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WO1993021213A1 - 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 Download PDF

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Publication number
WO1993021213A1
WO1993021213A1 PCT/GB1993/000796 GB9300796W WO9321213A1 WO 1993021213 A1 WO1993021213 A1 WO 1993021213A1 GB 9300796 W GB9300796 W GB 9300796W WO 9321213 A1 WO9321213 A1 WO 9321213A1
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Prior art keywords
formula
compound
group
alkyl
bear
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PCT/GB1993/000796
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English (en)
Inventor
Peter Robert Bernstein
Andrew Shaw
Ashokkumar Bhikkappa Shenvi
Royston Martin Thomas
Peter Warner
Donald John Wolanin
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Zeneca Limited
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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 Limited filed Critical Zeneca Limited
Priority to JP5518139A priority Critical patent/JPH07505875A/ja
Priority to EP93910159A priority patent/EP0636144A1/fr
Publication of WO1993021213A1 publication Critical patent/WO1993021213A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal 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
  • non-lymphocytic 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
  • 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.
  • R 0 is (1-5C)alkyl
  • R is hydrogen
  • R is an acyl group of formula A.X.CO- in which A.X-, taken together, is hydrogen, triflupromethyl, 2,2,2-trifluoroethoxy, amino, methoxyamino, 2,2,2-trifluoroethylamino, RbRcN.O-, RaOCONH-, R 1 SO 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, 1-methylpiperid-4-yl, or 5-methyl-1,3-dioxacyclohex-5-ylmethyl;
  • R is a sulfonyl group of formula D.W.SO 2 - in which D.W-, taken together, is hydroxy, amino, di(lower alkyl)amino, 2,2,2-trifluoroethylamino, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl or trifluoromethyl; or
  • W 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-(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heteroaryl or heteroaryl(1-3C)-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 acyloxy, COORa, CH 2 COORa, CONRbRc, CH 2 CONRbRc, COO(CH 2 ) 2 NReRf, cyano, SO 2 R 1 CONRdSO 2 R 1 , NReRf, NRgCHO, NRgCOR 2 , NRgCOOR 2 , NRhCQNRiRj , NRkSO 2 R 3 , SO 2
  • 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,
  • NReRf is a cyclic radical selected from a group consisting of 2-pyrrolidinon-1-yl, succinimido, oxazolidin-2-on-3-yl, 2-benzoxazolinon-3-yl, phthalimido and cis-hexahydrophthalimido;
  • R 1 -R 4 are independently trifluoromethyl, (1-6C)alkyl,
  • R 5 and R 6 are, independently, hydrogen or lower alkyl
  • R 5 and R 6 is hydrogen or methyl and the other of R 5 and R 6 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;
  • Q 1 and Q 2 which may be the same or different, is each hydroxy or OR 7 , 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 O, S or N, wherein R 7 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, trimethylene 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 0 is isopropyl, a compound of formula I may be viewed as a valyl (or "borovaline”) derivative. In general, a compound of formula I having the (S)-configuration at the chiral center indicated by "*", which corresponds to the L-alanyl
  • 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.
  • ee enantiomeric excess
  • 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
  • radicals R A , R 1 , R, R 5 and R 6 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 1 and Q 2 be chiral.
  • R 0 is ethyl or isopropyl.
  • a particular value for W is a direct bond or imino.
  • G is (1-3C)alkyl, aryl(1-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 (1-10C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
  • (3-6C)cycloalkyl or (3-10C)cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl.
  • heteroaryl(1-3C)alkyl is methylene, ethylene or trimethylene.
  • aryl is phenyl, indenyl, indanyl or naphthyl.
  • 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.
  • a particular value for COORa is carboxy or methoxycarbonyl.
  • a particular value for NRgCOR 2 is trifluoroacetylamino.
  • a particular value of CONRdSO 2 R 1 is N-phenylsulfonylcarbamoyl or
  • R 0 is isopropyl.
  • a more particular value for J is oxygen.
  • a more particular value for 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,
  • phenylsulfonyl N-methylsulfonylcarbamoyl, N-phenylsulfonylcarbamoyl, amino, dimethylamino, oxazolidin-2-on-3-yl, acetylamino,
