WO1993009135A1 - Peptides inhibant la liberation d'il-1 beta - Google Patents

Peptides inhibant la liberation d'il-1 beta Download PDF

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Publication number
WO1993009135A1
WO1993009135A1 PCT/EP1992/002472 EP9202472W WO9309135A1 WO 1993009135 A1 WO1993009135 A1 WO 1993009135A1 EP 9202472 W EP9202472 W EP 9202472W WO 9309135 A1 WO9309135 A1 WO 9309135A1
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WO
WIPO (PCT)
Prior art keywords
formula
radical
compound
amino
alkyl
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Application number
PCT/EP1992/002472
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English (en)
Inventor
Richard Heng
Trevor Glyn Payne
Laszlo Revesz
Beat Weidmann
Original Assignee
Sandoz Ltd.
Sandoz-Patent-Gmbh
Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H.
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.)
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Application filed by Sandoz Ltd., Sandoz-Patent-Gmbh, Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Sandoz Ltd.
Priority to EP92922580A priority Critical patent/EP0611375A1/fr
Priority to SK511-94A priority patent/SK51194A3/sk
Priority to JP5508146A priority patent/JPH07500828A/ja
Publication of WO1993009135A1 publication Critical patent/WO1993009135A1/fr
Priority to NO941629A priority patent/NO941629L/no
Priority to FI942061A priority patent/FI942061A/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/545—IL-1
    • 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
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptides having pharmaceutical utility, processes for their production, pharmaceutical compo-sitions comprising them and their use as pharmaceuticals.
  • R is hydrogen, an amino protecting group or optionally ring substituted benzyloxy
  • a 1 is Val, Leu, Ala, lie or trimethylsilyl-Ala
  • a 2 is Phe or Tyr
  • n 0 or 1
  • a 3 is a direct bond, Val, Leu, Ala, lie, trimethylsilyl-Ala or a divalent radical of formula (a)
  • vherein ring A is optionally substituted by hydroxy or
  • C 1-4 alkoxy is a direct bond or a divalent radical of formula (b) wherein R 1 is hydrogen or C 1-4 alkyl, and
  • Y 1 is the residue attaching to the ⁇ -carbon atom of an ⁇ -amino acid and optionally protected, -CH 2 -CH 2 -N(C 1-4 alkyl) 2 , imidazol-2-yl-methyl, benzimidazol-2-yl-methyl, 1H-1,2,4-triazol-3-yl- methyl, pyrazol-3-yl-methyl, indazol-3-yl-methyl or a radical of formula (c) or (d)
  • each of R 2 and R 3 independently, is hydrogen
  • each of R 4 and R 5 independently is hydrogen
  • R 6 is H or C 1-4 alkyl
  • a 5 is hydrogen; CF 3 ; a radical -Z 1 -Z 2 -Y 2 wherein each of Z 1 and Z 2 independently is a direct bond or an ⁇ -amino acid residue and Y 2 is NH 2 , C 1-4 alkylamino, di-(C 1-4 alkyl)amino or a heterocyclic radical attached by a nitrogen to Z 2 ; a radical -CH 2 -X 1 -Y 3 wherein X 1 is O or S and Y 3 is heteroaryl; a radical -CH 2 -Y3; or a radical of formulae (k) to (m)
  • Y 4 is tri-(C 1-4 alkyl)methyl or a residue ring B is pyridyl
  • - ring C is phenyl or pyridyl
  • each of R 7 and R 8 independently is C 1-4 alkyl, C 1-4 alkoxy,
  • each of R 9 , R 10 and R 11 independently is nitro, cyano,
  • R 12 is C 1-6 alkyl
  • X is a divalent radical of formula (f) ,
  • a 5 is -Z 1 -Z 2 -Y 2 or a radical of formulae (k) to (o) as defined above, or OR 13 or NR 14 R 15 wherein R 13 is C 1-12 al- kyl optionally substituted by OH or interrupted by 0 and each of R 14 and R 15 is independently hydrogen, C 1-12 al- kyl, C 5-7 cycloalkyl or benzyl, or
  • X is a divalent radical of formula (g)
  • a 5 is -Z 1 -Z 2 -Y 2 as defined above, or
  • X is a divalent radical of formula (h) or (j)
  • a 5 is a radical of formulae (k) to (o), -CH 2 -Y 3 or
  • a 3 and A 4 can be a direct bond when n is 0, and each of A 3 and A 4 is other than a direct bond when n is 1. and the physiologically-hydrolysable and -acceptable esters or amides thereof, in free form, in salt form or in the form of complexes.
  • protecting groups as R are e.g. disclosed in "Protective Groups in Organic Synthesis", T. W. Greene, J.Wiley & Sons NY (1981), 219-287, for example acyl such as acetyl, methoxysuccinyl, hydroxysuccinyl or benzoyl optionally substituted on the phenyl ring with e.g.
  • p-methoxycarbonyl p-methoxy or p-nitro
  • alkoxycarbonyl such as t-butyloxycarbonyl
  • arylmetho ⁇ xycarbonyl such as 9-fluorenylmethoxycarbonyl or benzyloxy carbonyl optionally substituted on the phenyl ring with p-methoxy, p-nitro, p-chloro or m-phenyl
  • arylmethyl such as benzyl optionally ring substituted with p-methoxy, p-nitro or p-chloro
  • arylsulfonyl such as phenylsulfonyl optionally ring substituted with p-methyl or p-methoxy, or naphthylsulfonyl optionally ring substituted with e.g. amino or di(C 1-4 alkyl)amino.
  • R is ring substituted benzyloxy, it is preferably benzyloxy substituted with hydroxy or C 1-4 alkoxy.
  • R is
  • Halogen is preferably fluorine or chlorine.
  • ⁇ -amino acid is meant a naturally occurring or commercially available or non natural ⁇ -amino acid or an optical isomer thereof.
  • a non natural ⁇ -amino acid is an ⁇ -amino acid which is not incorporated into a protein under mRNA direction, e.g. ⁇ -Nal, a fluoro- ⁇ -amino acid such as fluoroalanine, trimethylsilyl-Ala or an ⁇ -amino acid such as
  • n 1 is an integer from 1 to 6 and n 2 is an integer from 1 to 12.
