WO1994025049A1 - Acide boronique a substitution amidino et guanidino en tant qu'inhibiteur d'enzymes de type trypsine - Google Patents

Acide boronique a substitution amidino et guanidino en tant qu'inhibiteur d'enzymes de type trypsine Download PDF

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WO1994025049A1
WO1994025049A1 PCT/US1994/004058 US9404058W WO9425049A1 WO 1994025049 A1 WO1994025049 A1 WO 1994025049A1 US 9404058 W US9404058 W US 9404058W WO 9425049 A1 WO9425049 A1 WO 9425049A1
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pro
phe
borophe
nhc
alkyl
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PCT/US1994/004058
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John Matthew Fevig
Charles Adrian Kettner
Sheng-Lian O. Lee
David John Carini
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The Du Pont Merck Pharmaceutical Company
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Priority to JP6524316A priority Critical patent/JPH08509723A/ja
Priority to AU67038/94A priority patent/AU6703894A/en
Priority to CA002161216A priority patent/CA2161216A1/fr
Priority to EP94914776A priority patent/EP0696199A4/fr
Publication of WO1994025049A1 publication Critical patent/WO1994025049A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • 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 generally to ⁇ -aminoboronic acids and corresponding peptide analogs in which the alpha substituent is either an aromatic guanidino, isothiouronium, amidino group, halogen, cyano group or an aliphatic amidino, isothiouronium, or formamidino group.
  • Simple boronic acids are inhibitors of serine proteases.
  • Koehler et al. Biochemistry 10: 2477 (1971) reports that 2-phenylethane boronic acid inhibits chymotrypsin at millimolar levels.
  • ⁇ -aminoboronic acids The chemistry of ⁇ -aminoboronic acids was further expanded to the synthesis of peptide analogs containing boronic acid with positive charged sidechains, boroLysine, boroArginine, boroOrnithine, and isothiouronium analogs (EPA 0 293 881, 12/7/88).
  • This series of compounds have provided highly effective inhibitors of thrombin and other trypsin-like enzymes.
  • the boroArginine analogs specifically designed as thrombin inhibitors are highly effective in the
  • this group of compounds is extended to aliphatic amidino and formamidino, to aromatic amidino and guanidino, and to cyano and halogen substituted aromatic boronic acid analogs.
  • boroLysine which contain at least one unnatural amino acid residue.
  • Elgendy et al. Tetrahedron Lett . , 33, 4209-4212 (1992) have described peptides containing ⁇ -aminoboronic acids with aliphatic neutral sidechains which are thrombin inhibitors.
  • Kakkar in (WO 92/07869) has claimed peptide thrombin inhibitors of the general structure, X-Aa 1 -Aa 2 -NH-CH(Y)-Z where Aai and Aa 2 are unnatural amino acid residues.
  • Z is -CN, -COR,
  • aryl is phenyl or napthyl
  • halo F, Cl, Br, I
  • C1-C4-alkyl C1-C4-alkoxy, -NO 2 , -CF 3 , -S(O) r -C1-C4-alkyl, -OH, -NH 2 , -NH(C1-C4-alkyl), -N(C1-C4-alkyl) 2 , -CO 2 R 4 , or
  • R 3 is H, alkyl, aryl, alkylaryl, or an NH 2 -blocking group comprised of 1-20 carbon atoms;
  • R 4 and R 5 are independently
  • aryl is phenyl or napthyl
  • halo F, Cl, Br, I
  • C1-C4-alkyl C1-C7-alkoxy, -NO 2 , -CF 3 , -S(O) r -C1-C4-alkyl, -OH, -NH 2 , -NH (C1-C4-alkyl), -N(C1-C4-alkyl) 2 , -CO 2 R 4 , or
  • A is an amino acid residue or a peptide comprised of 2-20 amino acid residues
  • Y 1 and Y 2 when taken together Y 1 and Y 2 form a d) cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O,
  • n 0 or 1
  • p 0 to 3;
  • q 0 to 4.
  • r is 0 to 2;
  • R 2 is H
  • A is Pro or (D)Phe-Pro
  • Illustrative of the preferred compounds of this invention are the following: ⁇ Ac-(D)Phe-Pro-NH-CH[(CH 2 ) 4 CN]BO 2 -C 10 H 16
