WO1984000365A1 - Peptides synthetiques et leur preparation - Google Patents

Peptides synthetiques et leur preparation Download PDF

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Publication number
WO1984000365A1
WO1984000365A1 PCT/GB1983/000177 GB8300177W WO8400365A1 WO 1984000365 A1 WO1984000365 A1 WO 1984000365A1 GB 8300177 W GB8300177 W GB 8300177W WO 8400365 A1 WO8400365 A1 WO 8400365A1
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Prior art keywords
group
amino acid
residue
formula
ptg
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PCT/GB1983/000177
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English (en)
Inventor
Ian James Galpin
Anna Halina Wilby
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Nat Res Dev
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Publication date
Priority claimed from GB838306429A external-priority patent/GB8306429D0/en
Application filed by Nat Res Dev filed Critical Nat Res Dev
Publication of WO1984000365A1 publication Critical patent/WO1984000365A1/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
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase

Definitions

  • This invention relates to synthetic peptides and their preparation.
  • Certain micro-organisms have been found to produce both proteinase enzymes, e.g. papain, pepsin, trypsin and chymotrypsin, and inhibitors of these enzymes.
  • proteinase enzymes e.g. papain, pepsin, trypsin and chymotrypsin
  • inhibitors of these enzymes are described by H Umezawa and T Aoyagi in "Proteinases in Mammalian Cells and Tissues", edited by Barrett, Elsevier/North-Holland Biomedical Press 1977, pages 637-646.
  • proteinase inhibitors produced in animal and plant tissue which are proteins, these inhibitors are low molecular weight peptides.
  • the left-hand amino acid is "reverse bonded" via its amino group to the carbonyl group shown.
  • the amino acids are in the form of their L - enantiomers.
  • ["(al)” denotes an aldehyde group in place of a carboxylic acid group].
  • leupeptin analogues differing in their right-hand terminal amino acid residue and, unlike leupeptin, all are reported to be chymotrypsin inhibitors, Ito et al., Biochem. Biophys. Res. Commun. , 49 , 343-349 (1972).
  • the synthetic peptide Ac-Pro-Ala-Pro-Ala (al) is an elastase inhibitor, see R C Thompson, Biochemistry, 12, 47-51 (1973). Because of the specificity of their inhibitory action these proteinase inhibitors are useful in diagnosing the presence of the enzymes, which are involved in a variety of biological functions. Many proteinases are involved in the metabolic pathways associated with degradative diseases.
  • chymotrypsin cleaves the carboxyl link of phenylalanine in peptides and this cleavage is inhibited by chymostatin.
  • the present invention relates to synthetic peptides having inhibitory activity towards (inter alia) chymotrypsin and therefore useful for the above purposes, and in particular for the diagnosis and suppression of chymotrypsin and like enzymes in vitro and in vivo. It is expected that they will be useful in the treatment or muscular dystrophy which is brought about through the action of chymotrypsin on certain peptides in the pathway to this disease.
  • peptides which are compounds of formula (Org). CO. (BAA). (NAA). X' (al) (1) wherein:
  • Org represents an organic residue, preferably a hydrophobic residue
  • BAA represents the residue of a basic acyclic or aromatic amino acid which imparts to the amino acid a pKa of from about 10.5 to about 12.5;
  • NAA represents the residue of a neutral amino acid (being one with no charged side-chain);
  • X' (al) represents a phenylalanine, tyrosine or tryptophan residue in which the terminal carboxyl group has been replaced by an aldehyde group; and the stereochemical configuration of the X' group is of the L-amino acid kind; derivatives thereof having a functionally equivalent derivative of the aldehyde group, for example a semicarbazone (sc) , in place of the aldehyde group and the acid addition salts of any of these compounds.
  • the stereochemical configuration throughout is L, but any one or possibly more of the other groups, i.e. Org, BAA or NAA, can have the D-configuration. While the L-configuration is likely to impart greater binding activity to the peptide, the D- con figuration may serve to block degradation of the peptide by proteinases in vivo. Racemates are of course included in the invention.
  • peptides of the invention contain the residue of a basic acyclic or aromatic amino acid, preferably arginine.
