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WO1996041638A1 - Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives - Google Patents

Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives Download PDF

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Publication number
WO1996041638A1
WO1996041638A1 PCT/US1995/007463 US9507463W WO9641638A1 WO 1996041638 A1 WO1996041638 A1 WO 1996041638A1 US 9507463 W US9507463 W US 9507463W WO 9641638 A1 WO9641638 A1 WO 9641638A1
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WO
WIPO (PCT)
Prior art keywords
benzyloxycarbonyl
ketone
leucyl
phenylalanine
glycine
Prior art date
Application number
PCT/US1995/007463
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English (en)
Inventor
Roland E. Dolle
Todd L. Graybill
Irennegbe K. Osifo
Alex L. Harris
Matthew S. Miller
Original Assignee
Sanofi Winthrop, Inc.
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 Sanofi Winthrop, Inc. filed Critical Sanofi Winthrop, Inc.
Priority to CA002224721A priority Critical patent/CA2224721A1/fr
Priority to AU27043/95A priority patent/AU2704395A/en
Priority to PCT/US1995/007463 priority patent/WO1996041638A1/fr
Priority to EP95922312A priority patent/EP0840614A1/fr
Publication of WO1996041638A1 publication Critical patent/WO1996041638A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a series of novel amino acid analogs which exhibit selective inhibition of Calpain I, to compositions containing the novel amino acid analogs and methods for therapeutic use.
  • the Calpain I inhibitors described in this invention comprise novel amino acid derivatives which possess particular utility in treatment of neurodegenerative diseases.
  • Calpain is a cytosolic protease enzyme found in all mammalian tissue and cell types. There are two forms of the enzyme with different sensitivities to calcium; the high-sensitivity form, calpain I, is activated by a low calcium concentration (2-75 ⁇ M), and the low-sensitivity form, calpain II, is activated by a higher calcium concentration (200-800 ⁇ M) . Although calpain II is the prominant form, calpain I is concentrated in synapses and neuronal cell bodies and is thought to be involved in the phenomenon of long-term synaptic potentiation.
  • calpain The location of active calpain explain how calpain can promote: (1) down-regulation of membrane-associated active protein kinase C; (2) formation of a calpain-activated soluble kinase; and (3) reorganization of the cytoskeleton (Melloni, E., and Pontremoli, S. (1989), The Calpains, Trends Neurosci. 12, 438-44). Inactivation of the kinase results in repression of superoxide anion production, a process correlated to the protein kinase C- mediated phosphorylation of membrane proteins.
  • a limited number of peptidyl methyl ketone analogs constitute a well- known class of compounds having enzymatic (papain, cathepsin B) inhibition activity. These analogs, however, are essentially devoid of potency and selectivity in inhibiting calpain I. In spite of various known calpain inhibitors, no effective therapy has yet been developed for the majority of ischemia-induced neurodegenerative diseases, CNS disorders, and stroke. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.
  • Novel amino acid analogs having the formula (I) Z-A 3 -A 2 -A 1 - Q (I)
  • Z is H or a protecting group
  • a 3 and A 2 are independently an optionally protected valine, leucine, alanine, isoleucine, phenylalnine, tyrosine, glycine, 2-arylglycine having either D or L stereochemistry or a chemical bond;
  • a 1 is an optionally protected valine, leucine, isoleucine, alanine, phenylalanine, tyrosine, 2-phenyl-glycine, 2-phenethyl-glycine, 2- aryl-glycine;
  • Q is H, CH 2 OCOL, CH 2 OL, CH 2 SL, CH 2 X, NHNHCOCH 2 OCOL, NHNHCOCH 2 OL, NHNHCOCH 2 SL, wherein
  • L is an optionally substituted aryl or optionally substituted heteroaryl
  • X is CI, Br or F, and a pharmaceutically acceptable salt thereof.
  • X is CI, Br or F, and a pharmaceutically acceptable salt thereof.
  • Alkyl means a saturated or an unsaturated aliphatic hydrocarbon which may be either straight- or branched-chain. Preferred groups have no more than about 12 carbon atoms and may be methyl, ethyl and structural isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • Lower alkyl means an alkyl group as above, having 1 to 7 carbon atoms. Suitable lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and n-heptyl.
  • Aryl means phenyl and substituted phenyl.
  • Substituted phenyl means a phenyl group in which one or more of the hydrogens has been replaced by the the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl , heteroaryl, lower alkoxy, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholino-sulfonyl, and carbobenzoxy-methylsulfamoyi.
  • Heteroaryl means pyridyl, pyrimidyl, tetrazolyl or thiadiazolyl.
  • Substituted heteroaryl means a heteroaryl group in which one or more of the hydrogens has been replaced by the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, lower alkoxy, alkylsulfonyl , trifluoromethyl, morpholinoethoxy, morpholiho-sulfonyl, and carbobenzoxymethylsulfamoyl.
  • a “protecting group” is a radical attached to an oxygen, sulfur, or nitrogen atom, respectively, which radical serves to protect the oxygen, sulfur, or nitrogen functionally against undesired reaction. Such protecting groups are well known in the art, many are described in "The Peptides", E. Gross and J. Meienhofer, Eds. Vol. 3 Academic Press, NY (1981).
  • the N-protecting groups can be N-acyl, N-alkoxycarbonyl, N- arylmethoxycarbonyl and N-arylsulfonyl protecting groups.
  • Suitable O-protecting groups include benzyl, tert-butyl, methyl, tosyl ad carbobenzoxy groups.
  • S-protecting groups include methyl, tert-butyl, benzyl and carbobenzoxy groups.
  • Pharmaceutically acceptable salts include both acid and base addition salts.
  • Pharmaceutically acceptable acid addition salt refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyrubic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and p-toluenesulfonic acid and the like.
  • Pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically accceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occuring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procain, hydrabamine, choline, betaine, ethylendiamine, glucosamine, methylglucamine, theobromine, purines, peperiziner, piperidine, polyamine resins and the like.
  • basic ion exchange resins such as isopropylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, dicyclohexylamine, lysine, arginine,
  • organic non-toxic bases are isopropylamine, diethylamine, ethanol-amine, dicyclohexylamine, choline and caffeine.