  • Protecting groups which may be present in Y 1 are groups which protect the O, S or N functionality in the side chain amino groups of an ⁇ -amino acid.
  • N-protecti ⁇ g groups are e.g. as disclosed above for R, or C 3-5 alkyl such as isopropyl, formyl, a sugar residue such as 1-deoxy-fructosyl or ⁇ -glucosyl(1-4)- deoxyfructosyl, dihydroxy-C 3-6 alkyl such as dihydroxypropyl, C 5-7 cycloalkyl such as cyclohexyl or tropinyl.
  • S-protecting groups for hydroxy and thiol functionalities are known and may be e.g. methyl, t.-butyl or benzyl.
  • Y 2 is a heterocyclic radical, it may be e.g. a 5 or 6 membered ring, e.g. piperidino or pyrrolidinyl.
  • heteroaryl as Y 3 examples include e.g. 5-, 6- or 7-membered unsaturated heterocyclic radicals, comprising at least one nitrogen and optionally further heteroatoms such as N, O or S.
  • Y 3 is heteroaryl comprising from 1 to 4 nitrogen atoms, e.g. pyridyl, triazolyl, tetrazolyl, triazin-dionyl.
  • ring B of radical (o) the nitrogen atom may be in o-, m- or para.
  • ring C in radical (k) is pyridyl, it may be 3-, 4- or 5-pyridyl.
  • Radicals (e 1 ), (e 2 ), (f), (g) and (j) are derived from Asp and comprise one asymetric carbon atom and radical (h) comprises two asymetric carbon atoms and accordingly they lead to optical isomerism. It will be understood that the present invention includes all individual isomeric forms and diastereoisomers as well as mixtures, e.g. racemates, unless otherwise stated.
  • Radical of formula (e 1 ) attached to A 5 which is hydrogen may exist in both cyclic as well as in non-cyclic form e.g. as follows:
  • the present invention embraces both lactol and oxo-carboxylic acid forms, i.e. although compounds of formula I wherein X is a radical of formula (e 1 ) are defined for convenience by reference to the oxo-carboxylic acid form only, the invention is not to be understood as being in any way limited by the particular nomenclature or graphic representation employed. Similar considerations apply in relation to starting materials exhibiting lactol/oxo-carboxylic acid tautomerism as hereinafter described.
  • radical of formula (h) which may exist in both linear and cyclic form as follows:
  • esters and amides which are hydrolysable under physiological conditions to yield alcohols or amines which are themselves physiologically acceptable, i.e. which are non-toxic at the desired dosage levels.
  • esters or amides are obtained by esterification or
  • esters include esters with an aliphatic or alicyclic alcohol or polyol having 1 to 12 carbon atoms.
  • amides include amides with aliphatic amines, e.g. C 1-4 alkyl amine, C 1-4 alkoxy-C 1-4 alkyl amine such as ⁇ -methoxy-ethyl amine, or aniline.
  • the compounds of formula I may exist e.g. in free form, acid addition salt form or in the form of complexes thereof.
  • Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. Salt forms may also include those obtainable with the carboxylic group present in compounds of formula I, e.g. alkali metal salts such as sodium or potassium, or substituted or unsubstituted ammonium salts.
  • Complexes are e.g. formed from compounds of formula I on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca-and Zn-salts, and/or an addition of polymeric organic substances.
  • R is an amino protecting group or benzyloxy, preferably an amino protecting group.
  • R is preferably benzyloxy when n is 0 and A 3 is a radical of formula (a).
  • Each of A 3 and A 4 are other than a direct bond.
  • a 3 is a radical of formula (a) when n is 0.
  • a 3 is a direct bond, Val, Leu, Ala, lie or trimethylsily-Ala.
  • R 1 is hydrogen or methyl, preferably hydrogen.
  • Y 1 is the residue attaching to the ⁇ -carbon atom of an ⁇ -amino acid selected from Ala, Leu, His, Phe, Met, Trp,
  • Y 1 is a radical of formula (c). 8.
  • a 3 and A 4 may also form together a radical of formula (aa) when n is O.
  • m is 2 or 3.
  • X is a radical of formula (e 1 ) and A 5 is other than H.
  • X is a radical of formula (g).
  • X is a radical of formula (h) or (j).
  • R 6 is hydrogen or methyl, preferahly hydrogen.
  • Z 1 in A 5 is the residue of a natural ⁇ -amino acid, preferably of an aromatic/heterocyclic ⁇ -amino acid, particularly Pro.
  • Z 2 in A 5 is the residue of a natural ⁇ -amino acid, preferably an aliphatic ⁇ -amino acid, particularly an aliphatic ⁇ -amino acid without further functional group, most preferably Val.
  • X is a radical of formula (e 1 ) optionally esterified or
  • a 5 is a radical of formula (k), (1) or (o).
  • X is a radical of formula (e 1 ), (h) or j(j) optionally esterified or amidated and A 5 is -CH 2 -X 1 -Y 3 , preferably
  • X is a radical of formula (h) or (j) optionally esterified or amidated and A 5 is (k.).
  • X is a radical of formula (j) optionally esterified or
  • a 5 is a radical of formula (m).
  • Radical of formula (m) is monosubstituted, preferably in para, more preferably it is 4-nitrophenyl.
  • X has the D or L configuration.
  • the asymetric carbon in (j) bearing R 6 has the configuration R.