  • the basic amino acid will usually have the formula where R 1 represents an alkylene chain terminated by an amino or guanidine group.
  • the acyclic amino acids are more readily obtainable than capreomycidine, which is the cyclic amino acid present in chymostatin.
  • the neutral amino acid is preferably of formula where R 2 represents a polar or hydrophobic group, normally a hydrocarbyl group, especially alkyl or phenylalkyl. Examples of such amino acids are
  • the organic residue "Org” is preferably a hydrophobic residue which will often be a hydrocarbyl group or an oxyhydrocarbyl group, conveniently a group of formula - O - hydrocarbyl as in two preferred groups, viz. benzoxy and t-butoxy groups.
  • Such groups can arise, of course, through use of the benzyloxycarbonyl and t-butoxycarbonyl protective groups In synthesis.
  • the organic residue can be aliphatic or aromatic and can contain polar groups, e.g. amino or carboxyl, and one preferred such class of residues is amino acids linked via their terminal amino group to the CO group shown in formula (1) .
  • Phenylalanine, leucine, isoleucine and t-butylglycine are examples.
  • a lower alkyl group, especially methyl, is a suitable hydrocarbyl group; phenethyl (Ph-CH 2 -CH 2 -) and adamantyl are others. It can also be a heterocyclic ring-containing group.
  • the length of the main chain of the organic residue does not exceed 10 atoms and is preferably from 1 to 6 atoms, counting the shortest pathway along any ring as part of the chain.
  • the X' group is preferably a phenylalanine-derived residue.
  • aldehyde terminal group or its func tionally equivalent derivative is essential to the inhibitory properties of the compounds.
  • the functional mechanism responsible appears to be formation of a hemiacetal linkage between a hydroxyl group in the active site of the enzyme and the aldehyde group, i.e. of the form:
  • Enz represents the enzyme residue and "Pep” the residue of the peptide of the invention.
  • the hydroxyl group for serine residue No. 195
  • Semicarbazones, hemiacetals and diacetals are considered functionally equivalent derivatives of the aldehyde group.
  • the preferred synthetic peptides of the invention are
  • the acid addition salts can be any desired or convenient.
  • the strongly basic character of the free base makes It easy to acquire acid addition salts in acidic solution and generally the anion can be of any organic or inorganic acid, for example, chloride, bromide, iodide or p-toluene sulphonate.
  • the peptides of the invention are conveniently prepared from a starting compound of formula
  • PTG 1 represents a protecting group for the amine group of the residue X
  • X is an amino acid residue from phenylalanine, tyrosine or tryptophan
  • Y represents hydrogen (completing a terminal carboxyl group) or an ester-forming group, especially a methyl or ethyl group.
  • the starting compound if necessary with its amine group protected, is reduced to the aldehyde in one or more steps to give a compound of formula X' (al) or PTG - X' (al) , respectively, from which the protecting group PTG 1 , if present, is removed.
  • the aldehyde group is protected by any known means, conveniently as the semicarbazone, diacetal or hemiacetal, and the amino acid protecting group is removed.
  • the peptide chain is then built-up by any of the general methods of peptide synthesis which are described in the literature for build-up from the amino acid end. Preferably the build-up is carried out in stages, using In the first stage an amino acid of formula PTG 2 - (NAA)-OH where:
  • PTG 2 is a protecting group for the amino group, and NAA is as defined above, or its functional equivalent, i.e. an activated derivative effective for peptide synthesis, preferably a mixed or symmetrical anhydride or an active ester.
  • the mixed anhydride is suitably formed with pivalic (trimethylacetlc) acid.
  • An active ester would be, for example, an ester formed with p-nitrophenol or 2,4,5-trichlorophenol.
  • the product peptide has the formula: PTG 2 - (NAA) - X'(al) - (AP) where AP is the aldehyde-protecting group. Again, the amine protecting group PTG 2 is removed and the final amino acid or its functional equivalent is added. This amino acid has the formula
  • PTG 3 - (BAA) - OH where PTG 3 is a protecting group for the amine group, and BAA is as defined above.