  • compositions comprising one or more of the foregoing compounds and methods of using such compositions in the treatment of aberrant proteolysis such as thrombosis in mammals or as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.
  • Trp L-tryptophan
  • boronic acid is in the form of the free acid.
  • the pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated "-C 10 H 16 " and
  • CH NH
  • BSA benzene sulfonic acid
  • THF tetrahydrofuran
  • Boc- t-butoxycarbonyl-
  • Ac- acetyl
  • pNA p-nitro-aniline
  • the compounds of the present invention contain one or more chiral centers and that these stereoisomers may possess distinct physical and biological properties.
  • the present invention comprises all of the stereoisomers or mixtures thereof.
  • the pure enantiomers or diasteromers may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard
  • NH 2 -blocking group refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substitutes on these groups maybe either alkyl, aryl, alkylaryl which may contain the heteroatoms, O, S, and N as a substituent or as inchain component.
  • alkyl, aryl, alkylaryl which may contain the heteroatoms, O, S, and N as a substituent or as inchain component.
  • a number of NH 2 -blocking groups are recognized by those skilled in the art of organic synthesis. By definition, an NH 2 -blocking group may be removable or may remain
  • suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; alkyl and alkylaryl sulfonyl groups, such as n-propylsulfonyl, phenylmethyl and benzylsulfonyl; aromatic urethane protecting groups, such as, benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl or
  • amino acid residues refers to natural or unnatural amino acids of either D- or L-configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Ile, Irg
  • amino acids residues also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art.
  • the Peptides Vol 3, 3-88 (1981) discloses numerous suitable protecting groups and is incorporated herein by reference for that purpose.
  • Novel peptide boronic acids containing aliphatic sidechains were prepared by the series of reactions outlined in Scheme I.
  • An example of this product is 1 where the above intermediate is coupled to Ac-(D)Phe-Pro-OH. 1 was converted to the corresponding alkyl cyanide 2. by treatment with
  • the formamidino substituted boronic acid, 5 was prepared by the synthesis of the corresponding alkyl amine such as Ac-(D)Phe-Pro-boroOrn-C 10 H 16 4, Scheme 2 This in turn was prepared by treating 1 with sodium azide followed by hydrogenation (Kettner et al., 1990) The amine, 4, was treated with ethyl formimidate to yield the formamidino compound, 5.
  • N-substituted isothiouronium derivatives and N-substituted guanidines are readily prepared as shown in Scheme 2a.
  • Treatment of bromide 1 with a thiourea produces directly the isothiouronium 21.
  • Alternatively 1 can be converted to the amine 4 as shown in Scheme 2.
  • the amine A then is heated with a formamidinesulfonic acid in the presence of 4-DMAP to afford the guanidine 22 .
  • the required formamidinesulfonic acids can be prepared by oxidation of the corresponding thioureas, see: Walter and Randau, Liebigs Ann . Chem . 722, 98 (1969).
  • the substituted boronic acid, 7, is prepared by treating 4 with dimethyl cyanodithioiminocarbonate or diphenyl cyanodicarbonimiate to yield the S-methyl isourea (6) or O-phenyl isourea, respectively, using a procedure similar to that reported by Barpill et al. J. Hereocycli c Chem . 25, 1698 (1988), Scheme 3. This intermediate is treated with ammonia in either THF or alcohol to yield the desired product.
  • the aromatic substituted cyanides, H were converted to the corresponding amidino compound, 12 , using the same sequence of reactions described for preparation of the aliphatic amidino compound, 3 .
  • Aromatic guanidino inhibitors 20, were prepared from precursor R-boroPhe-C 10 H 16 .
  • scheme 7. The aromatic ring was nitrated by reaction with NO + BF 4- to yield 18. which was reduced to the corresponding amine, 19.
