WO1996031504A1 - Inhibiteurs de thrombine - Google Patents

Inhibiteurs de thrombine Download PDF

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Publication number
WO1996031504A1
WO1996031504A1 PCT/US1996/004460 US9604460W WO9631504A1 WO 1996031504 A1 WO1996031504 A1 WO 1996031504A1 US 9604460 W US9604460 W US 9604460W WO 9631504 A1 WO9631504 A1 WO 9631504A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
ring
hydrogen
heterocyclic ring
bicyclic heterocyclic
Prior art date
Application number
PCT/US1996/004460
Other languages
English (en)
Inventor
Dong-Mei Feng
Mark G. Bock
Roger M. Freidinger
Joseph P. Vacca
Bruce D. Dorsey
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP96911520A priority Critical patent/EP0820453A4/fr
Priority to AU54385/96A priority patent/AU698911B2/en
Priority to JP8530408A priority patent/JPH11503161A/ja
Publication of WO1996031504A1 publication Critical patent/WO1996031504A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • 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
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • 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
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.
  • European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
  • Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or ⁇ -keto carboxyl derivatives.
  • Thrombin inhibitors described in prior publications contain sidechains of arginine and lysine. These structures show low selectivity for thrombin over other trypsin-like enzymes. Some of them show toxicity of hypotension and liver toxicity.
  • European Publication 601 459 describes sulfonamido heterocyclic thrombin inhibitors, such as N-[4-f(aminoimino- methyl)amino]butyl]- 1 -[N-(2-naphthalenyIsulfonyl)-L-phenylalanyl]-L- prolinamide.
  • WO 94/29336 describes compounds which are useful as thrombin inhibitors.
  • A is C or N:
  • X 1 , X 2 and X 3 are independently selected from the group consisting of
  • Y attached to a ring carbon atom, is H, NH 2 or OH:
  • Z is -(CH 2 ) 1 -3-;
  • R 1 , R 2 , and R 2' are independently
  • a 5- to 10-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • R 1 may be joined with R 2 to form a four- to seven membered carbon ring in which zero to two carbon atoms may be substituted with heteroatoms independently selected from the list N, O and S, where n is 1 , 2, 3 or 4;
  • R 3 is hydrogen
  • R 2' OCONH, provided R 2' is not hydrogen.
  • R 2' SO 2 NH provided R 2' is not hydrogen, or
  • a 5- to 10-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • R7 is same or different
  • D is -CH 2 CH 2 -, -CH 2 -O-CH 2 -, or -CH 2 -NH-CH 2 -
  • R 6 is C 1 -4 alkyl
  • R 7 is hydrogen or C 1 -4 alkyl
  • G is (CH 2 ) q where q is 1 or 2; or
  • Trypsin-like enzymes (such as trypsin, thrombin, factor xa, kallikrein, plasmin, urokinase, and plasminogen activator) are serine dependent enzymes that catalyze hydrolysis at arginyl and lysyl peptide bonds.
  • the invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
  • the invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation. ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
  • the invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface. either covalently or noncovalently, a compound of the invention.
  • A is C or N
  • X 1 , X 2 and X 3 are independently selected from the group consisting of
  • Y attached to a ring carbon atom, is H, NH 2 or OH;
  • Z is -(CH 2 ) 1 -3-;
  • R 1 , R 2 , and R 2' are independently
  • phenyl mono- or di-halogenated phenyl
  • a 5- to 10-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • R 1 may be joined with R 2 to form a four- to seven membered carbon ring in which zero to two carbon atoms may be substituted with heteroatoms independently selected from the list N, O and S, where n is 1 , 2, 3 or 4;
  • R 3 is hydrogen
  • R 2' OCONH, provided R 2' is not hydrogen.
  • R 2' SO 2 NH provided R 2' is not hydrogen, or
  • R 4 is independently phenyl
  • a 5- to 10-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, OandS,
  • R7 is same or different
  • D is -CH 2 CH 2 -, -CH 2 -O-CH 2 -, or -CH 2 -NH-CH 2 -;
  • R 6 is C 1-4 alkyl
  • R 7 is hydrogen or C 1-4 alkyl
  • G is (CH 2 ) q where q is 1 or 2; or
  • Q is SCH 2 , or (CH 2 ) r where r is 1 or 2, and pharmaceutically acceptable salts thereof.
  • compounds of the invention have the following structure:
  • A is C or N
  • X 1 , X 2 and X 3 are independently selected from the group consisting of