  • the product is the tripeptide of formula PTG 3 - (NAA) - X'(al) - (AP) which is also part of the present invention, as a useful interme diate.
  • PTG 3 is the group Org. CO. in formula (1) or Is easily convertible thereinto.
  • the aldehyde protecting group is then removed to give the peptide of formula (1) :
  • PTG 1 , PTG 2 and PTG 3 are preferably the same, e.g. benzyloxycarbonyl, and this group can be liberated by hydro genolysis in the presence of p-toluenesulphonic acid (Tos.OH) giving the p-toluene sulphonate quaternary salt (Tos.O-H + ) amine, which is the functional equivalent of the amine.
  • the condensations are preferably carried out in a customary way of using dicyclohexyl carbodiimide (DCCI) with the addition of hydroxybenzotriazole (HO Bt) to suppress racemization.
  • DCCI dicyclohexyl carbodiimide
  • HO Bt hydroxybenzotriazole
  • the free aldehyde is conveniently liberated from its semicarbazone at the end of the synthesis using formaldehyde and acid conditions.
  • gel filtration on "Sephadex LH20” followed by elution with N,N-dimethylformamide (DMF) is very effective.
  • AP are then removed in any customary way, e.g. as described above. It is also possible to synthesise the tripeptide of the invention by building up from the other end, i.e. from a starting amino acid derivative of formula PTG 3 - (BAA) - OH In such a reverse synthesis, the carboxyl group of the incoming amino acid or dipeptide would need to be protected.
  • C-terminal protecting groups well known in peptide chemistry can be used, e.g. methyl, ethyl, phenyl, benzyl or picolyl esters and substituted or unsubstituted amide or hydrazide groups. Additives for preventing racemization are preferably included e.g.
  • the incoming reagent is a dipeptide or when the X amino acid group (preferably phenylalanine) is to be added, the reagent is conveniently terminated by a protected aldehyde group, i.e. is of formula
  • the reaction conditions for the synthesis can be any customary in peptide synthesis and in the reactions of aldehydes, as appropriate.
  • the amino acid build-up can be carried out in solution or with the terminal amino acid or aldehyde attached to a resin.
  • the peptides are normally prepared as their acid addition salts, usually with a monovalent anion and therefore of formula HA where A denotes the anion.
  • the free base would, of course, not be prepared directly from the aldehyde (for fear of It undergoing a Cannizzaro reaction). Rather, the aldehyde would have to be generated as the last step of the synthesis.
  • the present invention also includes a pharmaceutical composition comprising a peptide as defined above as an active component thereof.
  • the compositions may take various forms, including those suitable for both oral and parenteral administration which are of Interest.
  • the peptide is usually formulated with some form of carrier material such as starch, lactose, dextrin, magnesium stearate and the like, whilst for the latter type of composition parenteral administration is of rather more interest, for example Intravenously, intramuscularly or subcutaneously, the peptide then usually being formulated with a diluent which is conveniently sterile and pyrogen-free.
  • Other forms of administration are possible, for example nasally when a diluent is again used, although not necessarily of a sterile and pyrogen-free nature.
  • Figure 2 is a similar graph to Figure 1 but with degree of displacement of chymotrypsin-bound proflavin plotted on the ordinate.
  • the ratio Ve/Vt refers to the ratio of volume of solvent eluted to the total bed volume of the column.
  • the Z.Arg (Tos OH) .Val.Phe semicarbazone (1.35g, 2mM) was dissolved in MeOH (42ml) and 0.5M HCl (20ml) and a 40% solution of formaldehyde (4.4ml) added. The solution was stirred for 4% hours and the course of the reaction monitored by tic The solution was diluted with brine and extracted with ethyl acetate and n-butanol, and combined extracts were then dried (MgSO 4 ) and the solution evaporated. This crude product was purified by gel filtration on Sephadex LH20, eluting with DMF.
  • FAB mass spectrum positive ion mode: m/e 539 (Z.Arg.Val.Phe(al) + 1); 362 (Z.Arg.Val + 1); 291 (Z.Arg + 1); ions also observed at 669 and 595 indicating that some dibutyl acetal was present.