  • the amine is converted to the guanidine by reaction with aminoiminomethane sulfonic acid [Mosher et al.
  • nitrile (Example 1, 0.40 g, 0.70 mmol) was dissolved in 50 mL of a cold solution of saturated HCI in methanol and the solution was stirred overnight at 4°C. The solution was then concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (50 mL), gaseous NH 3 was bubbled through the solution for 1 h, and the solution was heated at 50 °C for 3 h. Solvent was evaporated, the residue was suspended in minimum volume of methanol, and 0.11 g of benzenesulfonic acid (1 eq) was added. Methanol was evaporated and the residue was triturated with hexane to yield the desired product as a pale yellow powder (0.52 g, 99 % yield).
  • Ethyl formimidate ⁇ HCl was prepared by the procedure of Ohme and Schmitz Angew. Chem. Internat . Edit . 6 566 (1967) and Ac-(D)Phe-Pro-boroOrn-C 10 H 16 was prepared by the procedure of Kettner et al. (1990).
  • the formimidate (1.29 g, 11.7 mmol) and 4-N,N-dimethylaminopyridine (1.44 g) were added to a solution of Ac-(D)Phe-Pro-boroOrn-C 10 H 16 ⁇ BSA (2.78 g, 3.92 mmol) dissolved in 40 mL of ethanol.
  • the resulting solution was refluxed for 8 h. After removal of solvent, the residue was purified by chromatography using a column of SephedexTMLH 20 and methanol as a solvent to give pure product (1.28 g, 56 % yield).
  • Boc-Pro-boroOrn-C 10 H 10 ⁇ BSA was also prepared by the procedure described previously (Kettner et al. 1990). This peptide (3.0 g, 6.5 mmol) was dissolved in 25 mL of absolute ethanol, 4-N,N-dimethylaminopyridine (1.6 g, 12.9 mmol) and ethyl formimidate»HCl (1.4 g, 12.9 mmol) were added. The solution was heated on a 85 °C oil bath for 1 h. Solvent was evaporated and the residue was dissolved in methanol and was chromatogramed on a 2.5 X 100 cm column of LH20 in methanol to yield 1.3 g of the desired product.
  • Boc-(P)Phe-Pro-NHCH[(CH 2 ) 3 -NHC(NH)H]B(OH) 2 Boc-(D)Phe-Pro-NHCH[(CH 2 ) 3 - NHC(NH)H]BO 2 -C 10 H 16 .
  • 0.40 BSA, 0.60 HCI (Example 6, 0.16 g, 0.22 mmol) and phenyl boronic acid (0.13g, 1.1 mmol) were placed in mixture of 5 mL of ether and 5 mL of water and was allowed to stir for 4 h at room
  • the first intermediate, Cl-CH[CH 2 -(m-cyanophenyl)]BO 2 -C 10 H 16 was prepared from m-cyanobenzyl bromide and dichloromethyl boronate pinanediol.
  • Zinc dust (1.0 g) in 1 mL of THF was cooled to 0-5°C and a solution of m-cyanobenzyl bromide (1.37 g, 7.0 mmol) in 7 mL of THF was added dropwise (5 sec/drop). The reaction mixture was allowed to stir at 5°C for 2 h.
  • Cl-CH[CH 2 -(m-bromo-phenyl)]BO 2 -C 10 H 16 was prepared making the anion of m-bromobenzyl bromide and coupling it to dichloromethyl boronic acid pinanediol. This intermediate and the corresponding amine were prepared using the procedure described for Example 10. The amine was coupled to Ac-(D)Phe-Pro-OH using the method
  • the above product (0.060 g, 0.080 mmol) was dissolved in 0.5 mL of THF and was allowed to react with 1 equivalent of 30% aqueous ammonia for 30 min at room temperature. Four additional equivalent of ammonia were added and the solution was allowed to stir overnight at room temperature. A large excess of ammonia was added and the reaction mixture was allowed to stir 2 days at room temperature. The reaction mixture was diluted with methylene chloride and was washed with water and
  • ClCH[CH 2 C 6 H 4 -p-CN]BO 2 C 10 H 16 was prepared by making the anion of p-cyanobenzyl bromide and coupling it to dichloromethyl boronate pinanediol. This intermediate and the corresponding amine were prepared using the procedure described for Example 10. NH 2 CH [CH 2 C 6 H 4 -p-CN]BO 2 C 10 H 16 (Example 78) was coupled to Ac-(D)Phe-Pro-OH using the method described in Example 11.
  • Boc-(D)Phe-Pro-boroPhe(mCN)-C 10 H 16 was prepared by reacting Boc-(P)Phe-Pro-OH (0.43 g, 1.2 mmol), H-boroPhe(mCN)-C 10 H 16 ⁇ HCl (0.42 g, 1.2 mmol), N-methylmorpholine (0.26 mL, 2.4 mmol),
