EP0636144A1 - Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase - Google Patents

Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase

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Publication number
EP0636144A1
EP0636144A1 EP93910159A EP93910159A EP0636144A1 EP 0636144 A1 EP0636144 A1 EP 0636144A1 EP 93910159 A EP93910159 A EP 93910159A EP 93910159 A EP93910159 A EP 93910159A EP 0636144 A1 EP0636144 A1 EP 0636144A1
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EP
European Patent Office
Prior art keywords
formula
compound
group
alkyl
bear
Prior art date
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EP93910159A
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German (de)
English (en)
Inventor
Peter Robert Bernstein
Andrew Shaw
Ashokkumar Bhikkappa Shenvi
Royston Martin Thomas
Peter Warner
Donald John Wolanin
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Syngenta Ltd
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Zeneca Ltd
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Priority claimed from GB929208387A external-priority patent/GB9208387D0/en
Priority claimed from GB929217366A external-priority patent/GB9217366D0/en
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Publication of EP0636144A1 publication Critical patent/EP0636144A1/fr
Ceased legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06139Dipeptides with the first amino acid being heterocyclic
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06191Dipeptides containing heteroatoms different from O, S, or N
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • the present invention relates to certain heterocyclic derivatives, in particular, certain 1-pyridylacetamide compounds, which are inhibitors of human leukocyte elastase (HLE), also known as human neutrophil elastase (HNE), making them useful whenever such inhibition is desired, such as for research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which HLE is implicated.
  • HLE has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS), rheumatoid arthritis, atherosclerosis, pulmonary emphysema, and other inflammatory disorders, including airway inflammatory diseases characterized by increased and abnormal airway secretion such as chronic bronchitis and cystic fibrosis.
  • ARDS acute respiratory distress syndrome
  • rheumatoid arthritis rheumatoid arthritis
  • atherosclerosis CAD
  • pulmonary emphysema pulmonary emphysema
  • other inflammatory disorders
  • HLE has been implicated in certain vascular diseases and related conditions (and their therapy) in which neutrophil participation is involved or implicated, for example, in hemorrhage associated with acute non-ly phocytic leukemia, as well as in reperfusion injury associated with, for example, myocardial ischaemia and related conditions associated with coronary artery disease such as angina and infarction, cerebrovascular ischaemia such as transient ischaemic attack and stroke, peripheral occlusive vascular disease such as intermittent claudication and critical limb ischaemia, venous insufficiency such as venous hypertension, varicose veins and venous ulceration, as well as impaired reperfusion states such as those associated with reconstructive vascular surgery, thrombolysis and angioplasty.
  • the invention also includes intermediates useful in the synthesis of these heterocyclic derivatives, processes for preparing the heterocyclic derivatives, pharmaceutical compositions containing such heterocyclic derivatives and methods for their use.
  • is (1-5C)alkyl
  • R is hydrogen
  • R is an acyl group of formula A.X.C0- in which A.X-, taken together, is hydrogen, triflupromethyl, 2,2,2-trifluoroethoxy, amino, methoxyamino, 2,2,2-trifluoroethylamino, RbRcN.O-, RaOCONH-, R S0 2 NH-, RaOCO-, RbRcNCO- or RaCO-; or
  • R is an acyl group of formula A.X.CJ- in which
  • J is oxygen or sulfur
  • X is a direct bond, imino, oxy or thio
  • A is as defined below or
  • A is tetrahydropyran-4-yl, l-methylpiperid-4-yl, or 5-methyl-l,3-dioxacyclohex-5-ylmethyl;
  • R is a sulfonyl group of formula D.W.S0 ⁇ - in which D.W-, taken together, is hydroxy, amino, di(lower alkyl)amino, 2,2,2-tri- fluoroethylamino, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl or trifluoromethyl; or
  • is a direct bond, imino, carbonylimino, oxycarbonylimino or iminocarbonylimino;
  • R is a group G as defined below;
  • the group A, D or G is (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(l-3C)alkyl, aryl, aryl(1-3C)alkyl, heteroaryl or heteroaryl(l-3C)-alkyl wherein an aryl or heteroaryl moiety may bear one or more halogeno, nitro, methyl or trifluoromethyl groups and further wherein the group A, D or G may bear one or more substituents selected from a group consisting of hydroxy, lower alkoxy, lower 2 COORa, CONRbRc, CH 2 CONRbRc, C00(CH 2 ) 2 NReRf, cyano, NReRf, NRgCHO, NRgCOR 2 , NRgCOOR 2 , NRhCQNRiRj, , S0 2 NRnCOR 4 and P(0)(0Ra) 2 in which
  • Q is oxygen or sulfur
  • Ra-Rn are independently hydrogen, benzyl or lower alkyl; or, independently, a group NRbRc, NReRf, NRiRj or NRlRm is a cyclic radical selected from a group consisting of 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl which may bear a lower alkyl substituent at the 4-position; or, independently, a group NReRf is a cyclic radical selected from a group consisting of 2-pyrrolidinon-l- yl, succinimido, oxazolidin-2-on-3-yl, 2-benzoxazolinon-3-yl, phthalimido and cis-hexahydrophthalimido; and
  • R -R are independently trifluoromethyl, (1-6C)alkyl
  • R and R is, independently, hydrogen or lower alkyl
  • R and R is hydrogen or methyl and the other of R and R is a radical of formula E.Y- in which
  • E is aryl or heteroaryl, which aryl or heteroaryl independently may bear one or more of the substituents defined for A,
  • Y is a direct bond, methylene, ethylene or trans-vinylene
  • 1 2 Q and Q which may be the same or different, is each hydroxy or OR , or when taken together from a moiety derived from a physiologically acceptable dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or atoms which can be 0, S or N, wherein R is
  • Halogeno is fluoro, chloro, bromo or iodo.
  • Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such "propyl” embraces only the straight chain ("normal") radical, a branched chain isomer such as "isopropyl” being specifically referred to.
  • Lower alkyl and lower alkoxy refer to radicals containing one to about four carbon atoms.
  • Lower acyloxy refers to a radical containing one to about five carbon atoms.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one •derived by fusing a propenylene, tri ethylene or tetramethylene diradical thereto, as well as a stable N-oxide thereof.
  • a compound of formula I may exist in, and be isolated in, optically active and racemic forms. If a compound of formula I contains an additional chiral element, such compound of formula I may exist in, and be isolated in, the form of a diastereomeric mixture or as a single diastereomer. It is to be understood that the present invention encompasses a compound of formula I as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer.
  • a compound of formula I When R is isopropyl, a compound of formula I may be viewed as a valyl (or "borovaline") derivative.
  • a compound of formula I having the (S)-configuration at the chiral center indicated by "*", which corresponds to the L-alanyl configuration is preferred. Accordingly, it may be preferred to use the compound of formula I in a form which is characterized as containing, for example, at least 95%, 98% or 99% enantiomeric excess (ee) of the ( ⁇ S)-form.
  • a compound of formula I may exhibit polymorphism.
  • the compound may form solvates.
  • a compound may exist in more than one tautomeric form. It is to be understood, therefore, that the present invention encompasses any racemic or optically-active form, any polymorphic form, any tautomer or any solvate, or any mixture thereof, which form possesses inhibitory properties against HLE, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form or by synthesis from optically-active starting materials) and how to determine the inhibitory properties against HLE by the standard tests described hereinafter, derivatives
  • radicals R , R , R, R and R not contain nor introduce an additional element of chirality into the molecule beyond the chiral center indicated by "*" in formula I;
  • the boron substituents Q and Q may be chiral.
  • R is ethyl or isopropyl.
  • a particular value for W is a direct bond or imino.
  • G is (l-3C)alkyl, aryl(l-C)alkyl or heteroaryl(1-2C)alkyl which may bear one or more substituents as defined above for G or a part thereof.
  • a particular value of (1-6C)alkyl or (1-IOC)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, 3-methylbutyl, 1-ethylpropyl, hexyl or 4-methylpentyl.
  • a particular value of (3-6C)cycloalkyl or (3-10C)cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.
  • a particular value for the (1-3C)alkyl portion of (3-6C)cycloalkyl-(l-3C)alkyl ' , aryl(l-3C)alkyl or heteroaryl(l-3C)alkyl is methylene, ethylene or trimethylene.
  • a particular value for aryl is phenyl, indenyl, indanyl or naphthyl.
  • a particular value for heteroaryl is furyl, imidazolyl, tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl or quinolinyl (or its N-oxide).
  • a particular .value for lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl.
  • a particular value for lower acyloxy is acetoxy.
  • a particular value for lower alkoxy is methoxy, ethoxy, propoxy, isoproxy or t-butoxy.
  • a particular value for halogeno is bromo, chloro or fluoro.
  • COORa is carboxy or methoxycarbonyl.
  • NRgCOR is trifluoroacetylamino.
  • CONRdSO-R is N-phenylsulfonylcarbamoyl or
  • N-(4-chlorophenylsulfonyl)carbamoyl A particular value for A.X-, taken together, is tris(hydroxymethyl)methylamino, tris(acetoxymethyl)methylamino or 2,2-bis(hydroxymethyl)propoxy.
  • R is isopropyl.
  • J is oxygen.
  • X is a direct bond, imino or oxy.