  • the present invention also provides a compound of formula I wherein
  • a 3 is a direct bond, Val, Leu, Ala, lie or trimethylsilyl-Ala,
  • a 4 is as defined above, or A 3 and A 4 form together a radical of formula (aa) as defined above, and
  • X is a radical of formula (e 1 ) or (e 2 ) as defined above and
  • a 5 is H, or
  • X is a radical of formula (e 1 ) or (f) and A 5 is -Z 1 -Z 2 -Y 2 as defined above or a radical of formula (k), (l) or (m) wherein
  • iii)X is a radical of formula (g) and A 5 is -Z 1 -Z 2 -Y 2 , or iv) X is a radical of formula (j) and A 5 is a radical of formula
  • the present invention also provides a process for the production of a compound of formula I, which process comprises: a) removing at least one protecting group from a compound of formula I in protected form or adding a protecting group R at the N-terminal group of a compound of formula I; or b) converting one compound of formula I into another compound of formula I; or c) coupling together by an amide bond two peptide fragments, each of which contains at least one amino acid in protected or unprotected form and one peptide fragment containing a radical of formula (e 1 ) to (j) as defined above, the peptide fragments being such that a protected or unprotected peptide having the sequence according to formula I above is obtained and, if necessary, removing the protecting group or groups from a compound of formula I in protected form; or d) for the production of a compound of formula I wherein X is a radical of formula (e 1 ) or (h) and A 5 is a radical of formula (k), (l) or (o) or -
  • R-[A 1 -A 2 ] n -A 3 -A 4 -X'-CH 2 -Z a (III) wherein R, A 1 to A 4 and n are as defined above, X' is a radical of formula (e 1 ) or (h), and Z a is a leaving group, e.g. halogen, with a corresponding phenol, thiophenol or HX 1 -pyridine or an acid of formula HX 1 -CO-Y 4 or a functional derivative thereof or HX 1 -Y 3 ; or e) for the production of a compound of formula I
  • R, A 1 to A 5 and n are as defined above and R 16 is a C 1-12 aliphatic or alicyclic residue, oxidizing a compound of formula V
  • R, A 1 to A 5 , n and R 1 6 are as defined above, and recovering a compound of formula I thus obtained in free or salt form or in the form of a complex.
  • Processes (a) to (e) above may be carried out in accordance with standard techniques known in the art.
  • the removal of a protecting group in process step (a) may also include the removal of R on the N-terminal group of a compound of formula I.
  • R is benzyloxy carbonyl
  • this group may be removed by hydrogenation in the presence of a catalyst, e.g. Pd.
  • a compound of formula I wherein X comprises a carboxy group may be hydrolysed.
  • Suchhydrolysis may be effected by treatment with an appropriate alkali or by acid hydrolysis, for example in the presence of trifluoroacetic acid.
  • a compound of formula I wherein X comprises a carboxy group or an esterified caboxy group may be (trans) esterified or amidated.
  • ester formation or amidation may be carried out using any of the techniques known in the art, for example converting the carboxy group in a functional reactive group, e.g. a corresponding carbonyl halide or anhydri- de, or using a compound of formula I wherein X is a radical of formula (h) in the lactone form, and reacting such group with the selected alcohol or amine.
  • a compound of formula I wherein X is a radical of formula (g) for the production of a compound of formula I wherein X is a radical of formula (g), a compound of formula I wherein X is a radical of formula (e 1 ) or (e 2 ) and A 5 is H may be reacted with a compound of formula II
  • a compound of formula I wherein X is a radical of formula (e 1 ) may also be converted in accordance with known techniques into a compound of formula I wherein X is a radical of formula (e 2 ) and vice versa.
  • Process step (c) may be carried out by the techniques known in the art of peptide chemistry.
  • peptide fragment comprising a radical of formula (e 1 ) to (j) is also meant the radical itself bearing a protecting group on the -NR 6 - moiety and an appropriate ending, e.g. A 5 or CH 2 -Z a , on the other end.
  • Process step (d) may conveniently be effected using a Dess-Martin reagent, e.g. in the presence of a base or a halogen-precipita-ting silver salt, or according to the Swern oxidation procedures.
  • a Dess-Martin reagent e.g. in the presence of a base or a halogen-precipita-ting silver salt, or according to the Swern oxidation procedures.
  • protecting groups may be used for functional groups which do not participate in the reaction. These may be e.g. amino protecting groups, carboxy protecting groups, acetal groups etc. When the desired reaction is complete, the protecting groups may then be removed.
  • each of the above processes may be carried out using starting materials in the form of one or other of the individual optical isomers or in the form of mixtures [relating to the asymetric carbons present in radicals of formulae (e 1 ) to (j) as X or in such a radical precursor].
  • the starting materials are used as S- or R-enantiomers to produce a compound of formula I wherein the asymetric carbon in radicals of formulae (ei) to (j) has the S or R configuration, respectively.
  • Example 4 Z-Val-Phe-Asp(OH)-H
  • Example 5 Z-Val-His-Asp( OH) -H
  • a 3 , A 4 and A 5 are as defined below, may be prepared.
  • the (3R,4RS) derivative of the title compound may be prepared as follows:
  • a 3 , A 4 , R x and R y are as defined below, may be prepared.
  • Triethylamine (1.3 ml, 9.6 mmol), followed be ethylchloroformiate (0.92 ml, 9.6 mmol) are added to (3S)-3-(fluorenylmethoxycarbo-nyl)amino-3-carboxy-butanoic acid tert. butyl ester (3.5 g, 8.5 mmol) in THF (60 ml) at - 10 °. After 10 min., a solution of dia-zomethane in ether is added slowly, and the reaction mixture stirred for 45 min. at 0 - 5 °. HCl (2N) in ether is added at 5 -10 ° until gas evolution has ceased.
  • reaction mixture is eva-porated to dryness, taken up in acetone (50 ml) Nal (4 g) added and stirred for 1 hr at r.t. Ether (150 ml) is added, the reaction mixture filtered and evaporated. The residue is chromatographed (SiO 2 , EtOAc/hexane), yielding the title compound as slightly yellow crystals.
  • EXAMPLE 70 (3S)-3-(Fluorenylmethoxycarbonyl)amino-5(2,6- difflethylbenzoyloxy)-4-oxo pentanoic acid tert.butyl ester
  • compounds of the invention exhibit pharmaceutical activity and are, therefore, useful as pharmaceuticals.