  • cyanoborohydride (0.080 g, 1.3 mmol) was added and after 5 min glacial acetic acid (20 ⁇ L) were added. The reaction pH was ⁇ 7. After 5 h, additional acetic acid (20 ⁇ L) were added and the mixture was stirred for 1 h. The reaction mixture was poured into 20 mL of ethyl acetate and the organic phase was washed with 10 mL of saturated aqueous sodium chloride and dried over
  • the chloroform solution was washed with ice-cold 0.1 N hydrochloric acid (2 X 3 mL), ice-cold water (2 X 3 mL), and brine. The resulting organic solution was then dried over anhydrous magnesium sulfate, filtered, and
  • N-Acyl and N-peptide boronic acids which are described in the present invention represent a novel class of potent, reversible inhibitors of trypsin-like enzymes.
  • Trypsin-like enzymes are a group of proteases which hydrolyzed peptide bonds at basic residues
  • enzymes of the blood coagulation and fibrinolytic system required for hemostasis are enzymes of the blood coagulation and fibrinolytic system required for hemostasis. They are Factors II, X, VII, IX, XII, kallikrein, tissue
  • plasminogen activators urokinase-like plasminogen activator, and plasmin.
  • Enzymes of the complement system, acrosin (required for fertilization), pancreatic trypsin are also in this group. Elevated levels of proteolysis by these proteases can result in disease states. For example, consumptive coagulopathy, a condition marked by a decrease in the blood levels of enzymes of both the coagulation system, the fibrinolytic system and accompanying protease inhibitors is often fatal. Intervention by a synthetic inhibitor would clearly be valuable. More specifically, proteolysis by thrombin is required for blood clotting. Inhibition of thrombin results in an effective inhibitor of blood clotting. The importance of an effective inhibitor of thrombin is underscored by the observation that
  • the compounds of this invention When used in the processing of blood products, the compounds of this invention may be mixed with whole blood without the need for any additional
  • the compounds of this invention serve to inhibit blood coagulation thereby facilitating the processing of whole blood into desired cellular
  • the compounds may be removed, if so desired, by membrane ultrafiltration, dialysis, or diafiltration to afford the desired product.
  • membrane ultrafiltration dialysis, or diafiltration to afford the desired product.
  • anticoagulants like heparin allow them to be separated from desired products more easily.
  • v o is the velocity of the control in the absence of inhibitor
  • v s is the velocity in the presence of inhibitor
  • I is the concentration of inhibitor
  • K i is the dissociation constant of enzyme: inhibitor complex
  • S is the concentration of substrate
  • K m is the Michaelis constant
  • Plasma was prepared by diluting blood 1:10 with 3.2% aqueous citric acid and centrifuging. Buffer consisted of 0.10 M Tris, pH 7.4, containing 0.9% sodium chloride, and 2.5 mg/mL bovine serum albumin. Bovine thrombin was obtained from
  • Plasma (200 ⁇ L) and buffer (50 ⁇ L) containing inhibitor were
  • thrombin 50 ⁇ L
  • clotting times were measured. Controls were run under identical conditions except in the absence of inhibitor. The final concentration of thrombin was 4 NIH units/mL.
  • Ki values were measure at 25 °C at pH 7.5.
  • IC50 level of inhibitor required to prolong clotting to the time observed for 2 NIH units/mL thrombin in the absence of inhibitor.
  • Examples 4, 57, and 77 were shown to be effective following i.v. dosing and Examples 4, 56, 57, 60, and 66 effective following oral dosing.
  • oral administration of Examples 31 and 54 resulted in at least a 2-fold elevation in anticoagulant activity in an identical model except activity was measured by increases in thrombin clotting times.