  • This invention also contemplates pharmaceutically acceptable acid- addition salts of the compounds of Formula I. It is well known in the pharmacological arts that nontoxic addition salts of pharmacologically active amine compounds do not differ in activities from their free base. All stereoisomers as well as optical isomers related to the novel calpain inhibitory amino acid analogs described herein are also considered to be within the scope of this invention.
  • amino acid analogs of the present invention are selective calpain inhibitors. More particularly, the amino acid analogs of the present invention bind at the active site of the proteolytic enzyme, specifically calpain I.
  • the present invention further provides pharmaceutical compositions comprised of the above-described novel amino acid analog inhibitors and method of treating ischemia-induced neurodegenerative diseases, stroke, myocardial infarction, CNS disorders, and immunological diseases involving interleukin 1.
  • the first step of this procedure involves the synthesis of N-protected dipeptidic bromomethyl ketone (formula 2).
  • Methods for the preparation of various dipeptides (formula 1 ) are well established in the art.
  • the N- protected dipeptide (formula 1 ) which in some cases is commercially available, is then converted to the corresponding bromoketone (formula 2) by way of hydrobromination or hydrohalogenation of a diazomethyl ketone intermediate.
  • a displacement reaction of the bromomethyl or chloromethyl ketone by an aromatic carboxylic acid or alcohol (or thiol) then yields the desired arylcarboxymethyl ketone (formula 3) or aryloxy (or aryl-thio)methyl ketone (formula 4) of the invention.
  • the N-protected dipeptidic arylcarboxymethyl ketone (formula 3) is deprotected by conventional hydrogenolysis and the resulting free amino dipeptide analog (formula 5) is readily converted to the corresponding tripeptidic arycarboxymethyl ketone (formula 6) under standard peptide coupling conditions as shown in Scheme 1.
  • peptidic aldehydes for example formula 10
  • the peptidic aldehydes (for example formula 10) of this invention are readily prepared by synthesizing the corresponding peptidic N-methoxy-N- methylamide analogs (for example formula 9) via standard synthesis followed by LAH reduction of the above amides.
  • N-Benzyloxycarbonyl-L-leucyl-L-phenylalanine (10.16 g, 24.63 mmol) was dissolved in dry THF (100 mL) under nitrogen. The solution was cooled to -15°C, N-methylmorpholine (2.98 mL 22.1 mmol) was added followed by dropwise addition of isobutyl chloroformate (3.35 mL, 25.86 mmol) over a 5 min period. A solution of dried diazomethane in ether (50 mmol in 100 mL ether dried over Na 2 S O 4 ; from Diazald-Aldrich) was poured into the reaction mixture. The reaction mixture (-15°C) was allowed to slowly warm to 0°C after 1 hr, and then held 1 hr at room temperature.
  • the reaction mixture was cooled to 0°C, 47 mL of 50% HBr/AcOH added with stirring at 0°C, and the resulting mixture was transferred to a separatory funnel with 500 mL of water.
  • the aqueous phase was extracted with ethyl acetate (3x) and the organic layer was washed successively with water, 0.3N KHSO 4 , saturated NaHCO 3 solution, water, and brine.
  • 2,6-Difluorobenzoic acid (65 mg. 0.41 mmol) was added to a solution of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine bromo-methyl ketone (200 mg, 0.41 mmol) and potassium fluoride in dry DMF under nitrogen.
  • the reaction mixture was poured into ether and the organic layer was washed successively with water, 5% NaHCO 3 , water, and brine.
  • N-Methylmorpholine (117 mg, 1.06 mmol) was added to the above mixture and the resulting reaction mixture was stirred for 30 min at 0°C, and then stirred at room temperature overnight. The mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed successively with 0.3N KHSO 4 , saturated NaHCO 3 , and brine.
  • Example 40 Following the synthetic procedure described in Example 39, the following compounds were made. Example 40
  • Example 62 Following additional calpain inhibitors were synthesized.
  • Example 62 Following additional calpain inhibitors were synthesized.
  • Human red blood cells were obtained from the Northeastern New York Chapter of the American Red Cross. The isolation of calpain from human erythrocytes was similar to that described by Wang et al. (1988).
  • One unit of in-dated packed red cells was diluted with an equal volume of diluting/wash solution and centrifuged. The supernatant was removed and the procedure was repeated.
  • the washed cells were pooled, lysed with 700 mL of lysing solution and centrifuged to remove cell debris.
  • the membrane- free hemolysate was added to 500 mL DEAE-sephacel and the slurry was stirred gently at 4°C for 1 hour.
  • the tritated assay is a modification of that described by Gopalakrishna, R. and Barsky, S.H., Anal. Biochem., 148, 413,1985. All reagents, compound 25 ul, HEPES buffer 25 ul, CaCI 2 50 ul, enzyme 50 ul, and 3 H-acetyl Casein, were combined in 1 mL polystyrene titer plates. The plates were preincubated at 25°C for 5 min with gentle shaking prior to the addition of substrate. The incubation was continued for an additional 2 hours and was terminated with the addition of 0.5 mL ice cold 5% TCA.
  • the present invention includes a calpain inhibitor of this invention formulated into compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants or vehicles which are collectively referred to herein as carriers, for parenteral injection or oral administration, in solid or liquid form, for rectal or topical administration, or the like.
  • compositions can be administered to humans and animals either orally, rectally, parenterally (intravenous, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia
  • humectants as for example, glylcerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents as for example, cetyl alcohol and glycerol monostearate
  • ad customary excipient
  • ad such as sodium citrate or dicalcium phosphate
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, ground-nut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbon
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants as may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of the active ingredient in the compositions of the present invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors.
  • the total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts, for example, of from about 0.5 mg to about 10 mg per kilogram of body weight. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.

