+

WO1998020864A2 - Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives - Google Patents

Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives Download PDF

Info

Publication number
WO1998020864A2
WO1998020864A2 PCT/EP1997/006323 EP9706323W WO9820864A2 WO 1998020864 A2 WO1998020864 A2 WO 1998020864A2 EP 9706323 W EP9706323 W EP 9706323W WO 9820864 A2 WO9820864 A2 WO 9820864A2
Authority
WO
WIPO (PCT)
Prior art keywords
prevention
treatment
salicylate
group
acid
Prior art date
Application number
PCT/EP1997/006323
Other languages
English (en)
Other versions
WO1998020864A9 (fr
WO1998020864A3 (fr
Inventor
Mariagrazia Grilli
Marina Pizzi
Maurizio Memo
Pierfranco Spano
Original Assignee
Universita' Degli Studi Di Brescia - Dipartimento Di Scienze Biomediche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universita' Degli Studi Di Brescia - Dipartimento Di Scienze Biomediche filed Critical Universita' Degli Studi Di Brescia - Dipartimento Di Scienze Biomediche
Publication of WO1998020864A2 publication Critical patent/WO1998020864A2/fr
Publication of WO1998020864A9 publication Critical patent/WO1998020864A9/fr
Publication of WO1998020864A3 publication Critical patent/WO1998020864A3/fr

Links

Classifications

    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • 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
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/625—Salicylic acid; Derivatives thereof having heterocyclic substituents, e.g. 4-salicycloylmorpholine
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds