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Abstract

Nouvel acide α-aminoboronique et analogues peptidiques correspondants de la formule (I).
PCT/US1994/004058 1993-04-27 1994-04-21 Acide boronique a substitution amidino et guanidino en tant qu'inhibiteur d'enzymes de type trypsine WO1994025049A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP6524316A JPH08509723A (ja) 1993-04-27 1994-04-21 アミジノおよびグアニジノ置換ボロン酸トリプシン様酵素阻害剤
AU67038/94A AU6703894A (en) 1993-04-27 1994-04-21 Amidino and guanidino substituted boronic acid inhibitors of trypsin-like enzymes
CA002161216A CA2161216A1 (fr) 1993-04-27 1994-04-21 Inhibiteurs d'enzymes de type tryspine, a base de derives de substitution amidino et guanidino d'acide borique
EP94914776A EP0696199A4 (fr) 1993-04-27 1994-04-21 Acide boronique a substitution amidino et guanidino en tant qu'inhibiteur d'enzymes de type trypsine

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US5283593A 1993-04-27 1993-04-27
US08/052,835 1993-04-27
US20405594A 1994-03-02 1994-03-02
US08/204,055 1994-03-02

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0688788A1 (fr) * 1994-06-22 1995-12-27 Adir Et Compagnie Dérivés peptidiques de l'acide boronique ayant une activité inhibitant de protéase, leur procédé de préparation et les composition et les compositions pharmaceutiques les contenants
EP0724446A1 (fr) * 1993-10-07 1996-08-07 The Du Pont Merck Pharmaceutical Company Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine
US5561146A (en) * 1994-06-10 1996-10-01 Bristol-Myers Squibb Company Modified guanidino and amidino thrombin inhibitors
FR2739858A1 (fr) * 1995-10-11 1997-04-18 Synthelabo Derives de n-sulfonyl- et n-sulfamoylpeptidylprolinamide, leur preparation et leur application en therapeutique
WO2001027138A2 (fr) * 1999-10-13 2001-04-19 Tularik Inc. Modulateurs de traitement de srebp
US6239150B1 (en) 1995-07-26 2001-05-29 Mitsubishi Chemical Corporation Penicillaminamide derivatives
EP1396269A1 (fr) 2002-09-09 2004-03-10 Trigen Limited Sels d'acide boronique des metaux multivalents et leur utilisation dans la préparation de médicaments pour le traitement de la thrombose
US6933290B2 (en) 2001-05-30 2005-08-23 Novartis Ag 2-{N-(2-amino-3-(heteroaryl or aryl)propionyl)-aminoacyl}-amino}-alkylboronic acid derivatives
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7223745B2 (en) 2003-08-14 2007-05-29 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US7576206B2 (en) 2003-08-14 2009-08-18 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US8283367B2 (en) 2005-02-11 2012-10-09 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US8541590B2 (en) 2009-12-22 2013-09-24 Cephalon, Inc. Proteasome inhibitors and processes for their preparation, purification and use
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives

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EP0724446A1 (fr) * 1993-10-07 1996-08-07 The Du Pont Merck Pharmaceutical Company Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine
EP0724446A4 (fr) * 1993-10-07 1998-01-07 Du Pont Merck Pharma Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine
US5561146A (en) * 1994-06-10 1996-10-01 Bristol-Myers Squibb Company Modified guanidino and amidino thrombin inhibitors
EP0688788A1 (fr) * 1994-06-22 1995-12-27 Adir Et Compagnie Dérivés peptidiques de l'acide boronique ayant une activité inhibitant de protéase, leur procédé de préparation et les composition et les compositions pharmaceutiques les contenants
US6239150B1 (en) 1995-07-26 2001-05-29 Mitsubishi Chemical Corporation Penicillaminamide derivatives
FR2739858A1 (fr) * 1995-10-11 1997-04-18 Synthelabo Derives de n-sulfonyl- et n-sulfamoylpeptidylprolinamide, leur preparation et leur application en therapeutique
WO2001027138A2 (fr) * 1999-10-13 2001-04-19 Tularik Inc. Modulateurs de traitement de srebp
WO2001027138A3 (fr) * 1999-10-13 2001-11-29 Tularik Inc Modulateurs de traitement de srebp
US6649593B1 (en) 1999-10-13 2003-11-18 Tularik Inc. Modulators of SREBP processing
US6933290B2 (en) 2001-05-30 2005-08-23 Novartis Ag 2-{N-(2-amino-3-(heteroaryl or aryl)propionyl)-aminoacyl}-amino}-alkylboronic acid derivatives
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations
EP1396269A1 (fr) 2002-09-09 2004-03-10 Trigen Limited Sels d'acide boronique des metaux multivalents et leur utilisation dans la préparation de médicaments pour le traitement de la thrombose
EP1466917A1 (fr) 2002-09-09 2004-10-13 Trigen Limited Procédé der préparation des acides boroniques peptidiques et acides obtenus
US8058262B2 (en) 2003-08-14 2011-11-15 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US7576206B2 (en) 2003-08-14 2009-08-18 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US7915236B2 (en) 2003-08-14 2011-03-29 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US7223745B2 (en) 2003-08-14 2007-05-29 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US8546608B2 (en) 2003-08-14 2013-10-01 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US9233115B2 (en) 2003-08-14 2016-01-12 Millennium Pharmaceuticals Inc. Proteasome inhibitors and methods of using the same
US8283367B2 (en) 2005-02-11 2012-10-09 Cephalon, Inc. Proteasome inhibitors and methods of using the same
US8541590B2 (en) 2009-12-22 2013-09-24 Cephalon, Inc. Proteasome inhibitors and processes for their preparation, purification and use
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
US11866422B2 (en) 2016-06-21 2024-01-09 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives

Also Published As

Publication number Publication date
JPH08509723A (ja) 1996-10-15
CA2161216A1 (fr) 1994-11-10
TW286318B (fr) 1996-09-21
AU6703894A (en) 1994-11-21
IL109319A0 (en) 1994-07-31
EP0696199A1 (fr) 1996-02-14
EP0696199A4 (fr) 1997-06-25

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