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Abstract

L'invention concerne de nouveaux analogues d'acides aminés, et un de leurs sels pharmacologiquement acceptable, de formule (I): Z-A3-A2-A1-Q, dans laquelle Z représente H ou un groupe de protection; A3 et A2 représentent indépendemment valine, leucine, alanine, isoleucine, phénylalnine, tyrosine, glycine, 2-arylglycine, toutes éventuellement protégées, et présentant une stéréochimie D ou L ou une liaison chimique; A1 représente valine, leucine, isoleucine, alanine, phénylalnine, tyrosine, 2-phényl-glycine, 2-phénéthyl-glycine, 2-aryl-glycine, toutes éventuellement protégées; Q représente H, CH2OCOL, CH2OL, CH2SL, CH2X, NHNHCOCH2OCOL, NHNHCOCH2OL, NHNHCOCH2SL, où L représente aryle ou hétéroaryle éventuellement substitués; et X représente CI, Br ou F.
PCT/US1995/007463 1995-06-13 1995-06-13 Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives WO1996041638A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002224721A CA2224721A1 (fr) 1995-06-13 1995-06-13 Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives
AU27043/95A AU2704395A (en) 1995-06-13 1995-06-13 Calpain inhibitors for the treatment of neurodegenerative di seases
PCT/US1995/007463 WO1996041638A1 (fr) 1995-06-13 1995-06-13 Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives
EP95922312A EP0840614A1 (fr) 1995-06-13 1995-06-13 Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA002224721A CA2224721A1 (fr) 1995-06-13 1995-06-13 Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives
PCT/US1995/007463 WO1996041638A1 (fr) 1995-06-13 1995-06-13 Inhibiteurs de la calpaine destines au traitement de maladies neurodegeneratives