Definitions

  • the present invention relates to the use of selected non-steroidal antinflammatory compounds for the prevention and the treatment of glutamate receptor- mediated neuronal damages, such compounds being selected from:
  • A is H; (C1-C4 )-alkyl , optionally substituted with a carboxyl group; (C3-C4 )-alkenyl or alkynyl; phenyl optionally substituted with a carboxyl group; naphthyl; COR, SO3R; B is OR 1 ; NHR 2 ;
  • R is (C 1 -C 4 )-alkyl
  • R 1 is H; an ammonium cation; a pharmaceutically acceptable cation of an alkali or alkaline-earth metal or of an organic base; ( CiC4 )-alkyl , optionally substituted with a hydroxyl or phenoxyl group, which can in its turn
  • R2 is H; ( C -C 4 )-alkanoyl ;
  • X is OH; NH2; phenyl optionally substituted with one or more fluorine atoms; 4 , 5dihydro-2-phenyl-3H-benzindol-3- yl; p-aminobenzenesulfonamido; 4- [ (pyridinylamino )sulfo- nyl]phenyl-;
  • Y is H; OH; and the pharmaceutically acceptable salts and metabolites thereof;
  • Examples of cations deriving from pharmaceutically acceptable organic bases are aliphatic organic amines, such as glucamine, cyclic amines, such as orpholine, heterocyclic amines such as imidazole, and those deriving from a ino acids, such as lysine.
  • the compounds of general formula (I) comprise medicaments having antiinflammatory and/or analgesic and/or antipyretic activities (NSAID) selected from the group consisting of acetylsalicylic acid (ASA), sodium salicylate (NaSal), salicylamide , salicylamide- Oacetic acid, salacetamide , flufenisal, diflunisal, aceta ino- salol, calcium acetylsalicylate , benorylate , fendosal, salicyl-sulforic acid, etersalate, gentisic acid, glycol salicylate, mesalamine, imidazole salicylate, lysine acetylsalicylate, morpholine salicylate, 1-naphthyl salicylate, parsalmide , phenyl acetylsalicylate, salsa- late, sulfasalazine , olsalazine,
  • a preferred embodiment of the present invention provides the use of ASA or of its metabolite, NaSal, for the prevention and/or the treatment of glutamate receptor-mediated neuronal damages.
  • ASA is undoubtedly the most widely employed medicament among NSAIDs, thanks to it its very wide pharmacological spectrum which makes ASA suitable, at different dosages, as an analgesic, antinflammatory and antipyretic agent and for limiting the risk of cardiac diseases as well as episodic ischemic syndromes; recently the lower incidence of lung, colon and breast cancer following the repeated administration of ASA has been proved .
  • AD Alzheimer' disease
  • Glutamate is the most abundant excitatory neurotransmitter in the brain. However, under certain undefined conditions, it may become a potent excitotoxin. Its contribution to the neurodegeneration associated with several acute and chronic neurodegenerative disorders, including AD, is widely established [Lipton et al,, New Engl. J. Med. 330, 613-622 (1995); M. Memo et al . , Int. Rev. Psych. 7, 339 (1995)].
  • NMDA N- methyl-D-aspartate
  • acetylsalicylic acid ASA
  • NaSal sodium salicylate
  • salicylic acid salicylamide, salicyiamide-O-acetic acid and salacetamide and those ASA and NaSal derivatives having bioavailability characteristics at the brain level.
  • non-steroidal antiinflammatory compounds are particularly suitable for use in the prevention of glutamate receptor-mediated neuronal damages related to Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Parkinson' disease, cranial and spinal traumas, ulti- infarct dementia, Lewy Body dementia, AIDS-associated dementia, central and peripheral ischemic neuropathies, neuropathies due to anoxic and/or glyce ic damages, multiple sclerosis, infective and/or toxic neurodegenerative diseases, neurodegenerative syndromes in prion diseases, ataxias-telangiectasias , epilepsy- related neurodegenerative processes, metabolic neuropathies and other related neuropathologies .
