WO1997046553A1 - Inhibiteurs de la thrombine - Google Patents

Inhibiteurs de la thrombine Download PDF

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Publication number
WO1997046553A1
WO1997046553A1 PCT/GB1997/001385 GB9701385W WO9746553A1 WO 1997046553 A1 WO1997046553 A1 WO 1997046553A1 GB 9701385 W GB9701385 W GB 9701385W WO 9746553 A1 WO9746553 A1 WO 9746553A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
oxo
phenyl
benzyl
piperidin
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PCT/GB1997/001385
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English (en)
Inventor
Derek Edward Brundish
Lyndon Nigel Brown
Darren Mark Le Grand
Keith Allan Menear
Garrick Paul Smith
Mark Christopher Allen
Paul Ian Butler
Xiao-Ling Cockroft
Ian Timothy William Matthews
Clive Victor Walker
William Bernard Wathey
Original Assignee
Novartis Ag
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Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to AU29081/97A priority Critical patent/AU2908197A/en
Publication of WO1997046553A1 publication Critical patent/WO1997046553A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to new compounds which have activity as inhibitors of thrombin.
  • Y is a primary or secondary amino group
  • R 2 is the residue of a natural or synthetic amino acid
  • R 3 is hydrogen or a C ⁇ -C 8 alkyl chain which may be substituted by hydroxy or halogen
  • X is (CH 2 )n where n is 1, 2, or 3, or is CH 2 N or represents a fused phenyl ring which is optionally substituted by one or two methoxy groups or a salt thereof.
  • Y may have the formula
  • R 1 0 and Rn represent alkyl
  • the alkyl may be substituted by OH, COOR ⁇ where R ⁇ is H or alkyl, carbonyl or amide groups or by a heterocyclic ring.
  • Ri is a substituted alkyl group it may be substituted by OH, substituted hydroxyl, carboxyl, carboxyaikyi, phenyl or substituted amino. Preferably the substituent is in a terminal position.
  • Ri is a substituted phenyl ring it may be substituted by one or more halogen or alkyl groups or one or more groups OR 4 , SR 5 , NR 6 R7 or COOR ⁇ where each of R 4 to R ⁇ is H or alkyl or NR 6 R7 is NO 2 .
  • Halogen atoms in R and/or R 3 may be fluorine, chlorine, bromine or iodine, but preferably fluorine or chlorine.
  • Examples of the groups R include H, F, CI, N 3 , OH, OCH 3 . OSO2CH3, OSO 2 benzyl,
  • OCH 2 CH 2 OH and its 2-pyranyl ether OCH ⁇ COOH and its tert.-butyl ester, OCH2CON(CH 3 ) 2 , OCH 2 CONH(CH 2 )2OH, the corresponding morpholide OCH 2 COM ⁇ h, COOH and its methyl and tert.-butyl esters, SH, S(CH 2 ) 2 OH, S(CH 2 ) 3 OH, NH 2 , NHCH 3l NHC2H5, N(CH 3 )C 2 Hs.
  • NHC 3 H 7 (n), NHC 4 H 9 NHCH2CH2OH, NHCONH2, NHCONHC 2 H 5 , NHCH 2 CH 2 OCH 3 , N(CH 2 CH 2 OCH 3 ) 2 , NHCOCH 3 , N(CH 3 )CH 2 COOH, NHCH 2 COOH and its tert. ⁇ butyl ester, NHCH 2 pyridyl, N(CH 3 ) 2 , N(C 2 H 5 ) 2 , pyrrolidinyl, piperidinyl, 4- hydroxypiperidinyl, mo ⁇ holinyl, thiomo ⁇ hplinyi.
  • the ring may be, for example, a piperidine, py olidine, mo ⁇ holine, thio o ⁇ holine or piperazine ring, which may be optionally substituted.
  • the ring may be, for example, a phenyl, cyclohexane, benzothiazole, indole, indane, naphthalene, thiophene or thiazole ring.
  • Ri is derived from an amino alcohol, for instance, those obtained from optionally ring-substituted phenylalanines, tryptophans and pyridylalanines.
  • Examples of the group Ri include phenyl, cyclohexyl, 4-methoxyphenyl, 4- ethoxyphenyl, 3-4-di-methoxyphenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 4- hydroxyphenyl, 4-nitrophenyl, 4-aminophenyl, 4-methylphenyl, 2-pyridyl, thiazolyl, indolyl, methylthiomethyl, n-butyl.
  • Examples of the group R ⁇ -(CH 2 ) m include n-propyl, n-butyl, n-pentyl, iso- butyl, iso-pentyl, 5-hydroxy-pentyl, ca ⁇ oxylethyl, 4-phenylbutyl, n- butylcarbamoylethyl, 2-indanyl, 4-methylbenzyl, 2-aminobenzyl, 4- carboxybenzyl and its methyl ester, 2-pyridylmethyl, phenylethyl, 4- hydroxyphenylethyl and its methyl ether, 2-aminophenylethyl, carboxyundecyl, hydroxyethyloxyethyl.
  • R2 may be derived from the amino acids phenylalanine, tyrosine, dopa and its ethers such as the methylenedioxy ether, p-aminophenylalanine, p-nitrophenylalanine, naphthylalanine, benzothiazolylalanine, thiazolylalanine, cyclohexylalanine, the pyridylalanines, tryptophan, and fused 6/5 membered ring systems linked through the 6-membered ring and where the 5-membered ring contains one or more hetero atoms.