  • a more particular value for A is methyl, ethyl, phenyl, benzyl, phenethyl, pyridyl, thienyl, 5-tetrazolyi, thiazolyl, pyridylmethyl, thenyl, 5-tetrazolylmethyl,
  • a more particular value for D is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridyl, thienyl, 5-tetrazolyl, thiazolyl, quinolinyl, pyridylmethyl, thenyl, 5-tetrazolylmethyl, 2-(pyridyl)ethyl, 2-(thienyl)ethyl or 2-(thiazolyl)ethyl wherein the phenyl or heteroaryl group may bear one or two halogeno or methyl groups and further wherein the group D may bear a substituent selected from hydroxy, methoxy, t-butoxy, acetoxy, pivaloyloxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, dimethylcarbamoyl, 2-(dimethylamino)eth
  • G is methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, thenyl, 5-tetrazolylmethyl, or 2-(pyridyl)ethyl, wherein an alkyl carbon may bear an oxo.
  • the phenyl or heteroaryl group may bear one or two halogeno or methyl groups and further wherein the group G may bear a substituent selected from hydroxy, methoxy, acetoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, dimethylcarbamoyl, phenylcarbamoyl, pyridylcarbamoyl, methylsulfonylamino, amino, dimethylamino, acetylamino, nicotinoylamino, or trifluoroacetylamino.
  • R is, for example, hydrogen, trifluoroacetyl, hydroxyoxalyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 4-fluorophenoxycarbonyl, 4-bromophenoxycarbonyl, 4-methoxyphenoxycarbonyl, benzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 3-methylpyrid-4-ylmethoxycarbonyl, 2,6-dimethylpyrid-4-ylmethoxy- carbonyl, 2-pyridylmethoxycarbonyl, 6-methylpyrid-2-ylmethoxycarbonyl, 2-dimethylaminoethoxycarbonyl, acetyl, carbamoylmethylaminocarbonyl, 4-(N-phenylsulfonylcarbamoyl)phenylacetyl, sulfo, aminosulfonyl
  • Q and Q are, for example, hydroxy
  • One particular group of compounds of formula I is one in which Q , Q , R and R have any of the values defined above, R is hydrogen and R is hydrogen.
  • R is benzyl, the phenyl ring of which may bear a 3-fluoro, 4-fluoro, 4- rifluoromethyl, 4-methoxycarbonyl, 3-acetoxy, 3-hydroxy, 3-pivaloyloxy, 4-hydroxy, 4-pivaloyloxy, 3-trifluoroacetylamino or 3-amino substituent, and R is hydrogen.
  • a further particular group of compounds of formula I is one in which Q , Q , R and R have any of the values defined above, R is hydrogen, and R is 2-furyl, 2-thienyl, 3-pyridyl or phenyl in which the phenyl may bear one or two halogeno, trifluoromethyl, methyl, hydroxy, methoxy, tert-butoxy, methoxycarbonyl or carboxy substituents; and, more particularly, R is phenyl, 4-fluorophenyl 2-thienyl.
  • a pharmaceutically acceptable salt of an acidic compound of formula I is one made with a base which affords a pharmaceutically acceptable cation, which includes alkalai metal salts (especially lithium, sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from appropriate organic bases such as triethylamine, morpholine, piperidine and triethanol amine.
  • a pharmaceutically acceptable salt of a basic compound of formula I includes an acid-addition salt made with an acid which provides a .pharmaceutically acceptable anion, including for example, a strong acid such as hydrochloric, sulfuric or phosphoric acid.
  • a compound of formula I may be made by processes which include processes known in the chemical art for the production of structurally analogous heterocyclic and peptidic compounds. Such processes and intermediates for the manufacture of a compound of formula I as defined above are provided as further features of the invention and are illustrated by the following procedures in which the meanings of generic radicals are as defined above:
  • Conventional methods include, for example, removal of a benzyloxycarbonyl group by hydrogenolysis, removal of a benzyloxycarbonyl or tert-butoxycarbonyl group by treatment with a strong acid, for example with trifluoromethanesulfonic acid in an inert solvent such as dichloromethane, or basic hydrolysis of a trifluoroacetyl group.
  • (C) For a compound of formula I wherein R is an acyl group, acylation of a corresponding amine of formula I wherein R is hydrogen.
  • Convenient methods include, for example, when J is oxygen, the use of an activated carboxylie acid derivative, such as an acid halide, the use of a carboxylic acid and a coupling reagent, the use of an isocyanate for a compound wherein X is imino, and the use of a diactivated carbonic acid derivative, for example,
  • the sulfonylation is conveniently carried out in an inert solvent or diluent, such as dichloromethane, tetrahydrofuran or toluene, at about ambient temperature, using an organic base such as, for example, triethylamine or pyridine, or an inorganic base, such as sodium or potassium carbonate, as an acid acceptor. If a sulfonyl chloride is not commercially available, it may be obtained by a conventional method.