  • a further object of the present invention is the use of non-steroidal antiinflammatory compounds for the preparation of a medicament for the prevention and/or the treatment of glutamate receptor-mediated neuronal damages .
  • ASA and NaSal were added to the culture medium 5 in before the addition of glutamate.
  • Glutamate was used at a 50 ⁇ M concentration, which concentration is capable of reducing cell survival by 70-80 %.
  • the range of the concentrations used for both drugs is related, as it is shown in the following table, to the plasma levels reached during the antiinflammatory therapy of patients affected with rheumatic diseases.
  • a dose-dependent protection against glutamate-induced neurotoxicity was observed in the presence of both drugs.
  • the calculated value i.e. the mean effective concentration inducing a 50% effective response (hereinafter referred to as EC5 0 ) was 1.7 mM, with a maximum effect (equivalent to 83% protection) exerted at 3 M.
  • the concentration of NaSal giving 50% of protection was about 5 M, with a maximal response (87% protection) observed at 10 mM .
  • indomethacin was unable to prevent glutamate-evoked cell death at doses compatible with the plasma levels during drug chronic treatment, (1- 20 mM) (Table 1) .
  • hippocampus contains the neurons which are the most vulnerable to excitotoxic damage, namely the granular and pyramidal; additionally, the e_x vivo preparation represents an heterogeneous population of neurons which have been differentiated in vivo .
  • ASA effect of ASA was evaluated at concentrations ranging from 1 to 10 M.
  • a quantitative analysis of the results is summarized in Fig. 2.
  • ASA did not modify cell viability at 1 mM concentration, while at 3 M it specifically produced a significant neuroprotection in the CA3 region.
  • Higher concentrations of ASA elicited an almost complete prevention of NMDA effect even in CA1 and DG, besides CA3.
  • the drug did not modify per se neuron viability.
  • Cytosolic free calcium concentration was investigated in single cells by microfluorimetric technique using the fluorescent probe "Fura 2" (from Sigma) as described by M. Pizzi et al . in Mol. Pharmacol. 49, 586 (1996).
  • Cells were exposed to glutamate for 2 min in the chamber containing Mg 2+ -free Krebs-Ringer solution (KRS).
  • KRS Mg 2+ -free Krebs-Ringer solution
  • ASA and/or NaSal were added to the chamber 2 min before glutamate exposure. Fluorescence image acquisition and analysis were performed by MIRAcal (Multiple Image Rationing and Analysis with Calibration) system by Applied Imaging (UK).
  • ASA applied at neuroprotective concentrations ranging from 1 to 3 M, induced no changes in cell responsiveness to glutamate. It should be noted that the drug induced per se an exceedingly limited and transient increase in calcium concentration.
  • FIG. 3B A representative experiment performed utilizing 3 mM ASA is depicted in Fig. 3B.
  • rat cerebellar granule cells also results in upregulation of the NF-kB nuclear activity and of the transcriptional complex AP-1 (Fig.4).
  • Cells were exposed to 50 ⁇ M glutamate in the absence or presence of ASA (1, 3 mM) and NaSal (3, 10 M) and nuclear extracts were prepared 1 h after stimulation.
  • Nuclear extracts from rat cerebellar granule cells were subjected to an electrophoretic mobility-shift assay with ⁇ - 32 P-labeled oligonucleotide probes containing the immunoglobulin kB (lanes 1 to 6 ) and the AP-1 DNA binding sites (lanes 7 to 12).
  • Cells were either unstimulated (lanes 1 and 7) or stimulated with 50 ⁇ M glutamate (15-min pulse) in the absence (lines 2 and 8) or presence (lanes 3 to 6 and 9 to 12) of the drugs as indicated. Both drugs inhibited glutamate-induced increase of NF-kB activity in a concentration-dependent manner (Fig.4), with calculated EC50 values of 1.3 mM and 6 M for ASA and NaSal respectively.