  • the compounds of the invention inhibit IL-1 ⁇ secretion as indicated in the following in vitro test using THP-1 cells and in vivo test methods: a) 900 ⁇ l THP-1 cells (0.5 ⁇ 10 6 cells) together with 100 U
  • L-glutamine and 5 % heat-inactivated foetal calf serum are pipetted into 24 well culture plates. 100 ⁇ l of the compound to be tested are then added. After 3 hours at 37 ° C in 5 % CO 2 /95 % air, 10 ⁇ l lipopolysaccharide 500 ⁇ g/ml is added and the incubation continued for a further 40 hours. Appropriate controls (with and without stimulus, solvent) ar also included. The media are then removed and clarified by centrifugation at 1000 g for 10 min. 1.0 ml digitonin 0.01 % is added to the wells to lyse the cells which are loosened by scraping with a rubber policeman and left at 4 ° C for 10 min.
  • Lactate dehydrogenase measurements are then performed immediately and the samples stored at - 20 ° C until the other determinations can be made.
  • the assays are: IL-1 ⁇ (medium and lysate), IL-6 (medium), TNF- ⁇ (medium), PGE2 (medium and lysate), lactate dehydrogenase (LDH) and DNA (lysates).
  • IL-1 ⁇ , IL-6 and TNF- ⁇ assays are determined using commercially available ELISA kits (Cistron), PGE 2 is measured using a standard RIA and DNA fluorimetrically using DAPI.
  • the compounds of the invention selectively inhibit IL-1 ⁇ release in concentrations from about 0.01 to 100 ⁇ M.
  • IL-6, TNF- ⁇ , PGE2 and DNA levels remain substantially unaffected, and the compounds are non-toxic, since LDH release is unchanged.
  • IC 50 value concentration of compound which inhibits to 50% the release of IL-1 ⁇
  • a LPS-suspension (Sigma, No. L-5886; 100 ⁇ g/5ml glucose solution/kg s.c.) is injected in male Tuttlingen SD rats
  • the ED 50 is the dose causing a 50% inhibition of the temperature increase determined in the control rats.
  • compounds of examples 40 and 50 have each an ED 50 value of 0.01 mg/kg p.o. and compound of example 51 an ED 50 value of 0.05 mg/kg p.o. Carrageenan-Induced Paw Edema in the Rat
  • test compound 50FA male rats, 150-170g body weight, are used for each group.
  • the test compound is administered orally as a suspension in physiological saline/0.5% tragacanth 1 hour prior to the carrageenan injection.
  • Carrageenan (0.1ml of a 1% suspension in physiological saline) is given by subplantar injection into one hind paw.
  • the swelling of the paw is measured by means of an antiphlogometer according to Kemper & Amelm.
  • a control reading is taken immediately after the injection, and the swelling is measured after 3 and 5 hrs.
  • the mean value of the 3- and 5-hour reading is taken after deduction of the control reading, the values obtained from the treated animals are expressed as a percentage of the value obtained from non-treated controls.
  • the ED 50 is the dose causing a 50% inhibition of the carrageenan-induced swelling after 3 hrs.
  • compounds of the invention inhibit significantly the carrageenen-induced swelling when administered p.o. at a dosage in the range of from 0.02 to 5 mg/kg. It has for example been determined that compound of example 40 and 50 have an ED 50 value of 0.2 and 1 mg/kg p.o. respectively.
  • Compounds of the invention are therefore useful for the treatment of disorders with an aetiology associated with or comprising excessive IL-1 ⁇ release, e.g. in a wide variety of inflammatory states and diseases, for example tissus calcium depletion, degenerative processes in bone and cartilage, e.g.
  • osteoporosis of various genesis including e.g. climacteric or post-menopausal osteoporosis as well as osteoporosis consequential to old age, immobilization or trauma, arteriosclerosis and Alzheimer disease.
  • the required dosage will of course vary depen ⁇ ding on the mode of administration, the particular condition to be treated and the effect desired. In general however, satisfactory results are achieved at daily dosage rates of from about 0.001 to about 100 mg/kg, preferably 0.001 to about 10 mg/kg animal body weight. Suitable daily dosage rates for larger mammals, for example humans, are of the order of from about 0.1 mg to about 1 g/day, conveniently administered once, in divided dosages 2 to 4 x/day, or in sustained release form.
  • the present invention also provides: a) A method for the treatment of disorders with an aetiology
  • a method comprises administering to said subject an effective amount of a compound of formula I, a physiologically-hydrolysable and -acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof; b) A compound of formula I, a physiologically-hydrolysable and -acceptable ester or amide thereof or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical, for example for use as an agent, e.g. in the method as disclosed above.
  • the compounds of the invention may be administered by any con ⁇ ventional route, in particular nasally, enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally e.g. in the form of injectable solutions or suspensions or in a suppository form.
  • Unit dosage forms contain, for example from about 25 ⁇ g to 500 mg of a compound of the invention.
  • the compounds of the invention may be administered in free form or in pharmaceutically acceptable salt form.
  • Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
  • compositions comprising a compound of formula I, a physiologically-hydrolysable and -acceptable ester or amide thereof or a pharmaceutically acceptable salt thereof, as hereinbefore defined, together with a pharmaceutically acceptable diluent or carrier therefor.
  • Such compositions may be manufactured in conventional manner. They may comprise up to 99.9% by weight of active ingredient.

Abstract

Di-, tri et tétrapeptides dans lesquels le dernier α-aminoacide est à base d'acide aspartique et accolé à un reste A5 qui représente H; CH3: -Z1-Z2-Y2, Z1 et Z2 représentant chacun indépendamment une liaison directe ou un reste d'α-aminoacide et Y2 représentant NH2, alkylamino C1-4, di-(alkyle C1-4) amino ou un radical hétérocyclique relié par un azote à Z2; -CH2-X1-Y3, X1 représentant O ou S et Y3 représentant hétéroaryle; -CH2-Y3; phényle substitué; phénylthiométhylène ou phénoxyméthylène à substitution de cycle; pyridyloxyméthylène à substitution de cycle; ou un radical -CH2-X1-CO-Y4, X1 représentant O ou S et Y4 représentant trialkylméthyle, ou phényle ou pyridyle substitué. Ces peptides, sous forme libre ou sous forme de sel, présentent une activité pharmacologique, par exemple, des propriétés d'inhibition de la libération d'IL-1β.