  • phenylalanine tyrosine
  • dopa and its ethers such as the methylenedioxy ether, p-aminophenylalanine, p-nitrophenylalanine, naphthylalanine, benzothiazolylalanine, thiazolylalanine, cyclohexylalanine, the pyridylalanines, try
  • Examples of the groups R 2 -CH 2 - include 2-benzthiazolylmethyl, 2- benzoxazolylmethyl, 2-benzimidazolylmethyl, 2-naphthylmethyl, 2-(3- and 4-)pyridylmethyl, benzyl, 4-hydroxy benzyl, 4-methoxy benzyl, 4- ethoxybenzyl, cyclohexylmethyl, 4-nitrobenzyl, 4-aminobenzyl, 4- methylaminobenzyl, 4-dimethylaminobenzyl, 4-ethylaminobenzyl, 4- fluorobenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, 3,4- methylenedioxybenzyl, 4-acetylaminobenzyl, 4-formylaminobenzyl, 4- hydroxyaminobenzyl, 3-hydroxy-4-methoxybenzyl, 3-amino-4-hydroxybenzyl, 3-amino-4-methoxybenzyl
  • the group R 3 preferably has 2 or 3 carbon atoms and may be terminally substituted by hydroxy, fluorine or chlorine.
  • X is preferably CH 2 N or (CH 2 ) 2 .
  • X is CH N the two N atoms in the ring are preferably in the para positions and R 3 is then preferably attached to the N atom in X.
  • R 3 is then preferably attached to the N atom in X.
  • A-R is present, m is 1, A is -CHr and X is (CH 2 ) 2 .
  • the compounds of the invention can be considered as being in four parts, A, an amine moiety which is
  • the compounds of the invention may be made by various processes as outlined in Methods 1 to 3 below
  • chloropyridine sulfonyl-aminoacid (derivative) 1 deprotection (if needed) chloropyridine sulfonyl-amino acid i couple with base
  • the C-D coupling reaction may be carried out by reaction of the amino acid with the base and where the amino acid and the base are optionally protected.
  • the reaction of the amino acid with the base is carried out for instance as are coupling reactions of amino acids in the preparation of peptides and according to methods of protection, activation, coupling and deprotection or partial deprotection described in the literature (Houben Weyl, Methoden Der Organichen Chemie Vol. 15 Parts 1 & 2).
  • the aminoacyl base compounds can be prepared by protecting the ⁇ -amino group of the amino acid via acetylation, formylation, phthaloylation, trifluroacetylation, p-methoxybenzyloxyca ⁇ onylation, benzoylation, benzyloxyca ⁇ onylation, t-butyoxycarbonylation, arylsulfonylation, or tritylation and then condensing the formed N ⁇ - substituted amino acid with the base to give a protected form of the aminoacyl base by a conventional process such as the acid chloride method, azide method, mixed anhydride method, activated ester method, or carbodiimide method, with or without additives such as hydroxysuccinimide, hydroxybenzt ⁇ azole, diethyl phosphite or the like, and thereafter selectively removing the protective groups to give the desired compound
  • the reaction may be earned out by the condensation of an N ⁇ - arylsulfonyl aminoacyl halide, preferably a chlo ⁇ de, a mixed anhyd ⁇ de, or a similar activated species de ⁇ ved in situ from the ammo acid with at least an equimolar amount of the base
  • the condensation reaction can be earned out with or without an added solvent in the presence of a base Solvents such as dimethylformamide (DMF) or dimethylacetamide (DMF) or halogenated solvents such as chloroform or dichloromethane may be used
  • the amount of the solvent to be used is not c ⁇ tical and may vary from about 5 to 100 times the weight of the N°-arylsulfonyl ammo acid (VI) In the other cases the activating principle such as diethyl phosphite may be the solvent
  • the activated species is a py ⁇ dyl-sulfonyl aminoacyl halide it may be prepared by reacting a py ⁇ dyl-sulfonyl am o acid VII with at least an equimolar amount of a halogenating agent such as thionyl chlo ⁇ de, phosphorus oxychlo ⁇ de, phosphorus t ⁇ chlo ⁇ de, phosphorus pentachlo ⁇ de or phosphorus t ⁇ bromide.
  • a halogenating agent such as thionyl chlo ⁇ de, phosphorus oxychlo ⁇ de, phosphorus t ⁇ chlo ⁇ de, phosphorus pentachlo ⁇ de or phosphorus t ⁇ bromide.
  • the halogenation may be earned out with or without an added solvent
  • the preferred solvents are chlo ⁇ nated hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran and dioxan
  • Preferred reaction temperatures are in the range of -10°C to room temperature
  • the reaction time is not c ⁇ tical, but vanes with the halogenating agent and reaction temperature In general, a pe ⁇ od of 15 minutes to 5 hours is operable
  • the reaction may include reaction of the ammo acid with the base in the presence of condensing agent such as a carbodiimide, for instance dicyclohexyl-ca ⁇ odumide in the presence or absence of an activating species such as hydroxybenzot ⁇ azole or diethyl phosphite and in the presence of a base
  • the base used in the above reactions may be either an organic base such as Huenig Base, tnethylamine, N- methylmo ⁇ holine, or pyndine or an inorganic base such as sodium hydroxide or potassium carbonate.
