventors have found that a particular tacrolimus analogue, i.e. Compound (I), mentioned below, has an excellent neurotrophic activity but, unlike tacrolimus, has little or no immunosuppressive activity.
  • Compound (I) exerts superior levels of neurotropic activity compared to tacrolimus, for instance, as measured by its ability to increase neurite length.
  • the administration of Compound (I) is shown to induce axonal regeneration and speed recovery from nerve crush or spinal cord injuries.
  • Compound (I) exerts these advantageous neurotropic effects with little or no immunosuppressive activity compared to tacrolimus.
  • the present invention provides new uses for Compound (I) as a superior neurotrophic agent, as well as a neurotropic agent with little or no immunosuppressive activity.
  • the invention provides a neurotrophic agent or composition that comprises Compound (I).
  • this invention provides a method for preventing or treating neuronal injury/dysfunction that comprises administering Compound (I) to a mammal.
  • Compound (I) is useful for ameliorating, preventing, or treating neurological injury or dysfunction caused by damage or injury to, deterioration of, or disease of the nervous system, while advantageously having little or no immunosuppressive effect.
  • Compound (I) is useful for treating damage, deterioration or dysfunction caused by physical injury, nutritional disorders, ischemia, degenerative diseases, malignant diseases, infectious diseases, and by drug interactions, toxins or poisons.
  • Compound (I) is useful for treating neurological damage or dysfunction caused by neurosurgery, peripheral nerve injury, burns, encephalomyelitis, HIV, herpes, cancer, radiation treatment, drug interaction, folic acid or Vitamin B-12 deficiency, and by exposure to neurotoxins or chemicals such us lead.
  • Compound (I) is useful for preventing or treating neuronal injury and dysfunction, such as polymyositis (multiple myositis), Guillan-Barre syndrome, Meniere's disease, polyneuritis (multiple neuritis), mononeuritis (solitary neuritis), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, radiculopathy, neuropathy (such as diabetic neuropathy, chemotherapy-induced neuropathy, etc.), spinal cord injury, senile dementia, vascular dementia, multiple sclerosis, physical palsy, etc.
  • neuronal injury and dysfunction such as polymyositis (multiple myositis), Guillan-Barre syndrome, Meniere's disease, polyneuritis (multiple neuritis), mononeuritis (solitary neuritis), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, radiculopathy, neuropathy (such as diabetic neuro
  • This compound may be produced as described by U.S. Patent 5,376,663, Example 29.
  • Compound (I) used in the present invention it is to be understood that there may be conformers and one or more stereoisomers, such as optical and geometrical isomers due to asymmetric carbon atom(s) or double bond(s), and such conformers and isomers are also included within the scope of the compound in the present invention.
  • Compound (I) may also be in the form of a pharmaceutically acceptable salt, derivative, solvate or pro-drug, all of which are included within the scope of the present invention.
  • the solvate preferably includes a hydrate and an ethanolate.
  • a preferable form of Compound (I) is the following one:
  • Compound (I) in the present invention may be administered as a pure compound or as a mixture with another compound or other ingredients, preferably, in a pharmaceutical vehicle or carrier.
  • a pharmaceutical vehicle or carrier When Compound (I) is used in the form of a pharmaceutical preparation or composition it may be admixed with an organic or inorganic carrier, vehicle or excipient suitable for external (topical), oral, enteral, subcutaneous, intravenous, intramuscular, or parenteral applications.
  • it may be present in solid, semisolid or liquid composition, which contains Compound (I) as an active ingredient and one or more carriers, vehicles or excipients.
  • Typical carriers, vehicles or excipients include, but are not limited to conventional pharmaceutical carriers, medicinal or pharmaceutical agents, buffers, dispersants, emulsifying agents and adjuvants.