  • ASA and NaSal failed to modify the glutamate-mediated nuclear induction of the transcriptional complex AP-1 (Fig. 4). Therefore it is ascertained that, at concentrations compatible with plasma levels reached during treatment of chronic inflammatory states, salicylates prevent gluta ate-induced neurotoxicity.
  • the site of action common to ASA and NaSal, but not to indomethacin is the blockade of induction of NF-kB transcription nuclear factors, which is a indisputable prove of the relationship between neuroprotection and cellular event.
  • the results were obtained preparing primary cultures of cerebellar granule cells from cerebella of 8-day-old rats ( Sprague-Dawley ) .
  • the cultures were used at 10-12 days in vitro (DIV), and contained > 95% glutamatergic granule neurons.
  • Neurotoxicity was induced essentially as follows: cells were washed twice with Mg 2+ -free Locke solution [154 mM NaCl; 5.6 mM KC1; 3.6 mM NaHC0 3 ; 2.3 mM CaCl2,- 5.6 mM glucose; 5 mM HEPES (buffer solution base on N- [2-hydroxyethyl]-piperazin-N' -ethanesulfonic acid) free from magnesium ions and afterwards were incubated with 50 ⁇ M glutamate in Locke solution free from magnesium ions for 15 minutes (25°C).
  • Mg 2+ -free Locke solution [154 mM NaCl; 5.6 mM KC1; 3.6 mM NaHC0 3 ; 2.3 mM CaCl2,- 5.6 mM glucose; 5 mM HEPES (buffer solution base on N- [2-hydroxyethyl]-piperazin-N' -ethanesulfonic acid) free from magnesium ions
  • the glutamate- containing solution was then removed by aspiration and the cells were washed twice with Locke solution containing 1 mM Mg2S ⁇ 4, then returned to the incubator in their original medium. Cell survival was evaluated after 24 hours, according to the procedure by K.H. Johnes et al. J. Histochem, Cytochem. 33, 77 (1985).
  • Hippocampal slices were obtained from eight-day old Sprague-Dawley rats. Sections were prepared according to what described by J. Gathwaite et al., Neurosci. Lett. 97, 316 (1989). Transverse slices of hippocampus cut at a thickness of 0.5 mm by a Vibroslice ( Campden Instruments LTD, U.K.), were submerged in 2 ml of a Krebs solution containing 11 M glucose, equilibrated with 95% 0 2 - 5% C0 2 (pH 7.4), and preincubated at 37°C for 30 min. After that, 30 ⁇ m NMDA was added and incubation was carried out for 30 min.
  • non-steroidal antiinflammatory compounds according to the invention have an unexpected capability of effectively counteracting neurodegenerative conditions, by acting directly at the level of neuronal cells. It should be noted, with respect to those compounds of the invention defined at point (a), that such a characteristic makes their pharmacological spectrum wider than that of other NSAIDs . Therefore, it is unexpectedly possible to use the compounds of the invention previously defined at point (a) also in patients affected with neurodegenerative diseases associated with glutamate-mediated neuronal damages but not with inflammatory conditions, since said compounds have such double and distinct capability of acting as both antiinflammatory and antidegenerative agents .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation de composés anti-inflammatoires non stéroïdiens pour la prévention et le traitement de maladies neurodégénératives, telles que la maladie d'Alzheimer ou la maladie de Parkinson.
PCT/EP1997/006323 1996-11-13 1997-11-13 Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives WO1998020864A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT96MI002356A ITMI962356A1 (it) 1996-11-13 1996-11-13 Uso di composti derivati da molecole ad attivita' antinfiammatoria di tipo non steroideo per la prevenzione e il trattamento di
ITMI96A002356 1996-11-13