  • Y attached to a ring carbon atom, is hydrogen, NH 2 or OH;
  • R 1 , R 2 , and R 2' are independently
  • a 5- to 7-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • R 1 may be joined with R 2 to form a four- to seven membered carbon ring in which zero to two carbon atoms may be substituted with heteroatoms independently selected from the list N, O and S. where n is 1 , 2, 3 or 4; R 3 is
  • R 2' OCONH, provided R 2' is not hydrogen
  • R 2' SO 2 NH provided R 2' is not hydrogen, or
  • a 5- to-7- membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated. and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • G is (CH 2 ) q where q is 1 or 2; or
  • A is C or N:
  • X 1 and X 2 are independently selected from the group consisting of
  • Y attached to a ring carbon atom, is hydrogen, NH 2 or OH;
  • R 1 , R 2 , and R 2' are independently
  • a 5- to 7-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • R 1 may be joined with R 2 to form a four- to seven membered carbon ring in which zero to two carbon atoms may be substituted with heteroatoms independently selected from the list N, O and S, where n is 1 , 2, 3 or 4;
  • R 2' OCONH, provided R 2' is not hydrogen
  • R 2' SO 2 NH provided R 2' is not hydrogen, or
  • R 4 is independently
  • a 5- to-7- membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • G is (CH 2 ) q where q is 1 or 2; or
  • Y attached to a ring carbon atom, is hydrogen or NH 2 ;
  • R 1 , R 2 , and R 2' are independently
  • phenyl mono- or di-halogenated phenyl
  • a 5- to 7-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated. and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • R 1 may be joined with R 2 to form a four- to seven membered carbon ring in which zero to two carbon atoms may be substituted with heteroatoms independently selected from the list N, O and S, where n is 1 , 2, 3 or 4;
  • R 2' OCONH, provided R 2' is not hydrogen
  • R 2' SO 2 NH provided R 2 ' is not hydrogen, or
  • R 4 is independently phenyl
  • a 5- to-7- membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • G is (CH 2 ) q where q is 1 or 2, or
  • Y attached to a ring carbon atom, is H or NH 2 ;
  • R 1 , R 2 , and R 2' are independently
  • a 5- to 7-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated. and which consists of carbon atoms and from one to three heteroatoms selected from the croup consisting of N, O and S,
  • R 1 may be joined with R 2 to form a four- to seven membered carbon ring in which zero to two carbon atoms may be substituted with heteroatoms independently selected from the list N, O and S, where n is 1 , 2, 3 or 4;
  • R 2' OCONH, provided R 2' is not hydrogen
  • R 2' SO 2 NH provided R 2' is not hydrogen, or
  • R 4 is independently
  • a 5- to-7- membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group co nsisting of N, O and S,
  • G is (CH 2 ) q where q is 1 or 2, or
  • Y attached to a ring carbon atom, is hydrogen or NH 2 ;
  • R 1 , R 2 , and R 2' are independently
  • a 5- to 7-membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • R 1 may be joined with R 2 to form a four- to seven membered carbon ring in which zero to two carbon atoms may be substituted with heteroatoms independently selected from the list N, O and S, where n is 1 , 2, 3 or 4;
  • R 2' OCONH. provided R 2' is not hydrogen
  • a 5- to-7- membered mono- or bicyclic heterocyclic ring or bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated. and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S,
  • G is (CH 2 ) q where q is 1 or 2, or
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • a racemate or racemic mixture does not imply a 50:50 mixture of stereoisomers.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic
  • hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl. Bu is butyl); "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "Halo”, as used herein, means fluoro, chloro, bromo and iodo; and "counterion” is used to represent a small, single negatively- charged species, such as chloride, bromide, hydroxide, acetate, trifluroacetate, perchlorate. nitrate, benzoate, maleate, tartrate, hemitartrate, benzene sulfonate, and the like.
  • Cyclic alkyl, bicyclic alkyl, and tricyclic alkyl refer to saturated ring systems, including spiro systems, fused systems, and bridged systems, unsubstituted or substituted with oxygen to form carbonyl carbon systems, or C 1 -2 alkyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated. and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur
  • heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements examples include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,
  • pyrazolidinyl imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl. benzimidazolyl. thiadiazoyl, benzopyranyl, benzothiazolyl,
  • Morpholino is the same as morpholinyl.
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate. alginate. aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,
  • glycerophosphate hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate. and undecanoate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides.
  • Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or 1-ethyl-3-(3-dimethyl- aminopropyl) carbodiimide.
  • Other methods of forming the amide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester, Typically, solution phase amide coupling are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.
  • a 300-ml flask was dried in an oven and cooled down in a dry nitrogen atmosphere.
  • the flask was equipped with a rubber syringe cap and a magnetic stirring bar.
  • the flask was immersed in a ice-water bath , and 21 ml (21 mmole) of 1.0M borane solution in THF was introduced into the reaction flask, followed by 0.3 ml of THF.
  • 6- Aminonicotinamide (420 mg, 3.06 mmole) in 10 ml ot THF was introduced.
  • Step B Boc-D-3,3-Dicha-OH (1 -2)
  • N-(benzylsulfonyl)-D-3,4-Dichloro-Phe-Pro-OMe (2- 1 ) with H- Pro-OMe-HCl.
  • Step A Preparation of N-(benzylsulfonyl)-D-3,4 -Cl 2 Phe-OH(2- 1 )
  • Step B Preparation of N-(benzylsulfonyl)-D-3,4-dichlorophenyl- alanyl-N-(6-aminopyridin-3-yl)methyl-L-prolineamide
  • Anal.CHN C 3 1 H 37 N 5 O 4 •1.75 CF 3 CO 2 H•1.05 H 2 O.
  • Step A Preparation of 6-Amino-2,4-dimethyl-3-amino- methylpyridine
  • a 300-ml flask was dried in an oven and cooled down in a dry nitrogen atmosphere.
  • the flask was equipped with a rubber syringe cap and a magnetic stirring bar.
  • the flask was immersed in a ice-water bath, and 21 ml (21 mmole) of 1.0M borane solution in THF was introduced into the reaction flask, followed by 0.3 ml of THF.
  • 6- Amino-2,4-dimethyI-3-pyridinecarbonitrile (442 mg, 3.0 mmole) in 10 ml of THF was introduced.
  • Step B Preparation of BOC-D-3,3-Dicyclohexylalanyl-N-(6- amino-2,4-dimethylpyridin-3-yl)methyl-L-prolineamide
  • NMP was treated with DIEA to PH 8.5. and the resulting solution stirred at room temp, in an N 2 atmosphere for 8 h.
  • Step C Preparation of N-Boc-D-4-chlorophenylalanyI-L-proline carboxylic acid
  • Step D Preparation of 6-amino-3-(aminomethyl)pyridine-N-Boc- D-4-chlorophenylalanyl-L-proline amide
  • N-Boc-D-4-chlorophenyIalanine-L-proline carboxylic acid (1.22 g, 3.07 mmol) in 5 mL DMF was added 6-amino- 3-(aminomethyl)pyridine (0.434 g, 3.53 mmol), HOBt (0.501 g, 3.684 mmol), and EDC (0.706 g, 3.684 mmol), cooled to 0°C and added triethylamine (0.51 mL, 3.68 mmol).
  • Step E Preparation of N-D-4-chlorophenyl-alanyl-N-(6- aminopyridin-3-yl)methyl-L-proline amide
  • Step F Preparation of N-(t-butyloxy-carboxymethyl)-D-4- chlorophenyl-alanyl-N-(6-aminopyridin-3-yl)methyl-L- proline amide
  • Step D Preparation of (3(2R),4R)-3-(2-azido-3-(3,4-methylene- dioxyphenyl)-1 -oxopropyl)-4-(phenylmethyl)-2- oxazolidinone
  • the aqueous layer was acidified to pH 2 with 10% HCl and extracted with ethyl acetate (3x75 mL), the combined organic layer was washed with water ( 1 x20 mL), brine ( 1x20 mL). dried over MgSO 4 , filtered and concentrated to an oil. This material was used directly in the next step.
  • Step F Preparation of N-(2R)-azido-3-(3,4-methylene- dioxyphenyl)alanyl-L-proline methyl ester
  • Step H Preparation of N-(2R)-azido-3-(3,4-methylene- dioxyphenyl)alanyl-N-(6-amino-2-methylpyridin-3- yl)methyl- L-proline amide
  • reaction was warmed to RT after 1 h and quenched after 16 h by diluting into 100 mL of ethyl acetate and washed with sat'd NaHCO 3 ( 1 x25 mL), water (4x25 mL), brine ( 1 x20 mL), dried over MgSO 4 , filtered and concentrated to a foam.
  • Step I N-(2R)-amino-3-(3,4-methylenedioxyphenyl)alanyl-N- (6-amino-2-methylpyridin-3-yl)methyl- L-proline amide
  • N-(2R)-amino-3-(3,4-methylenedioxy- phenyl)alanyl-N-(6-amino-2-methylpyridin-3-yl)methyl-L-proline amide dihydrochloride (0.95 g, 0.184 mmol) in DMF (2 mL) cooled to 0°C was added N-morphilino-2-bromoacetamide (0.038 g, 0.184 mmol) and triethylamine (0.028 mL, 0.202 mmol).