  • an inert solvent or diluent such as dichloromethane, tetrahydrofuran or toluene
  • organic base such as, for example, triethylamine or pyridine
  • an inorganic base such as sodium or potassium carbonate
  • NHRh or NHRk i.e. an amino group of formula NReRf is which Re is hydrogen and Rf is Rg, Rh or Rk
  • NReRf an amino group of formula NReRf is which Re is hydrogen and Rf is Rg, Rh or Rk
  • a pharmaceutically acceptable salt of an acidic or basic compound of formula I when required, it may be obtained by reacting the acidic or basic form of such a compound of formula I with a base or acid affording a physiologically acceptable counterion or by any other conventional procedure.
  • the necessary starting materials for the above procedures may be made by procedures which are selected from standard techniques of heterocyclic chemistry and peptide chemistry, techniques which are analogous to the synthesis of known, structurally similar compounds, and techniques which are analogous to the above described procedures or the procedures described in the Examples.
  • compounds herein are represented as the 2-pyridone, rather than the 2-hydroxypyridine, tautomers.
  • a ketone of formula R .CH j .CO.R may be formylated, then cyclized with cyanoacetamide to afford a pyrid-2-one-3-carbonitrile of formula IV.
  • the ketone may be formylated with dimethylformamide dimethyl acetal in acetonitrile, then the isolated intermediate cyclized with cyanoacetamide, using sodium methoxide in dimethylformamide.
  • the ketone may be formylated using sodium methoxide and ethyl formate in tetrahydrofuran or ether, distilling the solvent, dissolving the resulting salt in water, adding acetic acid to pH 9, and heating with cyanoacetamide at 90 °C to achieve the cyclization.
  • the salt resulting from formylation with sodium methoxide and ethyl formate, followed by removal of the solvent may be cyclized with cyanoacetamide by heating an aqueous solution with piperidine acetate as a catalyst.
  • the product selectivity may be controlled by the cyclization (and formylation) method chosen.
  • cyclization of phenylacetone by Cyclization Method A affords 6-methyl-5-phenyl-pyrid-2-one-3-carbonitrile; but cyclization of phenylacetone by Cyclization Method C affords 6-benzylpyrid-2-one- 3-carbonitrile.
  • Hydrolysis of the cyano group of a compound of formula IV for example by heating with 48% hydrobromic acid in acetic acid (Hydrolysis Method A) or with sodium hydroxide solution in a pressure vessel (Hydrolysis Method B) affords a corresponding carboxy derivative of formula III.
  • R is E.Y- and Y is ethylene or trans-vinylene
  • Y is ethylene or trans-vinylene
  • cyclization of a ketone of formula R -CH-.CO.CH affords a 6-methyl pyridone derivative of formula IVa, for example, cyclizing acetone by Cyclization Method C.
  • Bis-metallation, followed by alkylation with a reagent of, for example, formula E.CH 2 .Br affords a corresponding nitrile of formula IV in which Y is ethylene.
  • An acid of formula III may be converted into a corresponding isocyanate of formula VI by a conventional method, for example by using triethylamine and diphenylphosphoryl azide in an inert solvent, for example dioxane or toluene, at an elevated temperature.
  • the isocyanate is not isolated, but is converted into a benzyl urethane of formula VII as also is shown in Scheme I.
  • a substituted amino pyridone of formula VII or Vila into a corresponding intermediate acetic acid of formula Ha or a corresponding intermediate amine of formula Vb may be carried out as outlined.
  • a pyridone of formula VII may be alkylated, for example with ethyl or t-butyl iodoacetate using sodium hydride in dimethylformamide, to afford a corresponding ester of formula XI, wherein Rq is a conveniently removable acid protecting group, for example ethyl or t-butyl.
  • Rq is a conveniently removable acid protecting group, for example ethyl or t-butyl.
  • R is subject to hindered rotation, for example when R is methyl and R is phenyl, or, for example, when R is hydrogen and R is 2-chlorophenyl, the ratio of N-alkylated product to O-alkylated product is increased.
  • An acid of formula XII is an acid of formula Ha in which R is benzyloxycarbonyl.
  • a preferred method for introducing the substituent R when it is a group G, particularly when it is an alkyl or substituted alkyl group, is by the use of a corresponding compound in which the pyridone 3-amino substituent bears an activating/protecting group of formula Rx, for example, benzyloxycarbonyl or trifluoroacetyl.
  • Rx an activating/protecting group of formula Rx
  • acylation of a compound of formula I wherein R is hydrogen with trifluoroacetic anhydride affords a corresponding compound of formula Va in which Rx is trifluoroacetyl, which compound also may be prepared by an alternative order of steps via the corresponding compound of formula IX.
  • a compound of formula VHIb is, itself, a corresponding compound of formula Va in which Rx is benzyloxycarbonyl.