  • the ability of the preferred synthetic tripeptides of the invention and their semicarbazones to bind and inhibit chymo trypsin has been investigated, and compared with the ability shown by chymostatin itself and by corresponding synthetic dipeptides not within the scope of the invention.
  • the effectiveness of the test peptides in binding to and inhibiting chymotrypsin was judged by their effect on the chymotryptic hydrolysis of glutaryl phenylalanine-7-amino-4-methylcoumarin (hereinafter "glutaryl-Phe 7 N Mec" for short) and their ability to displace chymotrypsin bound proflavin.
  • the chymotrypsin used was alpha-chymotrypsin from bovine pancreas and proflavin bought from the Sigma Chemical Company.
  • the N-2-hydroxyethylpiperazine-N-2-ethane sulphonic acid (HEPES) , glutaryl-Phe 7 N Mec and 7-amino-4 methylcoumarin were bought from Cambridge Research Biochemicals Limited. Chymostatin was bought from the Peptide Research Institute, Osaka, Japan. All the synthetic peptides tested were prepared by the present inventors.
  • a Perkin Elmer 3000 Fluorescent Spectrophotometer was used.
  • (1) Inhibiton Assay A series of fluorimeter cuvettes were prepared, each containing:-
  • the addition of chymotrypsin to free solution proflavin has a quenching affect on the fluorescence of the proflavin.
  • the degree of quenching is dependent on the concentration of chymotrypsin and will reach saturation.
  • concentration at which quenching by chymotrypsin reaches saturation is around 200 micromolar.
  • the binding constant is about 35.1 micromolar of chymotrypsin.
  • (b) contained 0.2 ml of chymotrypsin solution (about 13 micromolar) In 1 mM HCl, and aliquots of a solution of test peptide in varied concentrations in DMSO.
  • (c) contained 0.2 ml of chymotrypsin solution (about 13 micromolar) in 1 mM HCl, and aliquots of DMSO only. The level of fluorescence was recorded at an excitation wavelength of 445 nm and an emission wavelength of 504 nm for each concentration of test peptide.
  • the percentage displacement of proflavin was plotted versus the concentration of test peptide.
  • the inhibition constants (K i ) for the binding of the three tripeptide aldehydes were determined at 25oC by the spectrophoto metric measurement at 405 nm of the release of 4-nItroaniline from the substrate N-succinyl-Ala-Ala-Pro-Phe-4-nitroanilide, in 0.05M HEPES buffer, pH 8.0 containing 0.01M CaCl 2 .
  • Chymotrypsin (20 nM) was preincubated for 10 minutes with various concentrations of each inhibitor (added as solutions in dimethylsulphoxide; final concentration 1.0% (v/v).
  • the test enzyme chymotrypsin is a 23,000 molecular weight, pancreatic produced, digestive endopeptidase. As such it is specific for peptide linkages where the carbonyl function is contributed by aromatic amino acid residues, e.g. tyrosine, tryptophan and phenylalanine; but it also catalyses the hydrolysis of esters and amides of such amino acids. It may best be described therefore, as a transferer of acyl groups to acyl receptors. It possesses a hydrophobic binding site for the aromatic amino acid, and. a catalytic site for the removal and transfer of the acyl group. This catalytic site consists of three main residues forming a charge relay complex.
  • Serine 195 possesses a hydroxyl group which forms a hydrogen bond with the imidazole ring of Histidine 57, and this in turn forms another hydrogen bond with the carboxylate group of Aspartate 102. These interactions make use of the hydroxyl group on Serine 195 as a nucleophile.
  • the hydrophobic binding site first recognises and binds to an aromatic amino acid, and then the nucleophilic hydroxyl group attacks the carbon atom involved in the peptide linkage. This leads to the breaking of the link, the formation of an acyl enzyme complex and the release of a leaving group, which in the case of glutaryl-Phe 7 N Mec is the fluorescent product 7-amino-4-methylcoumarin.
  • the acyl enzyme complex is later hydrolysed to give back the enzyme and release an acyl group.