  • Compound (I) may also be compounded with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, eye drops, suppositories, solutions (saline, for example), emulsions, suspensions (olive oil, for example), ointments, aerosol sprays, creams, skin plasters, patches and any other form suitable for use.
  • non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, eye drops, suppositories, solutions (saline, for example), emulsions, suspensions (olive oil, for example), ointments, aerosol sprays, creams, skin plasters, patches and any other form suitable for use.
  • Suitable carriers include water, aqueous saline and dextrose solutions, oils, including animal, vegetable and synthetic oils, and petroleum products.
  • Other useful carriers include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • stabilizing, emulsifying, thickening, coloring agents, flavoring agents, and perfumes may be used.
  • Compound (I) is included in the pharmaceutical composition in an amount effective to produce the desired effect upon a particular disease process or condition.
  • Compound (I) is included in an amount sufficient to provide a neurotropic effect or stimulate nerve cell growth.
  • Mammals which may be treated using the method of the present invention include livestock mammals such as cows, horses, pigs, etc., domestic animals such as dogs, cats, rats, mice, rabbits, hamsters, etc., primates, and humans.
  • Preferable modes for the administration or application of products or compositions containing Compound 1 to humans include injection or oral administration.
  • While the therapeutically effective amount or dosage of Compound (I) may vary among individual patients and also depends upon the age and condition of each individual patient to be treated, a daily dose ranging from about 0.0001-1000 mg, preferably 0.001-500 mg and more preferably 0.01-100 mg of the active ingredient is generally given for treating diseases, and an average single dose of about 0.001- O.Olmg, 0.2-0. 5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.1-30 mg/kg/day. Compound (I) may also be administered or applied simultaneously, separately or sequentially with other agents having neurotrophic or nerve cell growth stimulating activity.
  • compositions according to the invention can be periodically administered to a mammalian subject (e.g., a human patient), in need of such treatment, to promote neuronal regeneration and functional recovery and to stimulate neurite outgrowth and thereby to treat various neuropathological states, including damage to peripheral nerves and the central nervous system caused by physical injury (e.g., spinal cord injury and trauma, sciatic or facial nerve lesion or injury, limb transplantation following amputation); disease (e.g., diabetic neuropathy); cancer chemotherapy (e.g., neuropathy induced by acrylamide, taxol, vinca alkaloids and doxorubicin); sequela ⁇ e.g. allophasis (such as articulation disorders), clouding of consciousness, dyskinesia, etc.
  • a mammalian subject e.g., a human patient
  • neurological disorders including, but not limited to, various peripheral neuropathic and neurological disorders including, but not limited to: trigeminal neuralgia, glosspharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured or prolapsed vertebral disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies such as those caused by lead, acrylamides, gamma-diketones (glue-sniffer's neuropathy), carbon disulfide, dapsone, ticks, porphyria, Gullain-Barre syndrome, Alzheimer's disease, Parkinson's disease, and Huntington's chorea.
  • peripheral neuropathies such as those caused by lead, acrylamides, gamma-diketones (glue-sniffer's neuropathy
  • a transsection of a peripheral nerve or a spinal cord injury can be treated by administering a nerve growth stimulating amount of the agent to the mammal and grafting to the peripheral nerve or spinal cord a nerve graft such as an allograft (Osawa et al., J Neurocytol 19:833-849, 1990; Buttemeyer et al., Ann. Plastic Surgery 35:396-401, 1995) or an artificial nerve graft (Madison and Archibald, Exp. Neurol. 128:266-275, 1994; Wells et al., Exp. Neurol. 146:395-402, 1997).
  • a nerve graft such as an allograft (Osawa et al., J Neurocytol 19:833-849, 1990; Buttemeyer et al., Ann. Plastic Surgery 35:396-401, 1995) or an artificial nerve graft (Madison and Archibald, Exp. Neurol. 128:266-275, 1994; Wells