  • the condensation reaction may be carried out at a temperature between -10° C and the boiling point of the solvent. Preferred condensation reaction temperatures are in the range from -10° C to room temperature.
  • the reaction time is not critical. In general, a period of from 5 minutes to 10 hours is operable.
  • the B-C reaction may be carried out for instance under conditions known for introducing arylsulfonyl groups onto amino substituted compounds.
  • the reaction may be carried out by the condensation of an aminoacid or aminoacyl amide with a substantially equimolar amount of 4- chloropyridine-3-sulfonyl chloride.
  • the condensation reaction is generally effected in a suitable inert solvent in the presence of an excess of a base, such as an organic base e.g. triethylamine, di-isopropylethylamine, pyridine, N-methyl or N-ethyl mo ⁇ holine or a solution of an inorganic base e.g. sodium hydroxide or potassium carbonate, at a temperature of 0°C to the boiling temperature of the solvent for a period of 10 minutes to 15 hours.
  • a base such as an organic base e.g. triethylamine, di-isopropylethylamine, pyridine, N-methyl or N-ethyl mo ⁇ holine or a solution of an inorganic base e.g. sodium hydroxide or potassium carbonate, at a temperature
  • the A-B reaction may be carried out by the condensation of the amine with a chloropyridine sulfonyl compound which already carries the aminoacid moiety and optionally the base as well.
  • the amine moiety A may be complex and be derived from 2 or 3 components such as a-b-c or b-c.
  • the amine can be pre ⁇ formed and reacted with the chloropyridine compound B-C-D to form A-B-C- D.
  • the amine may be reacted with B-C-D as b-c followed by adding a or it may be reacted as c, then a-b or as c then b then a.
  • the compounds of the invention may be formed:- (i) a-b-c + B-C-D ⁇ a-b-c-B-C-D
  • the product of formula I When the product of formula I is obtained from the condensation reaction in protected form, it may be purified by extraction and the solvent removed by such standard means as evaporation under reduced pressure and then converted to the compound of formula I by removing the protecting group by means of acidolysis or hydrogenolysis.
  • the acidolysis is generally effected by contacting the protected form of I and an excess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or trifluoroacetic acid, without a solvent or in a solvent, such as an ether e.g. tetrhydrofuran or dioxan, an alcohol e.g.
  • methanol or ethanol or acetic acid at a temperature of -10°C to 100°C, and preferably at room temperature for a period of 30 minutes to 24 hours.
  • the products are isolated by evaporation of the solvent and the excess acid, or by trituration with a suitable solvent followed by filtration and drying.
  • the products are in certain cases the acid addition salts of the compounds of formula I, which can easily be converted to a free amide by neutralisation.
  • the protected compound of formula I contains the benzoxyca ⁇ onyl protection group the removal is readily accomplished by hydrogenolysis.
  • any benzyl ester moiety is converted to the ca ⁇ oxyl group by the hydrogenolysis.
  • the hydrogenolysis is effected in an inert reaction solvent, e.g. methanol, ethanol, tetrahydrofuran or dioxan optionally in the presence of an acid such as acetic acid and in the presence of a hydrogen-activating catalyst e.g.
  • Raney nickel, palladium or platinum in a hydrogen atmosphere at a temperature of 0°C to the boiling temperature of the solvent for a period of 2 hours to 120 hours.
  • the hydrogen pressure is not critical, and atmospheric pressure is sufficient.
  • the products of formula I are isolated by filtration of the catalyst followed by evaporation of the solvent. They may be purified by trituration or recrystallisation from a suitable solvent, such as ethyl acetate, diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol, or may be chromatographed on silica gel, ion-exclusion gels or reverse-phase liquid chromatography supports.
  • the ca ⁇ oxylic acid or alcohol can be prepared from the ester derivative by conventional hydrolysis or acidolysis methods.
  • the conditions under which esterification, hydrolysis or acidolysis can be carried out will be apparent to those skilled in the art.
  • the compounds (I) of this invention in certain cases form acid addition salts with any of a variety of inorganic and organic acids. Some of the compounds containing a free ca ⁇ oxyl group form salts with any of a variety of inorganic and organic bases.
  • the product of the reactions described above can be isolated in the free form or in the form of salts.
  • the product can be obtained as acid addition salts by reacting one of the free bases with an acid, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like.
  • an acid such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like.
  • the product can be obtained as salts by reacting the free carboxyiic acid with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.
  • a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.
  • the chloropyridine sulfonyl chloride may be prepared from the corresponding hydroxypyridine sulfonic acid by chlorination.
  • chlorinating agents examples include phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosgene, benzotrichloride, thionyl chloride, chlorosulfonic acid, sulfur dichloride, sulfur and chlorine and chlorine.
  • Suitable solvents for the reaction include trifluoroacetic acid, dimethylformamide (DMF), dimethylacetamide (DMA), 1 ,3-dimethyl-2- imidazolidinone (DMID), and pyridine.
  • the reaction is conveniently carried out between -10°C and the boiling point of the solvent. It is advantageous to disperse or dissolve the sulfonic acid or its salt in the solvent whilst applying ultrasound.
  • reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform or the like.
  • the compounds of the formula I provide interesting compounds which contain potent and orally bioavailable inhibitors of serine proteases, especially thrombin.