  • the reaction was warmed to RT over 3 h and after 19 h the volatiles were removed in vacuo.
  • reaction was warmed to RT after 1 h and quenched after 16 h by diluting into 100 mL of ethyl acetate and washed with sat'd NaHCO 3 ( 1 x25 mL), water (4x25 mL), brine ( 1 x20 mL), dried over MgSO 4 , filtered and
  • Flash column chromatography (25x 150 mm column of SiO 2 , CH 2 CI 2 /CH 2 CI 2 saturated with NH 3 /MeOH gradient elution 60:38:2 to 60:37:3) provided 0.525 g of a foam.
  • K i for thrombin is the inhibition constant for the tested compound with human thrombin.
  • K i for trypsin is the inhibition constant for the tested compound with bovine trypsin. Rate constants were determined using the following in vitro procedures.
  • sar-PR-pna sarcosine-Pro-Arg-p- nitroanilide
  • p -Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm - 1 M - 1 .
  • Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ⁇ 0.1 K m into a solution containing enzyme or enzyme equilibrated with inhibitor.
  • V o /V i 1 + [I]/K i ( 1 )
  • the activities shown by this assay indicate that the compounds of the invention are therapeutical ly useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
  • Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
  • patient used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents. orthopedic prothesis. cardiac prosthesis, and extracorporeal circulation systems
  • the thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions.
  • intravenous bolus or infusion
  • intraperitoneal subcutaneous
  • intramuscular form all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be any effective but non-toxic amount of the compound desired.
  • the compounds may be administered intraoculariy or topically as well as orally or parenterally.
  • the thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation.
  • the thrombin inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol,
  • the thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the thrombin inhibitors may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinlypyrrolidone, pyran copolymer. polyhydroxy-propyl- methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the thrombin inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, poly lactic acid, polyglycolic acid, copolymers of poly lactic and polyglycolic acid, polyepsilon caprolactone. polyhydroxy butyric acid, polyorthoesters. polyacetals, polydihydropyrans.
  • the dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient: the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of the thrombin inhibitors when used for the indicated effects, will range between about 0.1 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 1.0- 100 mg/kg/day and most preferably I -20 mg/kg/day. Intravenously, the most preferred doses will range from about 0.01 to about 10
  • the thrombin inhibitors may be administered in divided doses of two, three, or four times daily. Furthermore, they can be administered in
  • intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
  • oral tablets can be prepared which contain an amount of active compound of between 100 and 500 mg. typically between 200 and 250 mg.
  • active compound typically between 100 and 500 mg.
  • thrombin inhibitor compound depending on weight and metabolism of the patient, would be administered between about 100 and 1000 mg active
  • the thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents,
  • carrier materials suitably selected with respect to the intended form of administration, that is. oral tablets, capsules, ehxers, syrups and the like, and consistent with convention pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate,
  • an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate,
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulo.se, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate. sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite. xanthan gum and the like.
  • thrombin inhibitors can also be co-administered with suitable anti-coagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
  • suitable anti-coagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies.
  • thrombin inhibitors enhance the efficiency of tissue plasminogen activator- mediated thrombolytic reperfusion.
  • Thrombin inhibitors may be administered first following thrombus formation, and tissue
  • plasminogen activator or other plasminogen activator is administered thereafter. They may also be combined with heparin, aspirin, or warfarin.