  • each of a compound of formula Va in which Rx is benzyloxycarbonyl or trifluoroacetyl is also a compound of formula I in which R is an acyl group.
  • Synthesis routes involving a cross coupling reaction to introduce a substituent R into intermediate compounds are outlined in Scheme III. These routes may be preferred when R has the value E.Y- and Y is methylene, ethylene or trans-vinylene.
  • a pyridone of formula VII in which R is hydrogen may be converted into, a corresponding 5-iodo pyridone of formula XXI by treatment with an iodinating agent, for example N-iodosucciniraide.
  • An appropriate halide for example a bromide of formula E.CH 2 .Br, may be converted into a corresponding organozinc reagent, for example E.CH ⁇ .Zn.Br, by treatment with zinc dust in tetrahydrofuran, and cross-coupled with an iodide of formula XXI using a palladium catalyst, such as dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(H) to afford a corresponding compound of formula VII in which R is E.Y- and Y is methylene.
  • a palladium catalyst such as dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(H)
  • a similar cross coupling utilizing a bromide of formula E.Y.Br in which Y is trans-vinylene may be useful to convert an iodide of formula XXI into a corresponding compound of formula VII in which R is E.Y- and Y is trans-vinylene.
  • a compound in which R is E.Y- and Y is trans-vinylene may be hydrogenated to afford a corresponding compound in which R is E.Y- •and Y is ethylene.
  • an iodide of formula XXI may be converted into a corresponding iodide of formula XXII which may be further cross coupled as described above to provide a corresponding compound of formula XI.
  • a pyridone of formula VHb which may be converted into a corresponding intermediate of formula Ha or formula Vb using a route similar to one outlined above for a compound of formula VII.
  • the 3-nitro pyridone may be alkylated first to provide an ester of formula XXIV.
  • the ester of formula XXIV may be converted into the corresponding acid of formula XXV.
  • the acid of formula XXV also may be obtained by allylation of the starting 3-nitro pyridone, followed by oxidative cleavage of the 1-allyl group using potassium permanganate.
  • an acid of formula XXV may be converted into a nitro derivative of formula XXVIH.
  • Reduction of the nitro group of a nitro derivative of formula XXVIH affords an amine of formula I in which R is hydrogen.
  • An analogous route from a nitro compound of formula XXIV involves first reducing the nitro group to afford a corresponding amino compound of formula XXIX.
  • Sustitution of the amino group of a compound of formula XXIX using a method similar to one described above affords a compound of formula Xlb, which may be further converted into a corresponding compound of formula Ha using a similar method to one described above for a compound of formula XI.
  • a compound of formula XI prepared by one of the methods described above can also be converted into a corresponding ester of formula Xlb, and further into a corresponding compound of formula Ha.
  • a protecting group may be used during all or portions of the above described processes; the protecting group then may be removed when the final compound or a required starting material is to be formed.
  • the order of steps in the sequences leading to the starting materials and products of the invention may be altered if appropriate considerations relative to coupling methods, racemization, deprotection methods, etc. are followed.
  • the potency of a Compound to act as an inhibitor of human leukocyte elastase (HLE) on the low molecular weight peptide substrate methoxy-succinyl-alanyl-alanyl-prolyl-valine-p-nitroanilide is determined as described in U.S. Patent 4,910,190.
  • the potency of an inhibitor is evaluated by obtaining a kinetic determination of the dissociation constant, K. , of the complex formed from the interaction of the inhibitor with HLE. If a Compound is found to be a "slow-binding" inhibitor of HLE, special methods of analysis to accurately determine K. values for the inhibition of HLE are carried out as described in U.S. Patent 4,910,190. In general, the K. values for Compounds of the invention which were tested are generally on the order of 10 ⁇ M or much less.
  • Acute Lung Injury Model Acute Lung Injury Model
  • Animal models of emphysema include intratracheal (i.t.) -administration of an elastolytic protease to cause a slowly progressive, destructive lesion of the lung. These lesions are normally evaluated a few weeks to a few months after the initial insult. However, these proteases also induce a lesion that is evident in the first few hours. The early lesion is first hemorrhagic, progresses to an inflammatory lesion by the end of the first 24 hours and resolves in the first week post insult. To take advantage of this early lesion, the following model (described in Williams, et al. , American Review of Respiratory Diseases (1991), 144, 875-838) was used.
  • Hamsters are first lightly anesthetized with Brevital. Phosphate buffered saline (PBS) pH 7.4, either alone or containing human leukocyte elastase (HLE), is then administered directly into the trachea. Twenty-four hours later the animals are killed and the lungs removed and carefully trimmed of extraneous tissue. Following determination of wet lung weight, the lungs are lavaged with PBS and total lavagable red and white cells recovered are determined. The values for wet lung weights, total lavagable red cells and total lavagable white cells are elevated in a dose-dependent manner following administration of HLE.