  • the compounds of the present invention are useful in compositions, combinations and methods for the treatment and prophylaxis of various diseases attributed to thrombin-mediated and thrombin-associated functions and processes. These include myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation, peripheral arterial occlusion, restenosis following arterial injury or invasive cardiotogical procedures including percutaneous transluminal coronary angioplasty, atrial fibrillation, acute or chronic atherosclerosis, edema and inflammation, various cell regulatory processes (e.g. secretion, shape changes, proliferation), cancer and metastasis, and neurodegenerative diseases.
  • the thrombin inhibitors of the present invention may be formulated into pharmaceutically useful compositions, such as by mixing with a pharmaceutically acceptable carrier or diluent. These compositions may be used for treating or preventing thrombotic diseases in a patient.
  • the thrombin inhibitors may be employed in compositions for preventing and/or treating thrombotic disease, and for decreasing the dosage of a thrombolytic agent required to establish reperfusion or prevent reocclusion in a patient.
  • the thrombin inhibitors of this invention may be used in compositions for decreasing reperfusion time or the incidence of acute reocclusion in a patient treated with a thrombolytic agent.
  • These compositions may comprise a pharmaceutically effective amount of a thrombin inhibitor of the present invention and a pharmaceutically effective amount of a thrombolytic agent.
  • the thrombin inhibitor and the thrombolytic agent work in a complementary fashion to dissolve blood clots, resulting in decreased reperfusion times and incidence of acute reocclusion in patients treated with them.
  • the thrombolytic agent dissolves the clot, while the thrombin inhibitor prevents newly exposed, clot-entrapped or clot-bound thrombin from regenerating the clot.
  • the use of the thrombin inhibitor in the compositions of this invention advantageously allows the administration of a thrombolytic reagent in dosages previously considered too low to result in thrombolytic effects if given alone. This avoids some of the undesirable side effects associated with the use of thrombolytic agents, such as bleeding complications.
  • Thrombolytic agents which may be employed in the combinations and compositions of the present invention are those known in the art. Such agents include tissue plasminogen activator purified from natural sources, recombinant tissue plasminogen activator, streptokinase, urokinase, prourokinase, anisoiated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, hybrids of the above and known, biologically active derivatives.
  • the thrombin inhibitor and the thrombolytic agent may be in the same or in separate dosage forms which are administered separately, but concurrently or sequentially.
  • the thrombin inhibitor may be given to the patient at a time from 5 hours before to 5 hours after administration of the thrombolytic agent.
  • the thrombin inhibitor is administered to the patient at a time from 2 hours before to 2 hours after administratiorrof the thrombolytic agent.
  • the compounds of the invention may also be used in combinations and compositions with other antithrombotic drugs such as aspirin, fibrinogen receptor blockers, platelet glycoprotein llb/llla antagonists, platelet aggregation inhibitors and the like.
  • antithrombotic drugs such as aspirin, fibrinogen receptor blockers, platelet glycoprotein llb/llla antagonists, platelet aggregation inhibitors and the like.
  • compositions of the invention may be administered to a patient in various ways e.g. enterally such as orally or rectally, parenterally or topically.
  • the compositions will be formulated using adjuvants and diluents suitable for the desired method of administration.
  • the compositions may be administered intravenously or intra-arterially as bolus or by continued infusion, intramuscularly - including paravertebrally and periarticulaiiy - subcutaneously, intracutaneously, intra-articularly, intrasynoviaily, intrathecally, intra-lesionally, periostally or by oral, nasal or topical routes.
  • they may be given by either passive or active methods, including by iontophoresis.
  • compositions are preferably administered intravenously either in a bolus form or as an infusion.
  • the thrombin inhibitor may be either suspended or dissolved in a sterile vial or ampoule and sealing.
  • adjuvants such as a local anesthetic, preservatives, stabilizers, solution promoters and/or buffers may also be dissolved in the vehicle.
  • the composition may then be frozen and lyophilized to enhance stability.
  • a surfactant or wetting agent and/or other adjuvant as mentioned above may be included in the composition to facilitate uniform distribution of its components.
  • Tablets and capsules e.g. gelatin capsules for oral administration may comprise the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, so ⁇ itol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salts and/or polyethylene glycol; for tablets also c) binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellolose and/or polyvinylpyrrolidone; if desired, d) disintegrants, e.g.
  • diluents e.g. lactose, dextrose, sucrose, mannitol, so ⁇ itol, cellulose and/or glycine
  • lubricants e.g. silica, talcum
  • starches starch derivatives such as sodium starch glycolate, crosca ⁇ mellose, agar, algi ⁇ ic acid or its sodium salt, or effervescent mixtures; e) wetting agents such as sodium lauryl sulphate; and/or f) absorbents, colourants, flavours and sweeteners.
  • Suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents.
  • Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstruction with water or another suitable vehicle before use.
  • Such liquid preparations may contain conventional additives.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylceilulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, polyethylene glycols, or acacia; non-aqueous vehicles, such as almond oil, fractionated coconut oil, and oily esters; and preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylceilulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats
  • emulsifying agents such as lecithin, sorbitan monooleate, polyethylene glycols, or acacia
  • non-aqueous vehicles such as almond oil, fractionated coconut oil, and oily esters
  • preservatives such as
  • compositions formulated for topical administration may, for example, be in aqueous jelly, oily suspension or emulsified ointment form.
  • compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
  • Transdermal systems may be made by applying an adhesive layer to a base layer, e.g. a peel-off protective layer, applying a reservoir to the base layer, the reservoir containg the active ingredient and optionally a polymeric material for forming a porous or permeable membrane and/or a penetration enhancer, and then applying an impermeable outer layer on top.
  • a base layer e.g. a peel-off protective layer
  • a reservoir e.g. a peel-off protective layer
  • the reservoir containg the active ingredient and optionally a polymeric material for forming a porous or permeable membrane and/or a penetration enhancer, and then applying an impermeable outer layer on top.
  • the dosage of active compound administered is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, and on the form of administration.
  • a preferred pharmaceutically effective dose of the thrombin inhibitor of this invention is from 0.01 mg/kg body weight of the patient to be treated to 50 mg/kg body weight, preferably from 0.1 to 1.0 mg/kg.
  • the amount used depends on the method of administration. Normally lower amounts are needed for parental administration than for enteral administration.
  • the dose for infusions may be higher than the range given, preferably from 0.01 to 1.0 mg/kg/hr.
  • a pharmaceutically effective dose of the thrombolytic agent may be between 10% and 80% of the conventional dosage range, i.e. the dosage used when that agent is employed in a monotherapy.
  • the compounds of the invention may also be used in the form of conjugates with materials such as polyethylene glycol. This would modify the pharmacokinetic properties of the compounds and result in lower doses being needed, or less frequent doses.
  • the thrombin inhibitors of the invention may also be used in compositions and methods for coating the surfaces of invasive or extra-co ⁇ oreal devices, resulting in a lower risk of clot formation or platelet activation in patients receiving or using such devices.
  • Surfaces that may be coated with the compositions of this invention include, for example, prostheses, artificial valves, vascular grafts, stent tubing, membranes and catheters. Methods for coating these devices are known to those of skill in the art. These include chemical cross-linking or physical adso ⁇ tion of the thrombin inhibitor-containing compositions on to the surfaces of the devices.
  • compositions containing the thrombin inhibitors of this invention may also be used in the treatment of tumor metastases, as indicated by the inhibition of metastatic growth.
  • metastatic tumors which may be treated by the thrombin inhibitors of this invention include carcinoma of the brain, carcinoma of the liver, carcinoma of the lung, osteocarcinoma and neoplastic plasma cell carcinoma.
  • compositions containing the thrombin inhibitors of the invention may also be used to inhibit thrombin-induced endoethelial cell activation, including the repression of synthesis of mediators, including platelet-activating factor (PAF), eicosanoids, endothelial-derived relaxing factor (EDRF) and endothelin, by endothelial cells.
  • PAF platelet-activating factor
  • EDRF endothelial-derived relaxing factor
  • endothelial cells endothelial cells.
  • the compositions have important applications in the treatment of diseases characterised by thrombin-induced inflammation and edema, which is thought to be mediated by PAF. Such diseases include adult respiratory distress syndrome, septic shock, septicemia, reperfusion damage, and for treating or preventing septicemia and other diseases.
  • the thrombin inhibitors of the invention or compositions comprising them may also be used as anticoagulants for extraco ⁇ oreal blood, for instance in such processes as dialysis procedures, blood filtration, or blood bypass during surgery at doses from 0.01 to 1.0mg/kg as well as in blood products which are stored extraco ⁇ oreaily for eventual administration to a patient and blood collected from a patient to be used for various assays.
  • blood products include whole blood, plasma, or any blood fraction in which inhibition of coagulation is desired.
  • the amount or concentration of thrombin inhibitor in these types of compositions is based on the volume of blood to be treated or, more preferably, its thrombin content, and may be from 0.01mg/60ml of extraco ⁇ oreal blood to 5mg/60ml of extraco ⁇ oreal blood.
  • the thrombin inhibitors of this invention may also be used to inhibit clot- bound thrombin, which is believed to contribute to thrombus growth and clot accretion, and to prevent thrombus extension. This is particularly important because commonly used anti-thrombin agents, such as heparin and low molecular weight heparin, are ineffective against clot-bound thrombin.
  • inhibitors of this invention may be used for treating neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, inflammatory diseases and cerebral ischaemia.
  • 2(S)-Amino-3-(4-fluoro-phenyl)-propionic acid (504mg) is suspended with stirring in dry THF (10ml) and borane/THF complex (1M, 5.5ml) is added over a period of 5 minutes. The mixture is stirred at 20°C for 18 hours and a solution of acetic acid in methanol, (1:4, by vol., 20ml) is added.
  • Methanesulfonic acid 2(S)-benzyloxycarbonylamino-3-phenyl-propyl ester (10g) is dissolved in dichloromethane (200ml) and pyrrolidine (23ml) is added. The mixture is stirred for 16 hours at 20°C. Solvent is removed by rotary evaporation and the residue is dissolved in ethanol (200ml) and stirred for 16 hours at 50°C. Solvent is removed by rotary evaporation and the residue is dissolved in dichloromethane (100ml). The solution is washed with portions (2x50ml) of water and brine, dried (MgSO 4 ) and solvent removed by rotary evaporation.