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Abstract

La présente invention concerne un composé qui inhibe la thrombine humaine et qui a la structure suivante (I) telle que (II).
PCT/US1996/004460 1995-04-04 1996-04-01 Inhibiteurs de thrombine WO1996031504A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96911520A EP0820453A4 (fr) 1995-04-04 1996-04-01 Inhibiteurs de thrombine
AU54385/96A AU698911B2 (en) 1995-04-04 1996-04-01 Thrombin inhibitors
JP8530408A JPH11503161A (ja) 1995-04-04 1996-04-01 トロンビン阻害剤

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US41624495A 1995-04-04 1995-04-04
US08/416,244 1995-04-04

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AU (1) AU698911B2 (fr)
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Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
EP0820287A1 (fr) * 1995-04-10 1998-01-28 Merck & Co., Inc. Inhibiteurs de la thrombine
US5792779A (en) * 1997-02-19 1998-08-11 Merck & Co., Inc. Pyridinone thrombin inhibitors
US5798377A (en) * 1996-10-21 1998-08-25 Merck & Co., Inc. Thrombin inhibitors
US5869487A (en) * 1996-10-24 1999-02-09 Merck & Co., Inc. Pyrido 3,4-B!pyrazines for use as thrombin inhibitors
US5872138A (en) * 1996-09-13 1999-02-16 Merck & Co., Inc. Thrombin inhibitors
US5932606A (en) * 1997-03-24 1999-08-03 Merck & Co., Inc. Pyrazinone, pyridinone, piperidine and pyrrolidine thrombin inhibitors
US5965692A (en) * 1995-12-21 1999-10-12 Astra Ab Prodrugs of thrombin inhibitors
US6011038A (en) * 1997-09-05 2000-01-04 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6017934A (en) * 1997-01-22 2000-01-25 Merck & Co., Inc. Thrombin inhibitors
US6087373A (en) * 1997-09-23 2000-07-11 Merck & Co., Inc. Thrombin inhibitors
US6093717A (en) * 1998-05-26 2000-07-25 Merck & Co., Inc. Imidazopyridine thrombin inhibitors
US6117888A (en) * 1998-09-28 2000-09-12 Merck & Co., Inc. Thrombin inhibitors
US6133256A (en) * 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
US6133297A (en) * 1997-09-30 2000-10-17 Merck & Co., Inc. Thrombin inhibitors
US6147078A (en) * 1998-05-19 2000-11-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6239132B1 (en) 1999-04-23 2001-05-29 Merck & Co., Inc. Thrombin inhibitors
US6255301B1 (en) 1996-06-07 2001-07-03 Astrazeneca Ab Amino acid derivatives and their use as thrombin inhibitors
WO2001047874A1 (fr) * 1999-12-24 2001-07-05 Smithkline Beecham P.L.C. Nouveaux composes et processus
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6265397B1 (en) 1997-06-19 2001-07-24 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6337394B2 (en) 1997-12-05 2002-01-08 Astrazeneca Ab Compounds
US6350745B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Thrombin inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6376499B1 (en) 1998-10-30 2002-04-23 Merck & Co., Inc. Thrombin inhibitors
US6387911B1 (en) 1999-11-23 2002-05-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6433186B1 (en) 2000-08-16 2002-08-13 Astrazeneca Ab Amidino derivatives and their use as thormbin inhibitors
US6455532B1 (en) 1999-06-04 2002-09-24 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6515011B2 (en) 2000-12-18 2003-02-04 Merck & Co., Inc. Thrombin inhibitors
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6528503B2 (en) 2000-12-18 2003-03-04 Merck & Co., Inc. Thrombin inhibitors
US6534510B2 (en) 2000-03-23 2003-03-18 Merck & Co., Inc. Thrombin inhibitors
US6599894B1 (en) 1999-01-13 2003-07-29 AstŕaZeneca AB Amidinobenzylamine derivatives and their use as thrombin inhibitors
US6610692B1 (en) 1998-10-30 2003-08-26 Merck & Co., Inc. Thrombin inhibitors
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
US6750243B1 (en) 1998-12-14 2004-06-15 AstraZeneća AB Amidino derivatives and their use as thrombin inhibitors
US6962905B1 (en) 1999-04-21 2005-11-08 Astrazeneca Ab Pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug
US7084134B2 (en) 2002-05-02 2006-08-01 Merk & Co., Inc. Thrombin inhibitors
US7129233B2 (en) 2000-12-01 2006-10-31 Astrazeneca Ab Mandelic acid derivatives and their use as thrombin inhibitors
US7144899B2 (en) 2001-02-09 2006-12-05 Merck & Co., Inc. Thrombin inhibitors
WO2006135323A1 (fr) * 2005-06-17 2006-12-21 Astrazeneca Ab Derives de 2-oxo-1,2,5,6-tetrahydropyridine inhibiteurs de thrombines
US7202236B2 (en) 2002-05-31 2007-04-10 Astrazeneca Ab Modified release pharmaceutical formulation
WO2007082666A1 (fr) * 2006-01-12 2007-07-26 Bayer Healthcare Ag Acylaminoimidazoles
US7273858B2 (en) 2002-05-31 2007-09-25 Astrazeneca Ab Salts
US7645751B2 (en) 2000-12-01 2010-01-12 Astrazeneca Mandelic acid derivatives and their use as thrombin inhibitors
US7820645B2 (en) 2006-12-06 2010-10-26 Astrazeneca Ab Crystalline forms
WO2014081618A1 (fr) * 2012-11-20 2014-05-30 Merck Sharp & Dohme Corp. Inhibiteurs de thrombine
RU2607045C2 (ru) * 2011-07-07 2017-01-10 Калвиста Фармасьютикалз Лимитед Бензиламиновые производные как ингибиторы калликреина плазмы