  • PBS Phosphate buffered saline
  • HLE human leukocyte elastase
  • Compounds that are effective elastase inhibitors can prevent or diminish the severity of the enzyme-induced lesion resulting in lower wet lung weight and reduced values for total lavagable cells, both red and white, relative to administration of HLE alone.
  • Compounds can be evaluated by administering them intratracheally as solutions or suspensions in PBS, either with or at various times prior to the HLE challenge (400 ⁇ g), or by dosing them intravenously or orally as solutions at various times prior to the HLE challenge (100 ⁇ g) to determine their utility in preventing an HLE lesion.
  • a solution of a Compound is conveniently prepared using 10% polyethylene glycol 400/PBS or 10% polyethylene glycol 400/water.
  • base e.g.
  • HNE human neutrophil elastase
  • the compounds are then dosed by mouth to male Syrian hamsters at a fixed time* such as 30 or 90 min, prior to intratracheal administration of 50 ⁇ g/animal of HNE in 300 ⁇ L phosphate buffered saline (PBS) pH 7.4.
  • PBS phosphate buffered saline
  • the animals are killed with an overdose of pentobarbital sodium, the thorax opened and the lungs and trachea removed.
  • the excised lungs are lavaged with three changes of 2 mL normal saline via a tracheal cannula.
  • the recovered lavages are pooled, the volumes (about 5 mL) are recorded and the lavages stored at 4 °C until assayed.
  • the thawed lavages and a sample of whole hamster blood are sonicated to disrupt erythrocytes and appropriately diluted into individual wells of a 96-well microtiter plate.
  • the optical densities (0D) of the disrupted lavages and blood samples are determined at 405 nm.
  • the ( ⁇ L blood equivalents) / (mL lavage) are determined by comparing the OD of the test samples with the OD of the standard curve prepared from whole hamster blood.
  • the total ⁇ L equivalents of blood recovered is determined by multiplying recovered lavage volume by the ( ⁇ L blood equivalents) / (mL lavage) for each sample.
  • - Results are reported as % inhibition of hemorrhage with respect to PBS treated controls when the test compound is given at a specified dose and time prior to administration of HNE.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a Compound and a pharmaceutically acceptable diluent or carrier.
  • another feature of the invention is a method of using a Compound of the invention in the treatment of a disease or condition in a mammal, especially a human, in which HLE is implicated.
  • a Compound of the present invention may be administered to a warm-blooded animal, particularly a human, in need thereof for treatment of a disease in which HLE is implicated, in the form of a conventional pharmaceutical composition, for example as generally disclosed in U.S. Patent 4,910,190.
  • the preferred mode of administration may be via a powdered or liquid aerosol.
  • a Compound of the invention may be administered in the same manner as cromolyn sodium via a 'Spinhaler' (a trademark) turbo-inhaler device obtained from Fisons Corp. of Bedford, Massachusets at a rate of about 0.1 to 50 mg per capsule, 1 to 8 capsules being administered daily for an average human.
  • Each capsule to be used in the turbo-inhaler contains the required amount of a Compound of the invention with the remainder of the 20 mg capsule being a pharmaceutically acceptable carrier such as lactose.
  • a Compound of the invention may be administered using a nebulizer such as, for example, a 'Retec' (trademark) nebulizer, in which the solution is nebulized with compressed air.
  • the aerosol may be administered, for example, at the rate of one to about eight times per day as follows: A nebulizer is filled with a solution of a Compound, for example 3.5 mL of solution containing 10 mg/mL; the solution in the nebulizer is nebulized with compressed air; and the patient breathes normally (tidal volume) for eight minutes with the nebulizer in his mouth.
  • the mode of adminstration may be oral or parenteral, including subcutaneous deposit by means of an osmotic pump.
  • a compound of the invention may be conventionally formulated in an oral or parenteral dosage form by compounding about 10 to 250 mg per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice, e.g. as described in U.S. Patent 3,755,340.
  • parenteral administration a 1 to 10 mL intravenous, intramuscular or subcutaneous injection would be given containing about 0.02 mg to 10 mg/kg of body weight of a compound of the invention 3 or 4 times daily.
  • the injection would contain a compound of the invention in an aqueous isotonic sterile solution or suspension optionally with a preservative such as phenol or a solubilizing agent such as ethylenedia inetetraacetic acid (EDTA).
  • a preservative such as phenol
  • a solubilizing agent such as ethylenedia inetetraacetic acid (EDTA).