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Cited By (18)

* Cited by examiner, † Cited by third party
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WO1998038990A1 (fr) * 1997-03-07 1998-09-11 Hoechst Marion Roussel, Inc. Methode de traitement d'un trauma associe a des lesions du cerveau, de la moelle epiniere ou de nerfs peripheriques au moyen de carbobenzyloxy phenylalaninals di- et tri-pepetidiques n-proteges
WO1998050065A2 (fr) * 1997-05-05 1998-11-12 Marion Sangster Eckmiller Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie
WO2000055124A2 (fr) * 1999-03-15 2000-09-21 Axys Pharmaceuticals, Inc. Composes et compositions utilises comme inhibiteurs de protease
WO2002062830A1 (fr) * 2001-02-05 2002-08-15 Neurotell Ag Derives de tripeptides pour le traitement de maladies neurodegeneratives
ES2219187A1 (es) * 2003-05-14 2004-11-16 Consejo Sup. Investig. Cientificas Inhibidores de calpaina.
US6977256B2 (en) 2001-11-14 2005-12-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin S inhibitors
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7064123B1 (en) 2000-12-22 2006-06-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7122524B2 (en) 2001-02-05 2006-10-17 Neurotell Ag Tripeptides and tripeptide derivatives for the treatment of postlesional disease of the nervous system
US7129213B2 (en) 2001-02-05 2006-10-31 Neurotell Ag Tripeptides and tripeptide derivatives for the treatment of neurodegenerative diseases
US7163922B2 (en) 2001-02-05 2007-01-16 Neurotell Ag Tripeptide derivatives for the treatment of postlesional diseases of the nervous system
US7196099B2 (en) 2001-09-14 2007-03-27 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7932266B2 (en) 2004-12-16 2011-04-26 Consejo Superior De Investigaciones Cientificas Isoquinoline derivatives as calpain inhibitors
US9181296B2 (en) 2008-03-26 2015-11-10 Novozymes A/S Stabilized liquid enzyme compositions
EP2971065A4 (fr) * 2013-03-15 2016-12-21 Univ Leland Stanford Junior Composés de sonde basée sur l'activité, compositions et méthodes d'utilisation
US9527811B2 (en) 2009-05-07 2016-12-27 AbbVie Deutschland GmbH & Co. KG Carboxamide compounds and their use as calpain inhibitors
WO2018119476A1 (fr) 2016-12-23 2018-06-28 The Board Of Trustees Of The Leland Stanford Junior University Composés sondes par activité, compositions et méthodes d'utilisation
US11828752B2 (en) 2017-03-30 2023-11-28 The Board Of Trustees Of The Leland Stanford Junior University Protease-activated contrast agents for in vivo imaging

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GB2069484A (en) * 1980-02-04 1981-08-26 Ajinomoto Kk Method of producing n-benzyloxycarbonyl-l-aspartic acid
JPH04273826A (ja) * 1991-02-27 1992-09-30 Dainippon Ink & Chem Inc 抗ｒｓウイルス剤
US5444042A (en) * 1990-12-28 1995-08-22 Cortex Pharmaceuticals Method of treatment of neurodegeneration with calpain inhibitors

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
GB2069484A (en) * 1980-02-04 1981-08-26 Ajinomoto Kk Method of producing n-benzyloxycarbonyl-l-aspartic acid
US5444042A (en) * 1990-12-28 1995-08-22 Cortex Pharmaceuticals Method of treatment of neurodegeneration with calpain inhibitors
JPH04273826A (ja) * 1991-02-27 1992-09-30 Dainippon Ink & Chem Inc 抗ｒｓウイルス剤

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998038990A1 (fr) * 1997-03-07 1998-09-11 Hoechst Marion Roussel, Inc. Methode de traitement d'un trauma associe a des lesions du cerveau, de la moelle epiniere ou de nerfs peripheriques au moyen de carbobenzyloxy phenylalaninals di- et tri-pepetidiques n-proteges
WO1998050065A2 (fr) * 1997-05-05 1998-11-12 Marion Sangster Eckmiller Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie
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EP4310504A2 (fr) 2016-12-23 2024-01-24 The Board of Trustees of the Leland Stanford Junior University Composés sondes à base d'activité, compositions et procédés d'utilisation
US12059482B2 (en) 2016-12-23 2024-08-13 The Board Of Trustees Of The Leland Stanford Junior University Activity-based probe compounds, compositions, and methods of use
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