  • the space between the transected ends of the peripheral nerve or spinal cord is preferably filled with a non-cellular gap-filling material such as collagen, methyl cellulose, etc., or cell suspensions that promote nerve cell growth, such as Schwann cells (Xu et al., J. Neurocytol. 26:1-16, 1997), olfactory cells and sheathing cells (Li et al. Science 277:2000-2002, 1997).
  • the nerve growth promoting agent can be included together with such cellular or non-cellular gap-filling materials, or administered systemically before, during or after the nerve graft procedure.
  • compound (I) is useful for treating or preventing the neuronal injury/dysfunction polymyositis (multiple myositis), Guillain-Barre syndrome, Meniere's disease, polyneuritis (multiple neuritis), mononeuritis (solitary neuritis), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, radiculopathy, diabetic neuropathy, chemotherapy-induced neuropathy, senile dementia, vascular dementia, multiple sclerosis, physical palsy, or spinal cord injury.
  • neuronal injury/dysfunction polymyositis multiple myositis
  • Guillain-Barre syndrome Meniere's disease
  • polyneuritis multiple neuritis
  • mononeuritis solitary neuritis
  • Alzheimer's disease Parkinson's disease
  • ALS amyotrophic lateral sclerosis
  • radiculopathy diabetic neuropathy, chemotherapy-induced neuropathy, senile dementia, vascular dementia,
  • Example 1 Treatment with Compound (I) Significantly Increases Neurite Lengths of
  • Embryonic hippocampal neurons were obtained from rat pups on embryonic day 18.5 ("E18.5"), according to Banker and Cowan (Brain Research, 1977, 126: 397-425). Briefly, the hippocampal regions were removed, minced, and incubated in 100 LU. papain at 37°C for 45 min, and the cells were resuspended in complete neuronal medium: minimal essential medium without L-glutamine (GIBCO, Grand Island, NY), 1.5ml/100ml medium of high glucose minimal essential medium (GIBCO), O.lml/lOOml medium of serum extender (Hito + Tm; Collaborative Research Inc, Lexington, MA), glutamine (GIBCO), 5% fetal calf serum (GIBCO).
  • coverslips 500 cells/coverslip coated with poly-L-lysine.
  • the coverslips were inverted onto dishes that had been precoated with a monolayer of cortical astrocytes.
  • Hippocampal neurons (identified by their characteristic polarity and dendrites) were examined daily and randomly photographed (9-12 frames/coverslip) at 72 h. Axon (defined as the longest process) lengths were measured on photographic prints using a Houston Instrument HI-PAD digitizing tablet connected to an IBM XT computer with appropriate software (Bioquant IN, R & M Biometrics, Nashville, TN); only processes more than threefold of the cell body length were measured. Data from identically treated coverslips (three or four per group) were not different and therefore were combined. Mean values were calculated and compared using a one-way (groups treated with Compound (la) or tacrolimus versus an untreated control group) ANOVA followed by Newman-Kuels multiple comparisons test (WINKS 4.62 professional edition).
  • SH-SY5 Y human neuroblastoma cells were maintained in DMEM medium (GIBCO) supplemented with 10% fetal calf serum (SIGMA), 501.U./ml of penicillin, and 50 ⁇ g/ml streptomycin (GIBCO) at 37°C in 7% CO 2 .
  • Cells were plated in six-well plates at 15,000 cells/well and treated with 0.4 ⁇ M aphidicolin (SIGMA). At 5 days, cells were washed and treated with nerve growth factor (NGF) at 10 ng/ml (to induce process outgrowth) in the presence or absence of tacrolimus (10 nM) or Compound (la) (1 nM).
  • NGF nerve growth factor
  • Compound (la) was dissolved in vehicle comprising 30% dimethylsulfoxide (DMSO):70% saline.
  • vehicle comprising 30% dimethylsulfoxide (DMSO):70% saline.
  • Three axotomized rats received subcutaneous daily injections either Compound (la) (1 or 5 mg/kg) or an equivalent volume of vehicle (30% DMSO in saline) (5 l/kg)
  • the rats were deeply anesthetized with 4% halothane, heparinized, and perfused with 4% paraformaldehyde in 0.1 M sodium phosphate buffer (pH 7.4) for 10s followed by 5% glutaraldehyde (1L) in 0.1 M sodium phosphate buffer (pH 7.4) and fixed at 4°C for 24 h.
  • Tissues were sampled from the sciatic nerve at a known (5 mm) distance from the crush site. In the present study, only the data from the branch of the posterior tibial nerve supplying the soleus muscle are reported.