Publications (3)

Publication Number Publication Date
WO1998020864A2 true WO1998020864A2 (fr) 1998-05-22
WO1998020864A9 WO1998020864A9 (fr) 1998-08-27
WO1998020864A3 WO1998020864A3 (fr) 1998-10-15

Family

ID=11375202

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/006323 WO1998020864A2 (fr) 1996-11-13 1997-11-13 Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives

Country Status (2)

Country Link
IT (1) ITMI962356A1 (fr)
WO (1) WO1998020864A2 (fr)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5985930A (en) * 1996-11-21 1999-11-16 Pasinetti; Giulio M. Treatment of neurodegenerative conditions with nimesulide
EP1100504A2 (fr) 1998-07-02 2001-05-23 Eisai Co., Ltd. Compositions pharmaceutiques et leur utilisation
US6255347B1 (en) 1996-06-21 2001-07-03 Advanced Research And Technology Institute Methods and compositions comprising R-ibuprofen
WO2001072308A1 (fr) * 2000-03-28 2001-10-04 Neurotech Co., Ltd. Composition et methode prevenant la mort neuronale a l'aide de sulfasalazine
WO2002007721A3 (fr) * 2000-07-20 2002-04-18 Lauras As Methode
JP2003520199A (ja) * 1999-08-10 2003-07-02 ユーエイビー リサーチ ファンデーション 非ステロイド性抗炎症薬及び天然産コノトキシンを使用する外傷性脳及び脊髄損傷、並びに他の神経原性症状の治療方法
WO2003097024A1 (fr) * 2002-05-17 2003-11-27 Faust Pharmaceuticals Methodes de prevention et/ou de traitement de troubles neurologiques
EP1371366A1 (fr) * 2002-05-17 2003-12-17 Faust Pharmaceuticals Méthode de prévention et de traitement de troubles neurologiques
WO2003103657A1 (fr) * 2002-06-11 2003-12-18 株式会社医薬分子設計研究所 Traitements des maladies neurodegeneratives
WO2004035037A3 (fr) * 2002-10-21 2004-06-03 Univ Ramot Derives d'acide n-phenylanthranilique et de 2-benzimidazolone en tant que modulateurs de l'activite des canaux potassiques et/ou des neurones corticaux
JP2004519469A (ja) * 2001-01-26 2004-07-02 ノイ，インゴ・エス 多発性硬化症を処置するための医薬組成物
WO2005033059A1 (fr) * 2003-10-08 2005-04-14 Innovaprotean, S.L. Composes utiles pour le traitement de maladies associees a la formation de fibrilles amyloides
EP1645288A1 (fr) * 2004-10-07 2006-04-12 CTG Pharma S.r.l. Nouveaux régulateurs des facteurs de transcription nucleaire
EP1709963A3 (fr) * 1998-12-03 2007-12-26 MEDOSAN RICERCA S.r.l. Utilisation d' amtolmetin guacyl pour l'obtention d'un médicament pour contrecarrer d'aggregation des plaquettes sanguines
JP2008515805A (ja) * 2004-10-04 2008-05-15 ミリアド ジェネティクス， インコーポレイテッド アルツハイマー病のための化合物
WO2009083115A1 (fr) * 2007-12-21 2009-07-09 Paz Arzneimittel-Entwicklungsgesellschaft Mbh Médicament, sa fabrication et son utilisation pour le traitement de neuropathies douloureuses
US7626042B2 (en) 2002-06-06 2009-12-01 Institute Of Medicinal Molecular Design, Inc. O-substituted hydroxyaryl derivatives
EP2030615A3 (fr) * 2007-08-13 2009-12-02 ELFORD, Howard L. Inhibiteurs de la ribonucleotide reductase pour leur utilisation dans le traitement ou la prévention de maladies neuro-inflammatoires ou auto-immunes
US7632866B2 (en) 2002-10-21 2009-12-15 Ramot At Tel Aviv University Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
EP2213285A3 (fr) * 2003-12-19 2010-10-20 Novartis AG Utilisation d'agonistes du récepteur de sphingosine-1-phosphate (S1P) en combinaison avec un deuxième principe actif pour le traitement de maladies dégénératives des fonctions cérébrales.
EP2010187A4 (fr) * 2006-04-04 2010-11-17 Myriad Genetics Inc Composés pour le traitement de maladies et de troubles
JP2011520836A (ja) * 2008-05-13 2011-07-21 ジェンメディカ・セラピューティックス・ソシエダッド・リミターダ 代謝性障害を治療するのに有用なサリチレートコンジュゲート
WO2011091692A1 (fr) * 2010-01-29 2011-08-04 浙江大学 Utilisation d'un benzoate et de ses dérivés
US8029815B2 (en) 2004-04-28 2011-10-04 Elford Howard L Methods for treating or preventing restenosis and other vascular proliferative disorders
CN102816082A (zh) * 2010-01-29 2012-12-12 浙江大学 苯甲酰胺类衍生物及制备方法和应用
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
US20150086616A1 (en) * 2013-09-20 2015-03-26 Steven Lehrer Method for the prevention and treatment of alzheimer's disease
US9216966B2 (en) 2004-10-04 2015-12-22 John Manfredi Compounds for Alzheimer's disease
WO2016038379A1 (fr) * 2014-09-10 2016-03-17 Royal Holloway And Bedford New College Composé anticonvulsivant
US9597339B2 (en) 2013-02-01 2017-03-21 Glialogix, Inc. Compositions and methods for the treatment of neurodegenerative and other diseases
US20170143681A1 (en) * 2015-11-02 2017-05-25 Apkarian Technologies Llc Methods and compositions for treating pain
WO2017159484A1 (fr) * 2016-03-18 2017-09-21 学校法人同志社 DÉRIVÉ 2,4-DIAMINOPHÉNOL, ET AGENT D'INHIBITION DE L'AGRÉGATION DE TAU ET/OU DE L'AMYLOÏDE β
WO2022243507A1 (fr) * 2021-05-20 2022-11-24 Institut Du Cerveau Et De La Moelle Epiniere Tenoxicam pour le traitement de protéinopathies du système nerveux central