  • 3(S)-Benzyloxycarbonylamino-4-phenyl-butyric acid tert.-butyl ester is saponified using standard conditions to give 3(S)-benzyloxyca ⁇ onylamino-4- phenyl-butyric acid as a white solid. It has a 1 H NMR spectrum consistent with the claimed structure.
  • Solvent is removed by rotary evaporation and the residue is purified by flash chromatography on a column of silicagel using dichloromethane:methanol (49:1, by vol.) as eluant to give 1-(2(S)-benzyloxyca ⁇ onylamino-3-phenyl-propyl)-piperidine-4- ca ⁇ oxylic acid ethyl ester as a colourless oil. It has 1 H and 13C spectra consistent with the claimed structure.
  • Solvents are removed by rotary evaporation and the residue is purified by flash chromatography on a column of silicagel using ethyl acetate:hexane (3:17, by vol.) as eluant to give dibenzyl- ⁇ 2-phenyl- ⁇ (S)-[2-(tetrahydro-pyran-2(RS)- yloxy)-ethoxymethyl]-
  • Solvent is removed from the cooled mixture by rotary evaporation and the residue is purified by flash chromatography on a column of silicagel using ethanol:ethyl acetate (3:1, by vol.) as eluant to give ⁇ 1(S)-[4-(2-mo ⁇ holin-4-yl-2-oxo-ethyl)-piperazin-1- ylmethyl]-2-phenyl-ethyf ⁇ -carbamic acid benzyl ester as a pale yellow foam. It has 1 H and 13C NMR spectra consistent with the claimed structure. [M+H] +
  • aqueous phase is extracted with ethyl acetate (25ml) and the combined organic phases are washed with portions (50ml) of saturated aqueous sodium bicarbonate and brine, dried (MgSO ) and the solvent removed by rotary evaporation to give [2(S)-tert.-butoxycarbonylamino-3-(4-methoxy- phenyl)-propoxy]-acetic acid tert.-butyl ester which
  • the organic phase is d ⁇ ed (Na2SO4) and solvent removed by rotary evaporation to give an oil which is purified by flash chromatography on a column of silicagel using hexane:ethyl acetate (10:1 , by vol.) as eluant to give pure 4- (2-fluoro-ethyl)-p ⁇ peridine-1-ca ⁇ oxyl ⁇ c acid tert -butyl ester as a light yellow oil. This is converted to 4-(2-fluoro-ethyl)-p ⁇ pe ⁇ d ⁇ ne hydrochloride as desc ⁇ bed in Method 1 above.
  • Methanesulfonic acid 2-(1-benzoyl-p ⁇ pe ⁇ d ⁇ n-4-yl)-ethyl ester (41.5g) is dissolved in acetonit ⁇ le (150ml), powdered molecular sieve (4 Angstrom) is added followed by TBAF (1M in THF, 145ml) and the mixture is heated at reflux with exclusion of moisture for 2 hours The mixture is cooled, filtered and the filtrate washed with saturated aqueous sodium bicarbonate
  • ba 4-(1(S)-Hydroxymethyl-2-phenyl-ethylam ⁇ no)- 570.2 1 H, 13C pynd ⁇ ne-3-sulfon ⁇ c acid ⁇ 2-[4-(2-fluoro-ethyl)- p ⁇ pe ⁇ d ⁇ n-1-yl]-2-oxo-1(S)-py ⁇ d ⁇ n-3-ylmethyl- ethyfj-amide
  • Examples 1 di and 1dj are obtained by acidic deprotection of Examples 1ao and 1at using standard conditions.
  • Examples 1dk and 1dn are obtained by alkaline deprotection of Examples 1o and 1 be; 1dl and 1dm from the corresponding O-acetyl esters; and 1do from the corresponding methyl ester, using standard conditions.
  • Example 1dp is obtained by the action of borane:THF complex on Example
  • Examples 1t and 1 u, also 1y and 1z, are obtained by silicagel column chromatographic separation of diastereomeric mixtures resulting from reaction with racemic amines. In both cases, tentative stereochemical assignments are made on the bases of (i) the relative potencies of the pairs of compounds and (ii) their relative elution times on hplc analysis, by analogy with other diastereomeric pairs of known absolute configuration.
  • Examples 1 bl and 1bo are tentatively assigned their stereochemistries by analogy of their potencies and chromatographic behaviours to diastereomeric pairs of known absolute configuration.
  • Example 1dq is obtained by catalytic reduction of Example 1ab
  • Examples 1cb and 1cc, 1ce and 1cf, and 1cg and 1ch are isolated by silicagel column chromatography of diastereomeric mixtures.
  • Example 2(b) This is treated as described for Example 2(b) to give 2(S)-amino-1-[4-(2-fluoro-ethyl)-piperidin-1-yl]-3-.pyridin-2-yl- propan-1-one hydrochloride.