  • Tissues were placed in 0.1 M sodium phosphate buffer (pH 7.4), postfixed with 1% osmium tetroxide (in 0.1 M phosphate buffer) for 2.5 h, dehydrated in ethanol and embedded in plastic. Semithin sections were stained with uranyl acetate and lead citrate, mounted on film-supported 75 mesh grids, and examined in a JEOL 100 CX electron microscope.
  • mean values for recovery of function were compared using one-way ANOVA followed by the Newman-Keuls multiple comparisons test for comparison of individual values.
  • mean values for the number of axons were compared using one-way ANOVA followed by the Newman Keuls multiple comparisons test for comparison of individual values.
  • Morphological examination of the animals was conducted at 18 days following axotomy.
  • Compound (la) was dissolved in vehicle comprising 30% dimethylsulfoxide (DMSO): 10% saline.
  • vehicle comprising 30% dimethylsulfoxide (DMSO): 10% saline.
  • the spinal cord lesioned rats received subcutaneous daily injections the Compound (la) (2 mg/kg) or an equivalent volume of vehicle (30% DMSO in saline) (5ml/kg) for seven weeks following the surgery. Evaluation of functional recovery
  • Rats were allowed to move freely in an open field for 1 min and rated 0-6 according to the scale presented below.
  • Rats were tested on wooden beams (1.5m long) with decreasing width: 7.7cm, 4.7cm, 2.7cm and 1.7cm. Rats were allowed to walk on the bars, and the narrowest bar they could walk on without any slips in at least two trails was recorded.
  • the hind limbs of rats were inked and footprint were made on paper covering a narrow runway of 60cm length and 7.5cm width. A series of at least six sequential steps was used to determine the 5 -point footprint score. 0: Constant dorsal stepping or hind limb dragging, i.e. no footprint is visible
  • Example 5 Compound (la) Binds to FKBP12. but Unlike Tacrolimus Exerts Little or No
  • the binding assay was performed according to a similar manner to that of Tamura, K., et al (Biochemical arid Biophysical Research Communications, Vol. 202, No. 1, 437-499, 1994). The results are shown in Table 8.
  • Compound (I) provides a potent neurotrophic or nerve cell growth stimulating activity, though it has no immunosuppressive activity. Accordingly, the present invention provides a useful neurotrophic agent for stimulating or promoting neuronal growth or regeneration, particularly when an immunosuppressive effect is not advantageous or desired.
  • An article of manufacture comprising packaging material and Compound (I) identified in the above contained within said packaging material, wherein said Compound (I) is therapeutically effective for preventing or treating neuronal dysfunction, and wherein said packaging material comprises a label or a written material which indicates that Compound (I) can or should be used for preventing or treating neuronal injury/dysfunction.
  • a commercial package comprising the pharmaceutical composition containing Compound (I) identified in the above and a written matter associated therewith, wherein the written matter states that Compound (I) can or should be used for preventing or treating neuronal injury/dysfunction.
  • compositions such as a cell suspension, tissue, or graft comprising a cell treated with Compound (I).
  • Such compositions are useful for repairing damage to the nervous system.
  • Such compositions may also include other nerve cell growth stimulating agents, such as other types of cell suspensions that promote or assist nerve cell growth, such as myelin- producing cells such as Schwann cells or oligodendrocytes, glial cells and sheathing cells; extracellular matrix material, such as collagen; or other specific neuroregulators such as cytokines, mitogenic factors, immunophilins, and neurotrophins, such as NGF-1, BDNF, CNTF, NT-3, NT-4 and NT-5.
  • nerve cell growth stimulating agents such as other types of cell suspensions that promote or assist nerve cell growth, such as myelin- producing cells such as Schwann cells or oligodendrocytes, glial cells and sheathing cells; extracellular matrix material, such as collagen; or other specific neuroregulators such as cytokines,
  • Grafts such as homografts, allografts or xenografts may also be treated with Compound (I) in order to facilitate neuronal outgrowth and their use as transplants and for other applications.