  • D dimethylphosphoryl or diethylphosphoryl.
  • 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,
  • 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,
  • phenylsulfonyl N-methylsulfonylcarbamoyl, N-phenylsulfonylcarbamoyl, N-(4-chlorophenylsulfonyl) carbamoyl, methylsulfonylamino, amino, dimethylamino, oxazolidin-2-on-3-yl, acetylamino,
  • G is methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, thenyl, 5-tetrazolylmethyl, or 2-(pyridyl)ethyl, wherein an alkyl carbon may bear an oxo. group and wherein 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,
  • R is, for example, hydrogen, trifluoroacetyl, hydroxyoxalyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 4-fluorophenoxycarbonyl, 4-bromophenoxycarbonyl, 4-methoxyphenoxycarbonyl, benzyloxycarbonyl,
  • butylaminosulfonyl tert-butylaminosulfonyl, cyclohexylaminosulfonyl, phenylsulfonyl (in which the phenyl may bear a chloro, nitro, amino, acetylamino, trifluoroacetylamino, methoxy, carboxy,
  • a particular value for Q 1 and Q 2 is, for example, hydroxy, methoxy, ethoxy or isopropoxy; or, when Q 1 and Q 2 are .taken together, a particular value is, for example, the residue derived from
  • One particular group of compounds of formula I is one in which Q 1 , Q 2 , R 0 and R have any of the values defined above, R 5 is hydrogen and R 6 is hydrogen.
  • Another particular group of compounds of formula I is one in which Q 1 , Q 2 , R 0 and R have any of the values defined above, R 5 is benzyl, the phenyl ring of which may bear a 3-fluoro, 4-fluoro, 4-trifluoromethyl, 4-methoxycarbonyl, 3-acetoxy, 3-hydroxy,
  • a further particular group of compounds of formula I is one in which Q 1 , Q 2 , R 0 and R have any of the values defined above, R 5 is hydrogen, and R 6 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
  • R 6 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:
  • 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.
  • 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,
  • thiocarbonic acid derivative for example, dimethyl trithiocarbonate, with an alcohol of formula A.OH, a thiol of formula A.SH or an amine of formula A.NH 2 .
  • a sulfonyl (or sulfamoyl) chloride of formula D.W.SO 2 .Cl particularly a sulfonyl (or sulfamoyl) chloride of formula D.W.SO 2 .Cl.
  • 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.
  • an 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
  • 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.
  • pyrid-2-one-3-carboxylic acid of formula III may be prepared as shown in Scheme I (set out, together with other Schemes, following
  • a ketone of formula R 5 ⁇ CH 2 .CO.R 6 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.
  • (Cyclization Method B) 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.
  • (Cyclization Method B) 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
  • Method C 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. For example, cyclization of phenylacetone by Cyclization Method A affords
  • 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.
  • 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. It will be clear to one skilled in the art that, in general, treatment of an isocyanate of formula VI with a selected alcohol or amine of formula A.X.H in which X is oxy or imino will provide a corresponding product of formula Vila in which X is oxy or imino, and that the product of formula Vila may be carried forward to an acetic acid of formula IIa using one of the routes outlined below.
  • a substituted amino pyridone of formula VII or Vila into a corresponding intermediate acetic acid of formula IIa 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 6 is subject to hindered rotation, for example when R 5 is methyl and R is phenyl, or, for example, when R 5 is hydrogen and R 6 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 IIa 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 VIIIb is, itself, a corresponding compound of formula Va in which Rx is
  • 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.
  • 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.
  • R 5 .CH 2 .CO.R 6 the corresponding 3-nitropyridone may be prepared in a manner analogous to Cyclization Method A by heating a
  • 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 IIa 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 IIa.
  • 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.
  • Compound pharmaceutically acceptable salt thereof (hereinafter, collectively referred to as a "Compound”) may be demonstrated by standard tests and clinical studies, including those described below.