  • Example 4bd is a 77:23 mixture of diastereomers (by hplc analysis)
  • Example 4bg requires isolation by silicagel column chromatography from a mixture of diastereomers
  • Examples 4bu and 4bv require saponification to precede the final hydrogenation step
  • Examples 4bw to 4by - modification of the side chain of the amino pyridine substituent is effected by 1 ,1-ca ⁇ onyl di-imadazole-assisted amide coupling as the last synthetic step
  • Examples 4bz and 4ca are as Examples 4bw to 4by with the addition of a final catalytic hydrogenation step
  • Example 4cb requires acidolytic deprotection as the final step
  • Example 5t is obtained by saponification of the 2-acetyloxyethyl precursor
  • Example 5k The following are prepared by treatment of Example 5k with tnethyl orthofonmate and tnethyl orthoacetate respectively under standard conditions
  • ba 4-(1(S)-Butylam ⁇ nomethyl-2-phenyl- 639 4 1H ethylam ⁇ no)-py ⁇ d ⁇ ne-3-sulfon ⁇ c acid ⁇ 1(S)-(4- amino-benzyi)-2-[4-(2-fluoro-ethyl)-p ⁇ pe ⁇ d ⁇ n-1- yl]-2-oxo-ethyl ⁇ -am ⁇ de
  • Example 6al requires further elaboration of the aminopy ⁇ dine substituent by alkylation with bromo-acetic a ⁇ d tert.-butyl ester followed by reduction (as the last step of Example 5)
  • Example 6am is isolated as a by-product in the preparation of Example 6al
  • Example 6an is produced by a ⁇ dolytic deprotection of Example 6al
  • Example 6bb is a 60:40 mixture of diastereomers (by hplc analysis)
  • Example 6bc is an 80.20 mixture of diastereomers (by hplc analysis)
  • Example 6bv is prepared as Examples 6aq to 6bu followed by a saponification step
  • Example 6bw is obtained by the treatment of Example 6av with propionyl chloride
  • Examples 6bx is obtained by treatment of Example 6cd with ethyl isocyanate
  • Example 6 requires a ⁇ dolytic deprotection of the tert.-butoxyca ⁇ onyl precursor
  • Example 6bz is obtained after treament of the approp ⁇ ate precursor with ethyl isocyanate followed by catalytic hydrogenation (as the last step of Example 5)
  • Examples 6ca and 6cb are obtained by a final saponification step
  • Example eg is obtained by acetylation of the approp ⁇ ate precursor
  • Example ch is obtained by catalytic reduction of Example 6cg
  • the filtrate is diluted with ethyl acetate (100ml), the organic layer is separated, washed with water (50ml), dried (MgSO4) and the solvent evaporated to give a residue which is purified by flash chromatography on a column of silicagel using hexane:ethyl acetate (1 :1 , by vol.) as eluant to give ⁇ 1(S)-(4-benzylamino-benzyl)-2-[4-(2-fluoro- ethyl)-piperidin-1-yl]-2-oxo-ethyl ⁇ -carbamic acid tert.-butyl ester as a yellow foam.
  • the mixture is stirred at room temperature for 1 hour, further portions of aqueous fomaldehyde (37% w/v, 1.5ml) and sodium cyanoborohydride (615mg) are added and the mixture is stirred for a further 30 minutes.
  • the mixture is extracted with ether (50ml).
  • the compounds are analysed for their effect on the human ⁇ -thrombin- catalysed hydrolysis of the substrate Kabi S-2238 (Kabi Vitrum (UK) Ltd).
  • the K m and K p values are derived from a Lineweaver-Burk plot of data, from which is calculated the K, value for the inhibitors
  • the potency of compounds with respect to human ⁇ -thrombin is expressed as their kinetic inhibition constant (K,).
  • Duplicate series of reaction mixtures are prepared comprising chromogenic substrate S-2238 (Kabi Vitrum) in Tris/HCI buffer (0.05M, pH 8.4) with a range of concentrations of substrate from 3.125 ⁇ M to 100 ⁇ M. The solutions are brought to 37°C in a thermostatically regulated heating block.
  • a compatible vehide water, methanol or DMSO
  • a compatible vehide water, methanol or DMSO
  • the reactions are started by the addition of human ⁇ - thrombin (Sigma, T-8885) to give a final activity of 0.0625 NIH units/ml.
  • the initial reaction rate (as change in abso ⁇ ance per minute) is measured using a Perkin Elmer Lambda 5 spectrophotometer (fitted with a cuvette holder thermostatted at 37°C) at 405nm over a period of 1 minute during which time the rate is linear and showing no signs of substrate depletion.
  • Freshly collected blood is immediately anticoagulated by mixing with one- tenth volume of trisodium citrate solution (3.8% w/v in distilled water). The blood is centrifuged at 1300 x g for 20 minutes to obtain platelet-poor plasma.
  • Aliquots of plasma are treated with solutions of experimental compound or vehide alone to give a range of concentrations from 0 to approximately 150 ⁇ M.
  • the APTTs of the treated plasma samples are determined using the standard method on the Instrumentation Laboratory ACL 300R coagulometer.
  • the principle of the assay is that citrated plasma (50 ⁇ l) is activated by incubating for 5 minutes at 37°C with bovine cephalin reagent (Instrumentation Laboratory (UK) Ltd, APTT (Ellagic Acid) Test Kit, 50 ⁇ l), before initiating coagulation by the addition of calcium chloride solution (20mM, 50 ⁇ l).
  • the time taken for coagulation of the plasma to occur is measured automatically by the Instrumentation Laboratory ACL 300R coagulometer.
  • APTT of the plasma is determined from a graph of concentration of experimental compound vs APTT.
  • Tablets suitable for oral administration are provided.
  • Tablets containing the ingredients indicated below may be prepared by conventional techniques.