  • an 10 mg/mL aqueous formulation of an acidic Compound may be prepared, for example by dissolving the Compound (10 mg), dibasic sodium phosphate heptahydrate, USP (11.97 mg), monobasic sodium phosphate, USP (0.74 mg) , sodium chloride, USP (4.50 mg) and sufficient 1 N sodium hydroxide solution or 0.05 M monobasic sodium phosphate solution to achieve pH 7.0-7.5 in sufficient water for injection, USP to afford 1.0 mL (1.01 g), followed by aseptic filtration, and sterile storage using standard procedures.
  • a Compound of the invention will be administered to humans at a daily dose in the range of, for example, 5 to 100 mg of the Compound by aerosol or 50 to 1000 mg intravenously, or a combination of the two.
  • a daily dose in the range of, for example, 5 to 100 mg of the Compound by aerosol or 50 to 1000 mg intravenously, or a combination of the two.
  • generally equivalent amounts of a pharmaceutically acceptable salt of the Compound also may be used.
  • Protocols for the administration of an HLE inhibitor and evaluation of the patients are described in the European Patent Applications with Publication Numbers 458535, 458536, 458537, and 463811 for the treatment or prevention of cystic fibrosis, ARDS, bronchitis, and hemorrhage associated with acute non-lymphocytic leukemia or its therapy, respectively; and a Compound of the invention may be used similarly for the treatment of those diseases and conditions either alone or in combination with another therapeutic agent customarily indicated for the treatment of the particular condition.
  • a Compound of the invention may conveniently be administered by a parenteral route, either alone or simultaneously or sequentially with other therapeutically active agents customarily administered for the condition.
  • reversed phase chromatography means flash chromatography over octadecylsilane (ODS) coated support having a particle diameter of 32-74 ⁇ , know as "PREP-40-0DS" (Art 731740-100 from Bodman Chemicals, Aston, PA, USA); thin layer chromatography (TLC) was carried out on 0.25 mm silica gel GHLF plates (Art 21521 from Analtech, Newark, DE, USA); reversed phase-TLC (RP-TLC) was carried out Whatman MKC.gF plates (Art 4803-110 from Bodman Chemicals);
  • melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 250 MHz using DMS0-d ⁇ as solvent; conventional abbreviations for signal shape are used; for AB spectra the directly observed shifts are reported;
  • the title compound may be prepared by the following procedure:
  • Fraction 1 contained a significant amount of acetophenone and amino acetaldehyde dimethyl acetal.
  • Fraction 2 contained less than 5% acetophenone and acetal, and was used directly in the next step.
  • the NMR spectrum was obtained from a clean fraction of imine produced in a different run; 300 MHz NMR: 2.20 (s,3), 3.33 (s,6), 3.54 (d,2), 4.70 (t,l), 7.38-7.43 (m,3), 7.79-7.82 (m,2).
  • the reaction mixture was cooled to 70 C C, and benzyl alcohol (38.9.g) was added in one portion along with a dioxane wash (100 L) .
  • the reaction was heated at reflux for 18 hours, cooled and evaporated.
  • the residual oil was dissolved in ethyl acetate (1 L) and washed with 1 N hydrochloric acid:brine (1:1), followed by brine.
  • the organic layer was dried (MgSO,) and evaporated to give the crude mixture (249.5 g) .
  • a 2 L, three-necked flask was equipped with a mechanical stirrer, an addition funnel and a Claisen adapter holding a thermometer and a reflux condenser capped with a nitrogen inlet.
  • the flask was charged with a tetrahydrofuran (275 mL) solution of the product from Example I.e. (40.5 g).
  • the addition of tert-butanol (275 mL) caused precipitation of the aldehyde starting material.
  • the reaction mixture was cooled to 15 °C with an ice-water bath, and 2-methyl-2-butene (250 mL) was added in one portion.
  • the triethylborate and the Grignard reagent were simultaneously added dropwise over a 2 hour period, while maintaining an internal temperature of less than -50 °C. Upon completion of the addition, the mixture was stirred for an additional 2 hours at -78 °C. The reaction was quenched by dropwise addition of concentrated hydrochloric acid (600 mL) over 1 hour. The temperature of the mixture rose from -78 °C to -20 °C, and the dark amber solution became colorless. The mixture was stirred overnight, evaporated, and extracted with ether. The combined extracts were washed with brine and dried (MgSO,). Evaporation gave crude (dihydroxy)isopropylborane as a white semi-solid (360.2 g).
  • This material was dissolved in ethyl acetate (1 mL), and the solution was placed in a 3 L, 3-necked flask equipped with a mechanical stirrer and a nitrogen inlet. To the solution was added 2,3-dimethyl-2,3-butanedio ⁇ (378 g) and anhydrous magnesium sulfate (200 g). The mixture was allowed to stir for 70 hours, the solids were removed by filtration, and the filtrate was evaporated to yield an amber oil. The oil was purified by two fractional distillations at reduced pressure.