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Abstract

L'invention concerne des dérivés de tacrolimus présentant des niveaux élevés d'activité neurotrophique et de faibles niveaux d'activité immunosuppressive. Ces composés constituent des agents neurotrophiques très utiles, en particulier dans la prévention ou le traitement d'une lésion/dysfonction neuronale.
PCT/US2001/050419 2000-12-29 2001-12-31 Analogues de tacrolimus neurotrophiques WO2002053159A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
IL15666401A IL156664A0 (en) 2000-12-29 2001-12-31 Tacrolimus derivatives and pharmaceutical compositions containing the same
KR1020037008787A KR100794204B1 (ko) 2000-12-29 2001-12-31 신경 친화성 타크로리무스 유사체
EP01991558A EP1353671A4 (fr) 2000-12-29 2001-12-31 Analogues de tacrolimus neurotrophiques
JP2002554109A JP2004527472A (ja) 2000-12-29 2001-12-31 神経栄養性タクロリムスアナログ
BR0116762-6A BR0116762A (pt) 2000-12-29 2001-12-31 Análogos tacrolimus neurotróficos, métodos e uso dos mesmos
AU2002231277A AU2002231277B2 (en) 2000-12-29 2001-12-31 Neurotrophic tacrolimus analogs
MXPA03005941A MXPA03005941A (es) 2000-12-29 2001-12-31 Analogos tacrolimus neurotroficos.
CA002433384A CA2433384A1 (fr) 2000-12-29 2001-12-31 Analogues de tacrolimus neurotrophiques
NZ527209A NZ527209A (en) 2000-12-29 2001-12-31 Neurotrophic tacrolimus analogs
HU0302521A HUP0302521A3 (en) 2000-12-29 2001-12-31 Neurotrophic tacrolimus analogs, pharmaceutical compositions containing them and their use
US10/451,361 US20040077676A1 (en) 2001-12-31 2001-12-31 Neurotrophic tacrolimus analogs
NO20032913A NO20032913D0 (no) 2000-12-29 2003-06-24 Neurotrofiske tacrolimusanaloger
ZA2003/05806A ZA200305806B (en) 2000-12-29 2003-07-28 Neurotropic tacrolimus analogs

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US25850000P 2000-12-29 2000-12-29
US60/258,500 2000-12-29

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EP (1) EP1353671A4 (fr)
JP (1) JP2004527472A (fr)
KR (2) KR20070030331A (fr)
CN (1) CN1293877C (fr)
AR (1) AR035411A1 (fr)
AU (1) AU2002231277B2 (fr)
BR (1) BR0116762A (fr)
CA (1) CA2433384A1 (fr)
CZ (1) CZ20032060A3 (fr)
HU (1) HUP0302521A3 (fr)
IL (1) IL156664A0 (fr)
MX (1) MXPA03005941A (fr)
NO (1) NO20032913D0 (fr)
NZ (1) NZ527209A (fr)
PL (1) PL366301A1 (fr)
RU (1) RU2288716C2 (fr)
WO (1) WO2002053159A1 (fr)
ZA (1) ZA200305806B (fr)

Cited By (6)