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5192753A (en) * 1991-04-23 1993-03-09 Mcgeer Patrick L Anti-rheumatoid arthritic drugs in the treatment of dementia
US5643960A (en) * 1994-04-15 1997-07-01 Duke University Method of delaying onset of alzheimer's disease symptoms
IT1282736B1 (it) * 1996-05-21 1998-03-31 Angelini Ricerche Spa Uso di derivati del p-amminofenolo per preparare composizioni farmaceutiche utili nel trattamento di malattie neurodegenerative

Cited By (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6255347B1 (en) 1996-06-21 2001-07-03 Advanced Research And Technology Institute Methods and compositions comprising R-ibuprofen
US6649811B2 (en) 1996-11-21 2003-11-18 Mount Sinai Of Medicine Of New York University Transgenic mouse expressing the human cyclooxygenase-2 gene and neuronal cell cultures derived therefrom
US5985930A (en) * 1996-11-21 1999-11-16 Pasinetti; Giulio M. Treatment of neurodegenerative conditions with nimesulide
US7226948B2 (en) 1996-11-21 2007-06-05 University Of Mount Sinai School Of Medicine Of The City Of New York Treatment of neurodegenerative conditions with nimesulide
EP1100504A2 (fr) 1998-07-02 2001-05-23 Eisai Co., Ltd. Compositions pharmaceutiques et leur utilisation
EP1709963A3 (fr) * 1998-12-03 2007-12-26 MEDOSAN RICERCA S.r.l. Utilisation d' amtolmetin guacyl pour l'obtention d'un médicament pour contrecarrer d'aggregation des plaquettes sanguines
JP2003520199A (ja) * 1999-08-10 2003-07-02 ユーエイビー リサーチ ファンデーション 非ステロイド性抗炎症薬及び天然産コノトキシンを使用する外傷性脳及び脊髄損傷、並びに他の神経原性症状の治療方法
US8513281B1 (en) * 1999-08-10 2013-08-20 Landon C. G. Miller Method of treating traumatic brain and spinal cord injuries and other neurogenic conditions using non-steroidal anti-inflammatory drugs and naturally occurring conotoxins
KR100417623B1 (ko) * 2000-03-28 2004-02-05 주식회사 뉴로테크 뇌질환 예방 및 치료용 조성물
JP2003528145A (ja) * 2000-03-28 2003-09-24 ニューロテック カンパニー リミテッド スルファサラジンを用いたニューロン死を妨げる組成物及び方法
WO2001072308A1 (fr) * 2000-03-28 2001-10-04 Neurotech Co., Ltd. Composition et methode prevenant la mort neuronale a l'aide de sulfasalazine
US6521640B1 (en) 2000-03-28 2003-02-18 Neurotech Co., Ltd. Method for interviewing neuronal death using sulfasalazine
AU780893B2 (en) * 2000-03-28 2005-04-21 Neurotech Co., Ltd. Composition and method for intervening neuronal death using sulfasalazine
WO2002007721A3 (fr) * 2000-07-20 2002-04-18 Lauras As Methode
CZ302448B6 (cs) * 2000-07-20 2011-05-25 Lauras As Farmaceutický prostredek
US7790738B2 (en) 2000-07-20 2010-09-07 Lauras As Methods of treating and preventing AIDS using of COX-2 inhibitors
AP1780A (en) * 2000-07-20 2007-09-26 Lauras As Use of cox-2 inhibitors for preventing immunodeficiency.
JP2004519469A (ja) * 2001-01-26 2004-07-02 ノイ，インゴ・エス 多発性硬化症を処置するための医薬組成物
WO2003097024A1 (fr) * 2002-05-17 2003-11-27 Faust Pharmaceuticals Methodes de prevention et/ou de traitement de troubles neurologiques
EP1371366A1 (fr) * 2002-05-17 2003-12-17 Faust Pharmaceuticals Méthode de prévention et de traitement de troubles neurologiques
US7626042B2 (en) 2002-06-06 2009-12-01 Institute Of Medicinal Molecular Design, Inc. O-substituted hydroxyaryl derivatives
CN100490793C (zh) * 2002-06-11 2009-05-27 株式会社医药分子设计研究所 神经变性疾病治疗药
JPWO2003103657A1 (ja) * 2002-06-11 2005-10-06 株式会社医薬分子設計研究所 神経変性疾患治療剤
JP4635130B2 (ja) * 2002-06-11 2011-02-16 株式会社医薬分子設計研究所 神経変性疾患治療剤
WO2003103657A1 (fr) * 2002-06-11 2003-12-18 株式会社医薬分子設計研究所 Traitements des maladies neurodegeneratives
EA011707B1 (ru) * 2002-06-11 2009-04-28 Инститьют Оф Медисинал Молекьюлар Дизайн. Инк. Лекарственное средство для лечения нейродегенеративных заболеваний
US7632866B2 (en) 2002-10-21 2009-12-15 Ramot At Tel Aviv University Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
US8618169B2 (en) 2002-10-21 2013-12-31 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
JP2006513154A (ja) * 2002-10-21 2006-04-20 ラモト アット テル アヴィヴ ユニヴァーシティ リミテッド カリウムチャネルおよび／または皮質ニューロン活性モジュレーターとしての、ｎ−フェニルアントラニル酸および２−ベンズイミダゾロンの誘導体