  • 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 i , of the complex formed from the interaction of the inhibitor with HLE. If a Compound is found to be a
  • K i . values for the inhibition of HLE are carried out as described in U.S. Patent 4,910,190.
  • the K i . values for Compounds of the invention which were tested are generally on the order of 10 -7 M or much less.
  • Animal models of emphysema include intratracheal (i.t.) -administration of an elastolytic protease to cause a slowly
  • 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
  • a solution of a Compound is conveniently prepared using 10% polyethylene glycol 400/PBS or 10% polyethylene glycol 400/water.
  • base e.g. sodium hydroxide solution
  • acid e.g. hydrochloric acid
  • 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.
  • a conventional pharmaceutical composition for example as generally disclosed in U.S. Patent 4,910,190.
  • a Compound of the invention may be administered in the same manner as cromolyn sodium via a 'Spinhaler' (a trademark)
  • 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.
  • 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
  • EDTA ethylenediaminetetraacetic acid
  • 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
  • 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
  • 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.
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 °C;
  • 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 18 F 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 when given, 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,
  • the intermediate 3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydropyridylacetic acid was prepared as follows: a. 3-Aza-4-phenylpent-3-enal dimethyl acetal. Acetophenone (60.6 g) and aminoacetaldehyde dimethyl acetal (78.9 g) were dissolved in toluene (650 mL) in a 1 L round-bottomed flask. A Dean-Stark trap, fitted with a reflux condenser, was attached to the reaction vessel and the solution was brought to reflux. The trap was drained after 17, 41, and 48 hours (30 mL each time). After 65 hours, the mixture was cooled and volatiles were evaporated to leave a yellow liquid (103.3 g). Fractional distillation gave two major fractions:
  • fraction 1 fraction 10.5 g (60-126 °C, 20-24 Pa); fraction 2, 78.66 g
  • 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,1), 7.38-7.43 (m,3), 7.79-7.82 (m,2).
  • b Dimethyl 4-aza-6,6-dimethoxy-3-phenylhex-2-enylidinemalonate.
  • Example 1.c. (99.6 g). Diphenylphosphoryl azide (103.9 g) and triethylamine (39.8 g) were each added to the reaction vessel in one portion and washed down with dioxane (50 mL each). The resulting solution was heated at gentle reflux (100 °C) for 1 hour. Gas evolution was vigorous at first but then subsided. The reaction mixture was cooled to 70 oC, and benzyl alcohol (38.9.g) was added in one portion along with a dioxane wash (100 mL). 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
  • 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 mixture was partially evaporated to leave an aqueous suspension of white solid.
  • the mixture was diluted with brine and extracted with chloroform. The combined extracts were dried (MgSO 4 ) and evaporated.
  • 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 waswarmed to 0 °C for 30 minutes, was cooled to -78 °C, and the product from Example 1.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.
  • a 2 L, 3-necked flask was equipped with a mechanical stirrer, a condenser capped with a nitrogen inlet and a Claisen adapter holding a thermometer and an addition funnel.
  • the vessel was charged with a hexane (1 L) solution of the product from Example 1.i., the solution was cooled to 3 °C (ice/water bath), and trifluoroacetic acid (226.5 g) was added over 10 minutes. The temperature of the mixture rose to 25 °C over the course of the addition and a white precipitate formed.
  • the intermediate 3-benzyloxycarbonylamino-2-oxo-1,2-dihydro-1-pyridylacetic acid was prepared as follows. a. Ethyl 3-nitro-2-oxo-1,2-dihydro-1-pyridylacetate. A solution of 3-nitropyrid-2-one (20 g) in dimethylformamide (600 mL) was cooled with an ice-water bath and sodium hydride (97%, 4.1 g) was added. Stirring was continued as the reaction warmed to room temperature over 25 minutes. The brown reaction mixture was cooled with an ice-water bath prior to addition of ethyl iodoacetate (20 mL). Stirring was continued overnight as the mixture warmed to room temperature.