  • the n-butyllithium was added dropwise over 3 hours while maintaining the internal temperature at -78 °C.
  • the reddish-brown solution was treated with the product from Example l.g. (128.0 g) by dropwise addition over 10 minutes.
  • the reaction mixture was stirred for 1 hour while warming slowly to -40 °C.
  • the mixture was cooled to -78 °C and a zinc chloride solution (490 mL, 1.0 M in ether) was added over 15 minutes.
  • the mixture was stirred for 15 minutes at -78 °C and allowed to warm to room temperature overnight.
  • the n-butyllithium was added dropwise to the cooled reaction vessel over 30 minutes.
  • the internal temperature was maintained in the range -78 to -60 °C during the course of the addition.
  • the reaction mixture was •warmed to 0 °C for 30 minutes, was cooled to -78 °C, and the product from Example l.h. (163.5 g) was added dropwise over 15 minutes.
  • the cooling bath was removed and the mixture was allowed to warm to room temperature overnight.
  • the orange suspension was filtered to remove solids and the filtrate was evaporated. The residue was filtered to remove solids and the filter cake was washed with ether.

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Abstract

La présente invention se rapporte à certains nouveaux dérivés hétérocycliques qui sont les dérivés de 1-pyridylacétamide de formule (I). Ces dérivés sont des inhibiteurs de l'élastase de leucocytes humains (ELH), dénommée également l'élastase de neutrophiles humains (ENH) et sont utilisés lorsque une telle inhibition est nécessaire, par exemple, pour des outils de recherche dans des études pharmacologiques et diagnostiques et analogues et pour le traitement de maladies affectant les mammifères chez lesquels l'ELH est impliquée. L'invention concerne également des intermédiaires utilisées pour effectuer la synthèse de cas dérivés hétérocycliques, les procédés de préparation de ces dérivés hétérocycliques, les compositions pharmaceutiques contenant ces derniers et des procédés pour leur utilisation.
EP93910159A 1992-04-16 1993-04-15 Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase Ceased EP0636144A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9208387 1992-04-16
GB929208387A GB9208387D0 (en) 1992-04-16 1992-04-16 Heterocyclic derivatives
GB929217366A GB9217366D0 (en) 1992-08-14 1992-08-14 Heterocyclic derivatives
GB9217366 1992-08-14
PCT/GB1993/000796 WO1993021213A1 (fr) 1992-04-16 1993-04-15 Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase

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US5693617A (en) * 1994-03-15 1997-12-02 Proscript, Inc. Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein
US5756466A (en) 1994-06-17 1998-05-26 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US6083903A (en) 1994-10-28 2000-07-04 Leukosite, Inc. Boronic ester and acid compounds, synthesis and uses
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6063794A (en) 1996-10-11 2000-05-16 Cor Therapeutics Inc. Selective factor Xa inhibitors
US6369080B2 (en) * 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
NZ500353A (en) 1997-04-14 2002-02-01 Cor Therapeutics Inc Cyclic diaza compounds that are selective inhibitors of factor Xa
EP0977773A1 (fr) 1997-04-14 2000-02-09 Cor Therapeutics, Inc. INHIBITEURS SELECTIFS DU FACTEUR Xa
WO1998046591A1 (fr) 1997-04-14 1998-10-22 Cor Therapeutics, Inc. INHIBITEURS SELECTIFS DU FACTEUR Xa
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
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US7122627B2 (en) 1999-07-26 2006-10-17 Bristol-Myers Squibb Company Lactam inhibitors of Hepatitis C virus NS3 protease
CA2376961A1 (fr) * 1999-07-26 2001-02-01 Bristol-Myers Squibb Pharma Company Inhibiteurs lactame de la protease ns3 du virus de l'hepatite c
WO2013084199A1 (fr) * 2011-12-07 2013-06-13 Universidade De Lisboa Hétérocycles de bore utiles en tant que nouveaux inhibiteurs de l'élastase des neutrophiles chez l'homme
JP6268014B2 (ja) * 2014-03-20 2018-01-24 富士フイルム株式会社 サラシノールの製造に有用な化合物およびそれらの製造法、サラシノールの製造法、ジオール基の保護方法および脱保護方法、並びにジオール基の保護剤
JP2023500182A (ja) 2019-09-17 2023-01-05 メレオ バイオファーマ 4 リミテッド 移植片拒絶反応、閉塞性細気管支炎症候群、及び移植片対宿主病の治療に使用するためのアルベレスタット
DK4106757T3 (da) 2020-04-16 2023-10-23 Mereo Biopharma 4 Ltd Fremgangsmåder der involverer neutrofil elastase-inhibitor alvelestat til behandling af luftvejssygdom medieret af alpha-1-antitrypsin-mangel
CA3234399A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'elastase neutrophile utilises dans le traitement de la fibrose

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