WO2004035037A3 (fr) * 2002-10-21 2004-06-03 Univ Ramot Derives d'acide n-phenylanthranilique et de 2-benzimidazolone en tant que modulateurs de l'activite des canaux potassiques et/ou des neurones corticaux
US8278357B2 (en) 2002-10-21 2012-10-02 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
WO2005033059A1 (fr) * 2003-10-08 2005-04-14 Innovaprotean, S.L. Composes utiles pour le traitement de maladies associees a la formation de fibrilles amyloides
EP2213285A3 (fr) * 2003-12-19 2010-10-20 Novartis AG Utilisation d'agonistes du récepteur de sphingosine-1-phosphate (S1P) en combinaison avec un deuxième principe actif pour le traitement de maladies dégénératives des fonctions cérébrales.
US8519006B2 (en) 2003-12-19 2013-08-27 Novartis Ag Use of sphingosine-1 phosphate (S1P) receptor agonists for the treatment of brain degenerative diseases
US8029815B2 (en) 2004-04-28 2011-10-04 Elford Howard L Methods for treating or preventing restenosis and other vascular proliferative disorders
JP2008515805A (ja) * 2004-10-04 2008-05-15 ミリアド ジェネティクス， インコーポレイテッド アルツハイマー病のための化合物
US9216966B2 (en) 2004-10-04 2015-12-22 John Manfredi Compounds for Alzheimer's disease
EP1809601A4 (fr) * 2004-10-04 2010-11-17 Myriad Genetics Inc Composes destines a la maladie d'alzheimer
EP1645288A1 (fr) * 2004-10-07 2006-04-12 CTG Pharma S.r.l. Nouveaux régulateurs des facteurs de transcription nucleaire
WO2006037623A3 (fr) * 2004-10-07 2007-07-19 Ctg Pharma S R L Nouveaux régulateurs de facteurs de transcription nucléaires
EP2010187A4 (fr) * 2006-04-04 2010-11-17 Myriad Genetics Inc Composés pour le traitement de maladies et de troubles
US9526707B2 (en) 2007-08-13 2016-12-27 Howard L. Elford Methods for treating or preventing neuroinflammation or autoimmune diseases
EP2030615A3 (fr) * 2007-08-13 2009-12-02 ELFORD, Howard L. Inhibiteurs de la ribonucleotide reductase pour leur utilisation dans le traitement ou la prévention de maladies neuro-inflammatoires ou auto-immunes
US9403756B2 (en) 2007-09-20 2016-08-02 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
WO2009083115A1 (fr) * 2007-12-21 2009-07-09 Paz Arzneimittel-Entwicklungsgesellschaft Mbh Médicament, sa fabrication et son utilisation pour le traitement de neuropathies douloureuses
JP2011520836A (ja) * 2008-05-13 2011-07-21 ジェンメディカ・セラピューティックス・ソシエダッド・リミターダ 代謝性障害を治療するのに有用なサリチレートコンジュゲート
CN102816082A (zh) * 2010-01-29 2012-12-12 浙江大学 苯甲酰胺类衍生物及制备方法和应用
WO2011091692A1 (fr) * 2010-01-29 2011-08-04 浙江大学 Utilisation d'un benzoate et de ses dérivés
US9918997B2 (en) 2013-02-01 2018-03-20 Glialogix, Inc. Compositions and methods for the treatment of neurodegenerative and other diseases
US9597339B2 (en) 2013-02-01 2017-03-21 Glialogix, Inc. Compositions and methods for the treatment of neurodegenerative and other diseases
US9980978B2 (en) 2013-02-01 2018-05-29 Glialogix, Inc. Compositions and methods for the treatment of neurodegenerative and other diseases
US9974798B2 (en) 2013-02-01 2018-05-22 Glialogix, Inc. Compositions and methods for the treatment of neurodegenerative and other diseases
US20150086616A1 (en) * 2013-09-20 2015-03-26 Steven Lehrer Method for the prevention and treatment of alzheimer's disease
WO2016038379A1 (fr) * 2014-09-10 2016-03-17 Royal Holloway And Bedford New College Composé anticonvulsivant
JP2017528478A (ja) * 2014-09-10 2017-09-28 ロイヤル・ホロウェイ・アンド・ベッドフォード・ニュー・カレッジＲｏｙａｌ Ｈｏｌｌｏｗａｙ Ａｎｄ Ｂｅｄｆｏｒｄ Ｎｅｗ Ｃｏｌｌｅｇｅ 抗痙攣化合物
US10301263B2 (en) 2014-09-10 2019-05-28 Royal Holloway And Bedford New College Anticonvulsant compound
US20170143681A1 (en) * 2015-11-02 2017-05-25 Apkarian Technologies Llc Methods and compositions for treating pain
US11419857B2 (en) 2015-11-02 2022-08-23 Apkarian Technologies Llc Methods and compositions for treating pain
WO2017159484A1 (fr) * 2016-03-18 2017-09-21 学校法人同志社 DÉRIVÉ 2,4-DIAMINOPHÉNOL, ET AGENT D'INHIBITION DE L'AGRÉGATION DE TAU ET/OU DE L'AMYLOÏDE β
JPWO2017159484A1 (ja) * 2016-03-18 2019-01-24 学校法人同志社 ２，４−ジアミノフェノール誘導体、及び、タウ及び／又はアミロイドβの凝集阻害剤
WO2022243507A1 (fr) * 2021-05-20 2022-11-24 Institut Du Cerveau Et De La Moelle Epiniere Tenoxicam pour le traitement de protéinopathies du système nerveux central