PCT/EP1992/002472 1991-11-04 1992-10-29 Peptides inhibant la liberation d'il-1 beta WO1993009135A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP92922580A EP0611375A1 (fr) 1991-11-04 1992-10-29 Peptides inhibant la liberation d'il-1 beta
SK511-94A SK51194A3 (en) 1991-11-04 1992-10-29 Peptides
JP5508146A JPH07500828A (ja) 1991-11-04 1992-10-29 ＩＬ−１β遊離を阻害するペプチド類
NO941629A NO941629L (no) 1991-11-04 1994-05-03 Peptider som inhiberer 1L-1
FI942061A FI942061A (fi) 1991-11-04 1994-05-04 IL-1 beta vapautumista estäviä peptidejä

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9123326.2 1991-11-04
GB919123326A GB9123326D0 (en) 1991-11-04 1991-11-04 Improvements in or relating to organic compounds

Publications (1)

Publication Number Publication Date
WO1993009135A1 true WO1993009135A1 (fr) 1993-05-13

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PCT/EP1992/002472 WO1993009135A1 (fr) 1991-11-04 1992-10-29 Peptides inhibant la liberation d'il-1 beta

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EP0618223A2 (fr) * 1993-03-08 1994-10-05 Sandoz Ltd. Peptides inhibent la libération d'interleukine 1-bêta utiles comme agents antiinflammatoires
EP0623606A2 (fr) * 1993-05-07 1994-11-09 Sterling Winthrop Inc. Peptide-kétones comme inhibiteurs de l'interleukin-1bêta convertant enzyme
EP0623592A1 (fr) * 1993-04-29 1994-11-09 Sterling Winthrop Inc. Analogues de peptides à adivité inhibitrice de l'interleukin 1 bêta protéase
EP0627926A1 (fr) * 1992-02-21 1994-12-14 Merck & Co., Inc. (a New Jersey corp.) DERIVES DE PEPTIDYLE UTILES COMME INHIBITEURS DE L'ENZYME CONVERTISSANT L'INTERLEUKINE-1$g(b)
EP0644198A1 (fr) * 1993-06-03 1995-03-22 Sterling Winthrop Inc. Alpha-hétéroaryloxyméthyl cétones comme inhibiteurs d'enzyme convertissant l'interleukine-1 bêta
EP0644197A1 (fr) * 1993-06-04 1995-03-22 Sterling Winthrop Inc. Peptidyl-phosphinyloxyméthyl-cétones comme inhibiteurs d'enzyme convertissant l'interleukine-1 bêta
WO1995015749A1 (fr) * 1993-12-08 1995-06-15 Prototek, Inc. Inhibiteurs de cysteine protease contenant des groupes partants heterocycliques
US5434248A (en) * 1991-06-21 1995-07-18 Merck & Co., Inc. Peptidyl derivatives as inhibitors of interleukin-1β converting enzyme
WO1995035308A1 (fr) * 1994-06-17 1995-12-28 Vertex Pharmaceuticals Incorporated INHIBITEURS DE L'ENZYME DE CONVERSION D'INTERLEUKINE-1$g(b)
GB2292149A (en) * 1994-08-09 1996-02-14 Ferring Res Ltd Peptide inhibitors of pro-interleukin-1beta converting enzyme
WO1996030395A2 (fr) * 1995-03-31 1996-10-03 Takeda Chemical Industries, Ltd. Inhibiteur de la protease de cysteine
EP0761680A2 (fr) * 1995-09-12 1997-03-12 Ono Pharmaceutical Co., Ltd. Composés de tétrazole ayant une activité inhibante d'enzyme convertissant l'Interleukine-1bêta
EP0764167A1 (fr) * 1994-06-08 1997-03-26 Sanofi Winthrop, Inc. Inhibiteurs au lactame bicyclique de l'enzyme de conversion de l'interleukine-1-beta
EP0767661A1 (fr) * 1994-08-02 1997-04-16 Sanofi Winthrop, Inc. Analogues d'acide aza-aspartique utilises comme inhibiteurs de l'enzyme de conversion de l'interleukine-1 beta
WO1997024339A1 (fr) * 1995-12-27 1997-07-10 Ono Pharmaceutical Co., Ltd. Derives de tetrazole et medicaments les contenant a titre d'ingredients actifs
US5656627A (en) * 1994-06-17 1997-08-12 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US5714484A (en) * 1993-12-08 1998-02-03 Prototek, Inc. α-(1,3-dicarbonylenol ether) methyl ketones as cysteine protease inhibitors
US5798442A (en) * 1995-04-21 1998-08-25 Merck Frosst Canada, Inc. Peptidyl derivatives as inhibitors of pro-apoptotic cysteine proteinases
US5843904A (en) * 1995-12-20 1998-12-01 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1βconverting enzyme
US5843905A (en) * 1993-06-04 1998-12-01 Vertex Pharmaceuticals, Incorporated Peptidic phosphinyloxymethyl ketones as interleukin-1β-converting enzyme inhibitors
US5847135A (en) * 1994-06-17 1998-12-08 Vertex Pharmaceuticals, Incorporated Inhibitors of interleukin-1β converting enzyme
US5866545A (en) * 1993-08-13 1999-02-02 Merck & Co., Inc. Substituted ketone derivatives as inhibitors of interleukin-1β converting enzyme
US5869519A (en) * 1996-12-16 1999-02-09 Idun Pharmaceuticals, Inc. C-terminal modified (n-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US5874424A (en) * 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US5877197A (en) * 1996-12-16 1999-03-02 Karanewsky; Donald S. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US5968927A (en) * 1996-09-20 1999-10-19 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US5985838A (en) * 1993-04-29 1999-11-16 Vertex Pharmaceuticals, Inc. Peptide analogs as irreversible interleukin-1β protease inhibitors
US6008217A (en) * 1995-12-20 1999-12-28 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
WO2000023421A1 (fr) * 1998-10-22 2000-04-27 Idun Pharmaceuticals, Inc. INHIBITEURS ACYLE(SUBSTITUE) DIPEPTIDYLE DE LA FAMILLE ICE/ced-3 DES CYSTEINES PROTEASES
US6083706A (en) * 1997-02-26 2000-07-04 Ciblex Corporation Inhibitors of leaderless protein export
US6184244B1 (en) * 1996-12-16 2001-02-06 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US6204261B1 (en) 1995-12-20 2001-03-20 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β Converting enzyme inhibitors