  • the phenylalanine aldehyde group possessed by chymostatin, and two of the synthetic peptides, Z-Arg-Leu-Phe aldehyde and Z-Leu-Phe aldehyde, apparently forms a hemiacetal linkage with the hydroxyl group of Serine 195 and thus prevents chymotrypsin from catalysing substrate hydrolysis.
  • Z-Arg-Leu-Phe aldehyde and Z-Leu-Phe aldehyde differ only in the presence of the basic amino acid arginine, yet Z-Arg-Leu-Phe aldehyde is approximately seventy times more effective as an inhibitor of chymotrypsin activity (Table 1).
  • this basic amino acid improves the effeciency of inhibition, and possibly it is the presence of arginine that allows the trlpeptide semicarbazones to function as a chymotrypsin inhibitor.
  • arginine that allows the trlpeptide semicarbazones to function as a chymotrypsin inhibitor.
  • the basic amino acid present is capreomycidine, but this cannot conveniently be synthesized. It is therefore an important achievement of the present invention to find that the capreomycidine can be replaced by a basic amino acid which can be synthesized easily.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

L'enzyme chymotrypsine possède de nombreuses fonctions biologiques. Il serait utile d'inhiber cet enzyme dans un but thérapeutique et pour effectuer des diagnostics. Il est toutefois difficile à synthétiser, car il contient l'acide aminé capréomycidine. La présente invention permet de produire des peptides qui sont des inhibiteurs alternatifs de la chymotypcine et peuvent être synthétisées plus facilement que la chymostatine. Les peptides de la présente invention sont des composés correspondants à la formule (Org). CO. (BAA). (NAA). X' (al) dans laquelle Org représente un reste organique, de préférence un groupe hydrocarbyle ou oxyhydrocarbyle; BAA représente le reste d'un acide aminé aromatique ou acyclique basique qui confère à l'acide aminé un pKa compris entre 10,5 environ et 12,4 environ et est de préférence un reste de lysine, arginine or ornithine; NAA représente le reste d'un acide aminé neutre (dépourvu de chaîne latérale chargée) et est de préférence une leucine, une valine, une isoleucine ou une phénylalanine; X' (al) représente un reste de phénylalanine, tyrosine ou tryptophane dans lequel le groupe carboxyle terminal a été remplacé par un groupe aldéhyde, et la configuration stéréochimique du groupe X' au moins, et de préférence la configuration générale est celle de l'acide aminé L; les dérivés de ce composé possèdent un dérivé du groupe aldéhyde à fonction équivalente à la place du groupe aldéhyde et des sels acides d'addition de n'importe lequel de ces composés. Les peptides peuvent être synthétisées par des procédés simples et conventionnels. Ils sont utiles dans le diagnostic de la chymotypsine et dans des applications thérapeutiques, par exemple dans le traitement de la dystrophie musculaire.
PCT/GB1983/000177 1982-07-19 1983-07-18 Peptides synthetiques et leur preparation WO1984000365A1 (fr)

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GB838306429A GB8306429D0 (en) 1983-03-09 1983-03-09 Synthetic peptides

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0342541A2 (fr) * 1988-05-13 1989-11-23 Abbott Laboratories Inhibiteurs de protéases rétrovirales
EP0363284A2 (fr) * 1988-10-07 1990-04-11 Merrell Pharmaceuticals Inc. Utilisation des inhibiteurs de peptidase pour la préparation de médicaments utiles dans le traitement de l'apoplexie
WO1990013561A1 (fr) * 1989-04-28 1990-11-15 The Boots Company Plc Agent therapeutique
WO1992014696A2 (fr) * 1991-02-22 1992-09-03 The Du Pont Merck Pharmaceutical Company α-AMINOALDEHYDES SUBSTITUES ET LEURS DERIVES
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
US5691368A (en) * 1995-01-11 1997-11-25 Hoechst Marion Roussel, Inc. Substituted oxazolidine calpain and/or cathepsin B inhibitors