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BRPI0914323A2 (pt) * 2008-06-23 2017-03-28 Astrazeneca Ab composto, formulação farmacêutica, uso de um composto, e, métodos de tratamento de uma condição e de tratamento e prevenção de distúrbios
GB2517908A (en) * 2013-08-14 2015-03-11 Kalvista Pharmaceuticals Ltd Bicyclic inhibitors

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US5510369A (en) * 1994-07-22 1996-04-23 Merck & Co., Inc. Pyrrolidine thrombin inhibitors

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JPS62114957A (ja) * 1985-11-13 1987-05-26 Suntory Ltd プロリルエンドペプチダ−ゼ阻害作用を有する新規ピロリジン誘導体およびその製法並びに用途
EP0699074B1 (fr) * 1993-04-30 2002-11-13 Merck & Co. Inc. Inhibiteurs de thrombine

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Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
EP0820287A1 (fr) * 1995-04-10 1998-01-28 Merck & Co., Inc. Inhibiteurs de la thrombine
EP0820287A4 (fr) * 1995-04-10 1998-07-29 Merck & Co Inc Inhibiteurs de la thrombine
US5965692A (en) * 1995-12-21 1999-10-12 Astra Ab Prodrugs of thrombin inhibitors
US6262028B1 (en) 1995-12-21 2001-07-17 Astrazeneca Ab Prodrugs of thrombin inhibitors
US7354905B2 (en) 1995-12-21 2008-04-08 Astrazeneca Ab Prodrugs of thrombin inhibitors
US6255301B1 (en) 1996-06-07 2001-07-03 Astrazeneca Ab Amino acid derivatives and their use as thrombin inhibitors
US6838478B2 (en) 1996-06-07 2005-01-04 Astrazeneca Ab Amino acid derivatives and their use as thrombin inhibitors
US5872138A (en) * 1996-09-13 1999-02-16 Merck & Co., Inc. Thrombin inhibitors
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US5798377A (en) * 1996-10-21 1998-08-25 Merck & Co., Inc. Thrombin inhibitors
US5869487A (en) * 1996-10-24 1999-02-09 Merck & Co., Inc. Pyrido 3,4-B!pyrazines for use as thrombin inhibitors
US6017934A (en) * 1997-01-22 2000-01-25 Merck & Co., Inc. Thrombin inhibitors
US5792779A (en) * 1997-02-19 1998-08-11 Merck & Co., Inc. Pyridinone thrombin inhibitors
US5932606A (en) * 1997-03-24 1999-08-03 Merck & Co., Inc. Pyrazinone, pyridinone, piperidine and pyrrolidine thrombin inhibitors
US6133256A (en) * 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6576657B2 (en) 1997-06-19 2003-06-10 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6265397B1 (en) 1997-06-19 2001-07-24 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6011038A (en) * 1997-09-05 2000-01-04 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6087373A (en) * 1997-09-23 2000-07-11 Merck & Co., Inc. Thrombin inhibitors
US6133297A (en) * 1997-09-30 2000-10-17 Merck & Co., Inc. Thrombin inhibitors
US6337394B2 (en) 1997-12-05 2002-01-08 Astrazeneca Ab Compounds
US6147078A (en) * 1998-05-19 2000-11-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6093717A (en) * 1998-05-26 2000-07-25 Merck & Co., Inc. Imidazopyridine thrombin inhibitors
US6117888A (en) * 1998-09-28 2000-09-12 Merck & Co., Inc. Thrombin inhibitors
US6376499B1 (en) 1998-10-30 2002-04-23 Merck & Co., Inc. Thrombin inhibitors
US6610692B1 (en) 1998-10-30 2003-08-26 Merck & Co., Inc. Thrombin inhibitors