US6306613B1 (en) 1997-02-26 2001-10-23 Ciblex Corporation Modulators of leaderless protein export and methods for identifying and using the same
US6426413B1 (en) 1998-03-09 2002-07-30 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
JP2002541237A (ja) * 1999-04-09 2002-12-03 サイトビア インコーポレイテッド カスパーゼインヒビターおよびその使用
US6525024B1 (en) 2000-04-17 2003-02-25 Idun Pharmaceuticals, Inc. Inhibitors of the ICE/ced-3 family of cysteine proteases
US6531474B1 (en) 1998-03-19 2003-03-11 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US7087604B2 (en) 2002-03-08 2006-08-08 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
US7157430B2 (en) 1998-10-22 2007-01-02 Idun Pharmaceuticals, Inc. (Substituted)acyl dipeptidyl inhibitors of the ICE/CED-3 family of cysteine proteases
US7288624B2 (en) 1994-06-17 2007-10-30 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US7381827B2 (en) 2004-03-12 2008-06-03 Vertex Pharmaceuticals Incorporated Processes and intermediates
US7417029B2 (en) 2000-05-19 2008-08-26 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US7531570B2 (en) 2004-05-27 2009-05-12 Vertex Pharmaceuticals Incorporated Treatment of diseases using ICE inhibitors
EP2241328A1 (fr) 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies
CN101979403A (zh) * 2010-09-13 2011-02-23 沈陵陵 新型半胱氨酸天冬氨酸广谱蛋白酶抑制剂及其制备方法和用途
US9116157B2 (en) 2010-11-05 2015-08-25 Brandeis University Ice-cleaved alpha-synuclein as a biomarker
US9352010B2 (en) 2011-07-22 2016-05-31 The J. David Gladstone Institutes Treatment of HIV-1 infection and AIDS
WO2017081641A1 (fr) 2015-11-13 2017-05-18 Novartis Ag Nouveaux dérivés de pyrazolo-pyrimidine

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PE20020500A1 (es) * 2000-09-13 2002-06-25 Vertex Pharma Derivados de piperidina, tetrahidroquinolina, tetrahidroisoquinolina como inhibidores de caspasas

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US5434248A (en) * 1991-06-21 1995-07-18 Merck & Co., Inc. Peptidyl derivatives as inhibitors of interleukin-1β converting enzyme
EP0627926A1 (fr) * 1992-02-21 1994-12-14 Merck & Co., Inc. (a New Jersey corp.) DERIVES DE PEPTIDYLE UTILES COMME INHIBITEURS DE L'ENZYME CONVERTISSANT L'INTERLEUKINE-1$g(b)
EP0627926A4 (fr) * 1992-02-21 1997-01-29 Merck & Co Inc DERIVES DE PEPTIDYLE UTILES COMME INHIBITEURS DE L'ENZYME CONVERTISSANT L'INTERLEUKINE-1-g(b).
US5430128A (en) * 1992-02-21 1995-07-04 Merck & Co., Inc. Peptidyl derivatives as inhibitors of interleukin-1β converting enzyme
EP0618223A3 (fr) * 1993-03-08 1996-06-12 Sandoz Ltd Peptides inhibent la libération d'interleukine 1-bêta utiles comme agents antiinflammatoires.
EP0618223A2 (fr) * 1993-03-08 1994-10-05 Sandoz Ltd. Peptides inhibent la libération d'interleukine 1-bêta utiles comme agents antiinflammatoires
EP0623592A1 (fr) * 1993-04-29 1994-11-09 Sterling Winthrop Inc. Analogues de peptides à adivité inhibitrice de l'interleukin 1 bêta protéase
AU676887B2 (en) * 1993-04-29 1997-03-27 Vertex Pharmaceuticals Incorporated Peptide analogs as irreversible interleukin-beta protease inhibitors
US5985838A (en) * 1993-04-29 1999-11-16 Vertex Pharmaceuticals, Inc. Peptide analogs as irreversible interleukin-1β protease inhibitors
US6576614B1 (en) 1993-04-29 2003-06-10 Vertex Pharmaceuticals Incorporated Peptide analogs as irreversible interleukin-1β protease inhibitors
EP0623606A2 (fr) * 1993-05-07 1994-11-09 Sterling Winthrop Inc. Peptide-kétones comme inhibiteurs de l'interleukin-1bêta convertant enzyme
EP0623606A3 (fr) * 1993-05-07 1994-12-07 Sterling Winthrop Inc. Peptide-kétones comme inhibiteurs de l'interleukin-1bêta convertant enzyme
EP0644198A1 (fr) * 1993-06-03 1995-03-22 Sterling Winthrop Inc. Alpha-hétéroaryloxyméthyl cétones comme inhibiteurs d'enzyme convertissant l'interleukine-1 bêta
AU690102B2 (en) * 1993-06-03 1998-04-23 Vertex Pharmaceuticals Incorporated Aplha-heteroaryloxymethyl ketones as interleukin-1beta converting enzyme inhibitors
EP0644197A1 (fr) * 1993-06-04 1995-03-22 Sterling Winthrop Inc. Peptidyl-phosphinyloxyméthyl-cétones comme inhibiteurs d'enzyme convertissant l'interleukine-1 bêta
US5843905A (en) * 1993-06-04 1998-12-01 Vertex Pharmaceuticals, Incorporated Peptidic phosphinyloxymethyl ketones as interleukin-1β-converting enzyme inhibitors
US5866545A (en) * 1993-08-13 1999-02-02 Merck & Co., Inc. Substituted ketone derivatives as inhibitors of interleukin-1β converting enzyme
US5714484A (en) * 1993-12-08 1998-02-03 Prototek, Inc. α-(1,3-dicarbonylenol ether) methyl ketones as cysteine protease inhibitors
US5486623A (en) * 1993-12-08 1996-01-23 Prototek, Inc. Cysteine protease inhibitors containing heterocyclic leaving groups
US6147188A (en) * 1993-12-08 2000-11-14 Prototek, Inc. α- (1,3- or 1, 2- dicarbonylenol ether methyl ketones as cysteine protease inhibitors
WO1995015749A1 (fr) * 1993-12-08 1995-06-15 Prototek, Inc. Inhibiteurs de cysteine protease contenant des groupes partants heterocycliques
US5663380A (en) * 1993-12-08 1997-09-02 Prototek, Inc. Cysteine protease inhibitors containing heterocyclic leaving groups