Also Published As

Publication number Publication date
ITMI962356A0 (it) 1996-11-13
ITMI962356A1 (it) 1998-05-13
WO1998020864A3 (fr) 1998-10-15

Similar Documents

Publication Publication Date Title
WO1998020864A2 (fr) Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives
WO1998020864A9 (fr) Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives
Rao et al. Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxygenase-2 inhibitor
US20060222671A1 (en) Dermatological compositions and salts for the treatment of dermatological diseases
ES2962890T3 (es) Uso del cannabidiol en el tratamiento del complejo de esclerosis tuberosa
Rohrbach et al. FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice
KR101660401B1 (ko) 신생혈관형성증 조절을 통한 알츠하이머 질환 및 관련 장애의 치료를 위한 신규 치료학적 접근법
ES2690061T3 (es) Composiciones para tratar la enfermedad de Parkinson
JP5835865B2 (ja) ロキソプロフェン含有医薬組成物
WO1998009603A2 (fr) Compositions contenant des anti-inflammatoires non steroidiens a enantiomeres r et methodes therapeutiques et prophylactiques employant ces compositions
JP5897804B2 (ja) ロキソプロフェン含有の医薬組成物
BR112015015858B1 (pt) Uso de uma composição farmacêutica de solução sólida no tratamento de uma inflamação crônica
Mathew et al. 6b, 11b-Dihydroxy-6b, 11b-dihydro-7H-indeno [1, 2-b] naphtho [2, 1-d] furan-7-one (DHFO), a small molecule targeting NF-κB, demonstrates therapeutic potential in immunopathogenic chronic inflammatory conditions
Jain et al. Amelioration of ER stress by 4-phenylbutyric acid reduces chronic hypoxia induced cardiac damage and improves hypoxic tolerance through upregulation of HIF-1α
WO1998040061A1 (fr) Utilisation d&#39;enantiomeres r d&#39;anti-inflammatoires non steroidiens pour la prevention de la maladie d&#39;alzheimer
EP2050453B1 (fr) Composes pharmaceutiques contenant du meloxicam, du tramadol et du paracetamol
JP5847085B2 (ja) チアゾリジンジオンエネルギー制限模倣剤
EA029454B1 (ru) Новая композиция соединения ацетаминофена без побочного эффекта на печень
AU2006228871A1 (en) Dermatological compositions and salts for the treatment of dermatological diseases
Aziz et al. Comparing the toxic effects of nonsteroidal anti-inflammatory drugs (celecoxib and ibuprofen) on heart, liver, and kidney in rats
US20070154540A1 (en) Composition for treatment of osteoarthritis containing apigenin as chondroregenerative agent
WO2011130817A1 (fr) Préparation pharmaceutique et procédé pour réduire l&#39;hépatotoxicité
US20230330049A1 (en) Compositions and methods of use of gamma-ketoaldheyde scavengers for treating, preventing or improving fibrosis of the liver
Chang et al. Tetramethylpyrazine decreases hypothalamic glutamate, hydroxyl radicals and prostaglandin-E 2 and has antipyretic effects
Yue et al. Embryo‐fetal developmental toxicity and toxicokinetics of loxoprofen tromethamine intravenously administered to pregnant rats

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
COP Corrected version of pamphlet

Free format text: PAGE 4/4, DRAWINGS, REPLACED BY A NEW PAGE 4/4

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载