US7241757B2 (en) 1998-12-14 2007-07-10 Astrazeneca Ab Amidino derivatives and their use as thrombin inhibitors
US6750243B1 (en) 1998-12-14 2004-06-15 AstraZeneća AB Amidino derivatives and their use as thrombin inhibitors
US6599894B1 (en) 1999-01-13 2003-07-29 AstŕaZeneca AB Amidinobenzylamine derivatives and their use as thrombin inhibitors
US6962905B1 (en) 1999-04-21 2005-11-08 Astrazeneca Ab Pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug
US6239132B1 (en) 1999-04-23 2001-05-29 Merck & Co., Inc. Thrombin inhibitors
US6455532B1 (en) 1999-06-04 2002-09-24 Merck & Co., Inc. Pyrazinone thrombin inhibitors
US6350745B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Thrombin inhibitors
US6387911B1 (en) 1999-11-23 2002-05-14 Merck & Co., Inc. Pyrazinone thrombin inhibitors
WO2001047874A1 (fr) * 1999-12-24 2001-07-05 Smithkline Beecham P.L.C. Nouveaux composes et processus
US6534510B2 (en) 2000-03-23 2003-03-18 Merck & Co., Inc. Thrombin inhibitors
US6716834B2 (en) 2000-05-16 2004-04-06 Astrazeneca Ab Thiochromane derivatives and their use as thrombin inhibitors
US6433186B1 (en) 2000-08-16 2002-08-13 Astrazeneca Ab Amidino derivatives and their use as thormbin inhibitors
US7645751B2 (en) 2000-12-01 2010-01-12 Astrazeneca Mandelic acid derivatives and their use as thrombin inhibitors
US7803954B2 (en) 2000-12-01 2010-09-28 Astrazeneca Ab Mandelic acid derivatives and their use as thrombin inhibitors
US7129233B2 (en) 2000-12-01 2006-10-31 Astrazeneca Ab Mandelic acid derivatives and their use as thrombin inhibitors
EP2186800A1 (fr) 2000-12-01 2010-05-19 Astra Zeneca AB Nouveaux dérivés d'acide mandélique et leur utilisant en tant qu'inhibiteurs de thrombine
US6528503B2 (en) 2000-12-18 2003-03-04 Merck & Co., Inc. Thrombin inhibitors
US6515011B2 (en) 2000-12-18 2003-02-04 Merck & Co., Inc. Thrombin inhibitors
US7144899B2 (en) 2001-02-09 2006-12-05 Merck & Co., Inc. Thrombin inhibitors
US7084134B2 (en) 2002-05-02 2006-08-01 Merk & Co., Inc. Thrombin inhibitors
US7202236B2 (en) 2002-05-31 2007-04-10 Astrazeneca Ab Modified release pharmaceutical formulation
US7273858B2 (en) 2002-05-31 2007-09-25 Astrazeneca Ab Salts
WO2006135323A1 (fr) * 2005-06-17 2006-12-21 Astrazeneca Ab Derives de 2-oxo-1,2,5,6-tetrahydropyridine inhibiteurs de thrombines
WO2007082666A1 (fr) * 2006-01-12 2007-07-26 Bayer Healthcare Ag Acylaminoimidazoles
US7820645B2 (en) 2006-12-06 2010-10-26 Astrazeneca Ab Crystalline forms
RU2607045C2 (ru) * 2011-07-07 2017-01-10 Калвиста Фармасьютикалз Лимитед Бензиламиновые производные как ингибиторы калликреина плазмы
WO2014081618A1 (fr) * 2012-11-20 2014-05-30 Merck Sharp & Dohme Corp. Inhibiteurs de thrombine
US9469608B2 (en) 2012-11-20 2016-10-18 Merck Sharp & Dohme Corp. Thrombin inhibitors

Also Published As

Publication number Publication date
AU5438596A (en) 1996-10-23
CA2216859A1 (fr) 1996-10-10
JPH11503161A (ja) 1999-03-23
EP0820453A1 (fr) 1998-01-28
EP0820453A4 (fr) 2001-08-29
AU698911B2 (en) 1998-11-12

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