US5925772A (en) * 1993-12-08 1999-07-20 Prototek, Inc. Cysteine protease inhibitors containing heterocyclic leaving groups
EP1391461A1 (fr) * 1994-06-08 2004-02-25 Vertex Pharmaceuticals Incorporated Inhibiteurs au lactame bicyclique de l'enzyme de conversion de l'interleukine-1-beta
EP0764167A4 (fr) * 1994-06-08 1997-09-17 Sanofi Winthrop Inc Inhibiteurs au lactame bicyclique de l'enzyme de conversion de l'interleukine-1-beta
EP0764167A1 (fr) * 1994-06-08 1997-03-26 Sanofi Winthrop, Inc. Inhibiteurs au lactame bicyclique de l'enzyme de conversion de l'interleukine-1-beta
US7772366B2 (en) 1994-06-17 2010-08-10 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US7288624B2 (en) 1994-06-17 2007-10-30 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6103711A (en) * 1994-06-17 2000-08-15 Vertex Pharmaceuticals, Incorporated Inhibitors of interleukin-1β converting enzyme
US5756466A (en) * 1994-06-17 1998-05-26 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US5716929A (en) * 1994-06-17 1998-02-10 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
WO1995035308A1 (fr) * 1994-06-17 1995-12-28 Vertex Pharmaceuticals Incorporated INHIBITEURS DE L'ENZYME DE CONVERSION D'INTERLEUKINE-1$g(b)
CZ298625B6 (cs) * 1994-06-17 2007-11-28 Vertex Pharmaceuticals Incorporated Inhibitory enzymu konvertujícího interleukin-1beta, zpusob jejich selekce a farmaceutické prostredky, které je obsahují
US5656627A (en) * 1994-06-17 1997-08-12 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US5847135A (en) * 1994-06-17 1998-12-08 Vertex Pharmaceuticals, Incorporated Inhibitors of interleukin-1β converting enzyme
EP1394175A1 (fr) * 1994-06-17 2004-03-03 Vertex Pharmaceuticals Incorporated inhibiteur de l'enzyme de conversion de l'interleukine 1 beta
US6025147A (en) * 1994-06-17 2000-02-15 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1 β converting enzyme
AP797A (en) * 1994-06-17 2000-01-07 Vertex Pharma Inhibitors of interleukin-1B converting enzyme.
EP2123665A3 (fr) * 1994-06-17 2010-02-03 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme de conversion d'interleukine-1$g(b)
EP2123665A2 (fr) 1994-06-17 2009-11-25 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme de conversion d'interleukine-1Beta
EP0767661A1 (fr) * 1994-08-02 1997-04-16 Sanofi Winthrop, Inc. Analogues d'acide aza-aspartique utilises comme inhibiteurs de l'enzyme de conversion de l'interleukine-1 beta
EP0767661A4 (fr) * 1994-08-02 1998-06-10 Sanofi Winthrop Inc Analogues d'acide aza-aspartique utilises comme inhibiteurs de l'enzyme de conversion de l'interleukine-1 beta
GB2292149A (en) * 1994-08-09 1996-02-14 Ferring Res Ltd Peptide inhibitors of pro-interleukin-1beta converting enzyme
WO1996030395A2 (fr) * 1995-03-31 1996-10-03 Takeda Chemical Industries, Ltd. Inhibiteur de la protease de cysteine
WO1996030395A3 (fr) * 1995-03-31 1996-12-27 Takeda Chemical Industries Ltd Inhibiteur de la protease de cysteine
US6162828A (en) * 1995-03-31 2000-12-19 Takeda Chemical Industries, Ltd. Cysteine protease inhibitor
US5798442A (en) * 1995-04-21 1998-08-25 Merck Frosst Canada, Inc. Peptidyl derivatives as inhibitors of pro-apoptotic cysteine proteinases
EP0761680A3 (fr) * 1995-09-12 1999-05-06 Ono Pharmaceutical Co., Ltd. Composés de tétrazole ayant une activité inhibante d'enzyme convertissant l'Interleukine-1bêta
EP0761680A2 (fr) * 1995-09-12 1997-03-12 Ono Pharmaceutical Co., Ltd. Composés de tétrazole ayant une activité inhibante d'enzyme convertissant l'Interleukine-1bêta
US5710153A (en) * 1995-09-12 1998-01-20 Ono Phramaceutical Co., Ltd. Tetrazole compound
US5874424A (en) * 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US8119631B2 (en) 1995-12-20 2012-02-21 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US5843904A (en) * 1995-12-20 1998-12-01 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1βconverting enzyme
EP2083014A2 (fr) 1995-12-20 2009-07-29 Vertex Pharmceuticals Incorporated Inhibiteurs d'enzyme à conversion d'interleukine-1ß
US6008217A (en) * 1995-12-20 1999-12-28 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6204261B1 (en) 1995-12-20 2001-03-20 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β Converting enzyme inhibitors
EP2295442A2 (fr) 1995-12-20 2011-03-16 Vertex Pharmaceuticals Incorporated Inhibiteurs d'enzyme à conversion d'interleukine-1ß
US6258948B1 (en) 1995-12-20 2001-07-10 Vertex Pharmaceuticals, Incorporated Inhibitors of Interleukin-1β converting enzyme
US7790713B2 (en) 1995-12-20 2010-09-07 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6162790A (en) * 1995-12-20 2000-12-19 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6376484B1 (en) 1995-12-27 2002-04-23 Ono Pharmaceutical Co., Ltd. Tetrazole compounds and pharmaceutical agents containing such derivative as an active ingredient
WO1997024339A1 (fr) * 1995-12-27 1997-07-10 Ono Pharmaceutical Co., Ltd. Derives de tetrazole et medicaments les contenant a titre d'ingredients actifs
US6136834A (en) * 1995-12-27 2000-10-24 Ono Pharmaceutical Co., Ltd. Tetrazole compounds and pharmaceutical agents containing such derivative