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WO2004078167A1 (fr) * 2003-03-04 2004-09-16 Astellas Pharma Inc. Utilisation de derives d'acide pipecolique non immunosuppresseurs pour induire une differenciation chondrogenique
WO2005067928A1 (fr) * 2004-01-20 2005-07-28 Astellas Pharma Inc. Methode de traitement des troubles de l'erection
WO2007082909A2 (fr) * 2006-01-18 2007-07-26 Institut Curie Methode de traitement de la maladie de huntington par inhibition de la dephosphorylation de la huntingtine a la position s421
WO2010010127A1 (fr) * 2008-07-23 2010-01-28 Novartis Ag Modulateurs du récepteur de sphingosine 1 phosphate et leur utilisation pour le traitement de l'inflammation musculaire
WO2014188197A1 (fr) * 2013-05-24 2014-11-27 Chronos Therapeutics Limited Tacrolimus pour emploi dans le traitement de maladies caractérisées par le dépôt d'agrégats de protéines dans les cellules neuronales
EP2817009A1 (fr) * 2012-02-23 2014-12-31 INSERM - Institut National de la Santé et de la Recherche Médicale Inhibiteurs de la calcineurine destinés à être utilisés dans le traitement des troubles vestibulaires entraînant des lésions

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JP2009102226A (ja) * 2006-02-14 2009-05-14 Meiji Milk Prod Co Ltd 脊髄損傷治療剤

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Cited By (9)

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Publication number Priority date Publication date Assignee Title
WO2004078167A1 (fr) * 2003-03-04 2004-09-16 Astellas Pharma Inc. Utilisation de derives d'acide pipecolique non immunosuppresseurs pour induire une differenciation chondrogenique
WO2005067928A1 (fr) * 2004-01-20 2005-07-28 Astellas Pharma Inc. Methode de traitement des troubles de l'erection
WO2007082909A2 (fr) * 2006-01-18 2007-07-26 Institut Curie Methode de traitement de la maladie de huntington par inhibition de la dephosphorylation de la huntingtine a la position s421
WO2007082909A3 (fr) * 2006-01-18 2007-09-07 Inst Curie Methode de traitement de la maladie de huntington par inhibition de la dephosphorylation de la huntingtine a la position s421
WO2010010127A1 (fr) * 2008-07-23 2010-01-28 Novartis Ag Modulateurs du récepteur de sphingosine 1 phosphate et leur utilisation pour le traitement de l'inflammation musculaire
EP2695615A3 (fr) * 2008-07-23 2014-04-30 Novartis AG Modulateurs du récepteur de sphingosine 1 phosphate et leur utilisation pour le traitement de l'inflammation musculaire
US9149459B2 (en) 2008-07-23 2015-10-06 Novartis Ag Sphingosine 1 phosphate receptor modulators and their use to treat muscle inflammation
EP2817009A1 (fr) * 2012-02-23 2014-12-31 INSERM - Institut National de la Santé et de la Recherche Médicale Inhibiteurs de la calcineurine destinés à être utilisés dans le traitement des troubles vestibulaires entraînant des lésions
WO2014188197A1 (fr) * 2013-05-24 2014-11-27 Chronos Therapeutics Limited Tacrolimus pour emploi dans le traitement de maladies caractérisées par le dépôt d'agrégats de protéines dans les cellules neuronales

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AU2002231277B2 (en) 2006-11-30
IL156664A0 (en) 2004-01-04
ZA200305806B (en) 2005-01-26
EP1353671A4 (fr) 2004-07-14
CN1538843A (zh) 2004-10-20
HUP0302521A2 (hu) 2003-11-28
KR20040007431A (ko) 2004-01-24
CA2433384A1 (fr) 2002-07-11
EP1353671A1 (fr) 2003-10-22
JP2004527472A (ja) 2004-09-09
MXPA03005941A (es) 2005-02-14
NO20032913D0 (no) 2003-06-24
NZ527209A (en) 2005-09-30
PL366301A1 (en) 2005-01-24
KR100794204B1 (ko) 2008-01-14
AR035411A1 (es) 2004-05-26
CZ20032060A3 (cs) 2004-01-14
CN1293877C (zh) 2007-01-10
BR0116762A (pt) 2004-08-10
RU2288716C2 (ru) 2006-12-10
HUP0302521A3 (en) 2007-03-28
KR20070030331A (ko) 2007-03-15
RU2003123493A (ru) 2005-01-20

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