  • Capsules of the below are made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un composé de formule générale (I), ou son sel, formule dans laquelle Y est un groupe amino primaire ou secondaire; R2 est le résidu d'un acide aminé naturel ou synthétique; R3 est hydrogène ou une chaîne alkyle C1-C8 qu'on peut substituer par hydroxy ou halogène; et X est (CH2)n où n est égal à 1, 2 ou 3, ou bien est CH2N ou représente un noyau phénylique condensé éventuellement substitué par un ou deux groupes méthoxy.
PCT/GB1997/001385 1996-06-01 1997-05-21 Inhibiteurs de la thrombine WO1997046553A1 (fr)

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AU29081/97A AU2908197A (en) 1996-06-01 1997-05-21 Thrombin inhibitors

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GB9611461.1 1996-06-01
GBGB9611461.6A GB9611461D0 (en) 1996-06-01 1996-06-01 New compounds

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CO (1) CO4940504A1 (fr)
GB (1) GB9611461D0 (fr)
ID (1) ID16990A (fr)
PE (1) PE69498A1 (fr)
WO (1) WO1997046553A1 (fr)
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1425029A1 (fr) * 2001-08-10 2004-06-09 Palatin Technologies, Inc. Peptidomimetiques de metallopeptides biologiquement actifs
US7078537B2 (en) * 2001-06-12 2006-07-18 Sk Corporation Phenylalkyl diamine and amide analogs
EP2253612A1 (fr) 2005-04-14 2010-11-24 Novartis AG Composés organiques
US20110275612A1 (en) * 2008-05-22 2011-11-10 Boehringer Ingelheim International Gmbh Alpha-substituted n-sulfonyl gylcine amides antagonists of ccr10, compositions containing the same and methods for using them
WO2012068106A2 (fr) 2010-11-15 2012-05-24 Exelixis, Inc. Benxazépines en tant qu'inhibiteurs de pi3k/mtor et leurs procédés d'utilisation et de fabrication
WO2012071509A2 (fr) 2010-11-24 2012-05-31 Exelixis, Inc. Benzoxazépines utilisées comme inhibiteurs de p13k/mtor et procédés d'utilisation et de fabrication

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112679448B (zh) * 2020-12-31 2022-08-19 苏州昊帆生物股份有限公司 N-(2-氨基乙基)吗啉的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0555824A1 (fr) * 1992-02-13 1993-08-18 Dr. Karl Thomae GmbH Dérivés de benzimidazolylalaninamide N-alpha-arylsulphonyl substitués, médicaments les contenant et procédés pour leur préparation
WO1994012181A1 (fr) * 1992-12-01 1994-06-09 Merck & Co., Inc. Antagonistes des recepteurs du fibrinogene
FR2727413A1 (fr) * 1994-11-25 1996-05-31 Synthelabo Derives de 5-(1h-imidazol-4-yl)-1-oxo-2-(phenylsulfonamino)- pentylpiperidine, leur preparation et leur application en therapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0555824A1 (fr) * 1992-02-13 1993-08-18 Dr. Karl Thomae GmbH Dérivés de benzimidazolylalaninamide N-alpha-arylsulphonyl substitués, médicaments les contenant et procédés pour leur préparation
WO1994012181A1 (fr) * 1992-12-01 1994-06-09 Merck & Co., Inc. Antagonistes des recepteurs du fibrinogene
FR2727413A1 (fr) * 1994-11-25 1996-05-31 Synthelabo Derives de 5-(1h-imidazol-4-yl)-1-oxo-2-(phenylsulfonamino)- pentylpiperidine, leur preparation et leur application en therapeutique

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7078537B2 (en) * 2001-06-12 2006-07-18 Sk Corporation Phenylalkyl diamine and amide analogs
EP1425029A1 (fr) * 2001-08-10 2004-06-09 Palatin Technologies, Inc. Peptidomimetiques de metallopeptides biologiquement actifs
EP1425029A4 (fr) * 2001-08-10 2006-06-07 Palatin Technologies Inc Peptidomimetiques de metallopeptides biologiquement actifs
EP2253612A1 (fr) 2005-04-14 2010-11-24 Novartis AG Composés organiques
US20110275612A1 (en) * 2008-05-22 2011-11-10 Boehringer Ingelheim International Gmbh Alpha-substituted n-sulfonyl gylcine amides antagonists of ccr10, compositions containing the same and methods for using them
US8859814B2 (en) * 2008-05-22 2014-10-14 Boehringer Ingelheim International Gmbh Alpha-substituted N-sulfonyl gylcine amides antagonists of CCR10, compositions containing the same and methods for using them
WO2012068106A2 (fr) 2010-11-15 2012-05-24 Exelixis, Inc. Benxazépines en tant qu'inhibiteurs de pi3k/mtor et leurs procédés d'utilisation et de fabrication
WO2012071509A2 (fr) 2010-11-24 2012-05-31 Exelixis, Inc. Benzoxazépines utilisées comme inhibiteurs de p13k/mtor et procédés d'utilisation et de fabrication

Also Published As

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AR008376A1 (es) 2000-01-19
GB9611461D0 (en) 1996-08-07
ZA974779B (en) 1997-12-01
AU2908197A (en) 1998-01-05
CO4940504A1 (es) 2000-07-24
PE69498A1 (es) 1998-11-27
ID16990A (id) 1997-11-27

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