US5736520A (en) * 1988-10-07 1998-04-07 Merrell Pharmaceuticals Inc. Peptidase inhibitors
US5760002A (en) * 1992-12-22 1998-06-02 The Proctor & Gamble Company Diflouro pentapeptide derivative anti-inflammatory agents
US5977074A (en) * 1993-10-01 1999-11-02 Merrell Pharmaceuticals, Inc. Inhibitors of β-amyloid protein production

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2759895B2 (ja) * 1991-08-30 1998-05-28 サノフィ インターロイキン１βプロテアーゼをコードするＤＮＡ配列単離体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046742A1 (fr) * 1980-08-25 1982-03-03 KabiVitrum AB Substrats peptidiques pour la détermination de l'activité de protéases
FR2490632A1 (fr) * 1980-09-19 1982-03-26 Nippon Kayaku Kk Derives de l-argininal et procede de preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046742A1 (fr) * 1980-08-25 1982-03-03 KabiVitrum AB Substrats peptidiques pour la détermination de l'activité de protéases
FR2490632A1 (fr) * 1980-09-19 1982-03-26 Nippon Kayaku Kk Derives de l-argininal et procede de preparation

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415981A1 (fr) * 1988-05-13 1991-03-13 Abbott Laboratories Inhibiteurs de protease retrovirale
EP0342541A2 (fr) * 1988-05-13 1989-11-23 Abbott Laboratories Inhibiteurs de protéases rétrovirales
EP0415981A4 (en) * 1988-05-13 1991-10-09 Abbott Laboratories Retroviral protease inhibitors
EP0342541A3 (fr) * 1988-05-13 1991-11-06 Abbott Laboratories Inhibiteurs de protéases rétrovirales
EP0363284A3 (fr) * 1988-10-07 1992-07-01 Merrell Pharmaceuticals Inc. Utilisation des inhibiteurs de peptidase pour la préparation de médicaments utiles dans le traitement de l'apoplexie
EP0363284A2 (fr) * 1988-10-07 1990-04-11 Merrell Pharmaceuticals Inc. Utilisation des inhibiteurs de peptidase pour la préparation de médicaments utiles dans le traitement de l'apoplexie
US5736520A (en) * 1988-10-07 1998-04-07 Merrell Pharmaceuticals Inc. Peptidase inhibitors
LT3827B (en) 1989-04-28 1996-03-25 Boots Co Plc Chimopapaine, pharmaceutical compositions containing thereof, process for purification of chimopapaine, inhibiting peptides and chromatographic carriers
GR900100315A (en) * 1989-04-28 1991-09-27 Boots Co Plc Therapeutic agent
WO1990013561A1 (fr) * 1989-04-28 1990-11-15 The Boots Company Plc Agent therapeutique
US5380656A (en) * 1989-04-28 1995-01-10 The Boots Company Plc Chymopapain and method of purifying it on an inhibitory dipeptide affinity column
US5468480A (en) * 1989-04-28 1995-11-21 The Boots Company Plc Pharmaceutical composition of purified chymopapain
WO1992014696A3 (fr) * 1991-02-22 1993-02-18 Du Pont Merck Pharma α-AMINOALDEHYDES SUBSTITUES ET LEURS DERIVES
WO1992014696A2 (fr) * 1991-02-22 1992-09-03 The Du Pont Merck Pharmaceutical Company α-AMINOALDEHYDES SUBSTITUES ET LEURS DERIVES
US5760002A (en) * 1992-12-22 1998-06-02 The Proctor & Gamble Company Diflouro pentapeptide derivative anti-inflammatory agents
US5498728A (en) * 1993-02-19 1996-03-12 Takeda Chemical Industries, Ltd. Derivatives of L-tryptophanal and their use as medicinals
US5716980A (en) * 1993-02-19 1998-02-10 Takeda Chemical Industries, Ltd. Alcohol or aldehyde derivatives and their use
EP0611756A3 (fr) * 1993-02-19 1994-11-30 Takeda Chemical Industries Ltd Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse.
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse
US5977074A (en) * 1993-10-01 1999-11-02 Merrell Pharmaceuticals, Inc. Inhibitors of β-amyloid protein production
US5691368A (en) * 1995-01-11 1997-11-25 Hoechst Marion Roussel, Inc. Substituted oxazolidine calpain and/or cathepsin B inhibitors

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GB8319305D0 (en) 1983-08-17
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