US6444663B2 (en) 1996-09-20 2002-09-03 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US6187771B1 (en) 1996-09-20 2001-02-13 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US5968927A (en) * 1996-09-20 1999-10-19 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US6184244B1 (en) * 1996-12-16 2001-02-06 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US5877197A (en) * 1996-12-16 1999-03-02 Karanewsky; Donald S. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US5869519A (en) * 1996-12-16 1999-02-09 Idun Pharmaceuticals, Inc. C-terminal modified (n-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US6083706A (en) * 1997-02-26 2000-07-04 Ciblex Corporation Inhibitors of leaderless protein export
US6306613B1 (en) 1997-02-26 2001-10-23 Ciblex Corporation Modulators of leaderless protein export and methods for identifying and using the same
US6426413B1 (en) 1998-03-09 2002-07-30 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US8691848B2 (en) 1998-03-19 2014-04-08 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
EP2261233A2 (fr) 1998-03-19 2010-12-15 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
US7358273B2 (en) 1998-03-19 2008-04-15 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
EP2261235A2 (fr) 1998-03-19 2010-12-15 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
EP2261234A2 (fr) 1998-03-19 2010-12-15 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
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US6531474B1 (en) 1998-03-19 2003-03-11 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
WO2000023421A1 (fr) * 1998-10-22 2000-04-27 Idun Pharmaceuticals, Inc. INHIBITEURS ACYLE(SUBSTITUE) DIPEPTIDYLE DE LA FAMILLE ICE/ced-3 DES CYSTEINES PROTEASES
US7157430B2 (en) 1998-10-22 2007-01-02 Idun Pharmaceuticals, Inc. (Substituted)acyl dipeptidyl inhibitors of the ICE/CED-3 family of cysteine proteases
US6242422B1 (en) 1998-10-22 2001-06-05 Idun Pharmacueticals, Inc. (Substituted)Acyl dipeptidyl inhibitors of the ice/ced-3 family of cysteine proteases
JP2002541237A (ja) * 1999-04-09 2002-12-03 サイトビア インコーポレイテッド カスパーゼインヒビターおよびその使用
US6525024B1 (en) 2000-04-17 2003-02-25 Idun Pharmaceuticals, Inc. Inhibitors of the ICE/ced-3 family of cysteine proteases
US6969703B2 (en) 2000-04-17 2005-11-29 Idun Pharmaceuticals, Inc. Inhibitors of the ICE/ced-3 family of cysteine proteases
EP2241328A1 (fr) 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies
US7417029B2 (en) 2000-05-19 2008-08-26 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US9994613B2 (en) 2000-05-19 2018-06-12 Vertex Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
EP2270005A1 (fr) 2000-05-19 2011-01-05 Vertex Pharmceuticals Incorporated Promédicament inhibiteur d'ECI
US9487555B2 (en) 2000-05-19 2016-11-08 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US9156880B2 (en) 2000-05-19 2015-10-13 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US8022041B2 (en) 2000-05-19 2011-09-20 Vertex Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US8329662B2 (en) 2000-05-19 2012-12-11 Vertexd Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US7776884B2 (en) 2002-03-08 2010-08-17 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptors activity
US7087604B2 (en) 2002-03-08 2006-08-08 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
US8293929B2 (en) 2004-03-12 2012-10-23 Vertex Pharmaceuticals Incorporated Processes and intermediates
EP2399916A1 (fr) 2004-03-12 2011-12-28 Vertex Pharmaceuticals Incorporated Procédé et intermédiaires pour la préparation d'acétals de l'acide aspartique, inhibiteurs de la caspase
US7381827B2 (en) 2004-03-12 2008-06-03 Vertex Pharmaceuticals Incorporated Processes and intermediates
EP2399915A1 (fr) 2004-03-12 2011-12-28 Vertex Pharmaceuticals Incorporated Procédé et intermédiaires pour la préparation d'acétals de l'acide aspartique, inhibiteurs de la caspase
US7834200B2 (en) 2004-03-12 2010-11-16 Vertex Pharmaceuticals Incorporated Processes and intermediates
EP2295054A1 (fr) 2004-05-27 2011-03-16 Vertex Pharmaceuticals Incorporated Traitement de maladies autoinflammatoires a l'aide d'inhibiteurs de l'ice
US7531570B2 (en) 2004-05-27 2009-05-12 Vertex Pharmaceuticals Incorporated Treatment of diseases using ICE inhibitors
CN101979403A (zh) * 2010-09-13 2011-02-23 沈陵陵 新型半胱氨酸天冬氨酸广谱蛋白酶抑制剂及其制备方法和用途
US9116157B2 (en) 2010-11-05 2015-08-25 Brandeis University Ice-cleaved alpha-synuclein as a biomarker
US9352010B2 (en) 2011-07-22 2016-05-31 The J. David Gladstone Institutes Treatment of HIV-1 infection and AIDS
US9956260B1 (en) 2011-07-22 2018-05-01 The J. David Gladstone Institutes Treatment of HIV-1 infection and AIDS
WO2017081641A1 (fr) 2015-11-13 2017-05-18 Novartis Ag Nouveaux dérivés de pyrazolo-pyrimidine

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FI942061A0 (fi) 1994-05-04
ZA928511B (en) 1994-05-04
PT101027A (pt) 1994-02-28
NO941629L (no) 1994-07-04
FI942061A (fi) 1994-05-04
SK51194A3 (en) 1995-02-08
AU2885292A (en) 1993-06-07
CZ106794A3 (en) 1994-12-15
HU9401303D0 (en) 1994-08-29
NO941629D0 (no) 1994-05-03
GB9123326D0 (en) 1991-12-18
MX9206306A (es) 1993-05-01
NZ244985A (en) 1995-06-27
JPH07500828A (ja) 1995-01-26
HUT68200A (en) 1995-05-29
CA2116653A1 (fr) 1993-05-13
EP0611375A1 (fr) 1994-08-24

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