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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.
PCT/GB1993/000796 1992-04-16 1993-04-15 Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase WO1993021213A1 (fr)

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JP5518139A JPH07505875A (ja) 1992-04-16 1993-04-15 α−アミノボロン酸ペプチドおよびエラスターゼ阻害物質としてのそれらの用途
EP93910159A EP0636144A1 (fr) 1992-04-16 1993-04-15 Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase

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GB929208387A GB9208387D0 (en) 1992-04-16 1992-04-16 Heterocyclic derivatives
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GB929217366A GB9217366D0 (en) 1992-08-14 1992-08-14 Heterocyclic derivatives

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5693617A (en) * 1994-03-15 1997-12-02 Proscript, Inc. Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein
US5780454A (en) * 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
WO2001007407A1 (fr) * 1999-07-26 2001-02-01 Bristol-Myers Squibb Pharma Company Inhibiteurs lactame de la protease ns3 du virus de l'hepatite c
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6211183B1 (en) 1997-04-14 2001-04-03 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369080B2 (en) * 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, 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
EP2123665A2 (fr) 1994-06-17 2009-11-25 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme de conversion d'interleukine-1Beta
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
WO2015141765A1 (fr) * 2014-03-20 2015-09-24 富士フイルム株式会社 Composes utiles dans la production de salacinol et procede de production de ceux-ci, procede de production de salacinol, procedes de protection et de deprotection de groupe diol, et agent protecteur de groupe diol
WO2021053058A1 (fr) 2019-09-17 2021-03-25 Mereo Biopharma 4 Limited Alvélestat destiné à être utilisé dans le traitement du rejet de greffe, du syndrome de bronchiolite oblitérante et de la maladie du greffon contre l'hôte
WO2021209740A1 (fr) 2020-04-16 2021-10-21 Mereo Biopharma 4 Limited Procédés impliquant l'alvélestat, un inhibiteur de l'élastase des neutrophiles, pour le traitement d'une infection à coronavirus
WO2023067103A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'élastase neutrophile utilisés dans le traitement de la fibrose

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0315574A2 (fr) * 1987-11-05 1989-05-10 Hoechst Aktiengesellschaft Inhibiteurs de la rénine
US4963655A (en) * 1988-05-27 1990-10-16 Mayo Foundation For Medical Education And Research Boron analogs of amino acid/peptide protease inhibitors
EP0509769A2 (fr) * 1991-04-18 1992-10-21 Zeneca Limited Amides hétérocycliques ayant une activité inhibante de HLE

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315574A2 (fr) * 1987-11-05 1989-05-10 Hoechst Aktiengesellschaft Inhibiteurs de la rénine
US4963655A (en) * 1988-05-27 1990-10-16 Mayo Foundation For Medical Education And Research Boron analogs of amino acid/peptide protease inhibitors
EP0509769A2 (fr) * 1991-04-18 1992-10-21 Zeneca Limited Amides hétérocycliques ayant une activité inhibante de HLE

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5693617A (en) * 1994-03-15 1997-12-02 Proscript, Inc. Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein
EP2123665A2 (fr) 1994-06-17 2009-11-25 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme de conversion d'interleukine-1Beta
US8378099B2 (en) 1994-10-28 2013-02-19 Millennium Pharmacueticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6747150B2 (en) 1994-10-28 2004-06-08 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US5780454A (en) * 1994-10-28 1998-07-14 Proscript, Inc. Boronic ester and acid compounds
US8003791B2 (en) 1994-10-28 2011-08-23 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6066730A (en) * 1994-10-28 2000-05-23 Proscript, Inc. Boronic ester and acid compounds, synthesis and uses
US7531526B2 (en) 1994-10-28 2009-05-12 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6617317B1 (en) 1994-10-28 2003-09-09 Millennium Pharmaceuticals, Inc. Boronic ester and acid compositions
US7119080B2 (en) 1994-10-28 2006-10-10 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6297217B1 (en) 1994-10-28 2001-10-02 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6548668B2 (en) 1994-10-28 2003-04-15 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6465433B1 (en) 1994-10-28 2002-10-15 Millennium Pharmaceuticals, Inc. Boronic ester and acid compounds, synthesis and uses
US6369080B2 (en) * 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6211183B1 (en) 1997-04-14 2001-04-03 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
US7122627B2 (en) 1999-07-26 2006-10-17 Bristol-Myers Squibb Company Lactam inhibitors of Hepatitis C virus NS3 protease
WO2001007407A1 (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
WO2015141765A1 (fr) * 2014-03-20 2015-09-24 富士フイルム株式会社 Composes utiles dans la production de salacinol et procede de production de ceux-ci, procede de production de salacinol, procedes de protection et de deprotection de groupe diol, et agent protecteur de groupe diol
JP2015182956A (ja) * 2014-03-20 2015-10-22 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
CN110003161A (zh) * 2014-03-20 2019-07-12 富士胶片株式会社 二醇基的保护方法、二醇基的保护剂及脱保护方法
CN110003161B (zh) * 2014-03-20 2022-01-04 富士胶片株式会社 二醇基的保护方法、二醇基的保护剂及脱保护方法
WO2021053058A1 (fr) 2019-09-17 2021-03-25 Mereo Biopharma 4 Limited Alvélestat destiné à être utilisé dans le traitement du rejet de greffe, du syndrome de bronchiolite oblitérante et de la maladie du greffon contre l'hôte
WO2021209740A1 (fr) 2020-04-16 2021-10-21 Mereo Biopharma 4 Limited Procédés impliquant l'alvélestat, un inhibiteur de l'élastase des neutrophiles, pour le traitement d'une infection à coronavirus
WO2023067103A1 (fr) 2021-10-20 2023-04-27 Mereo Biopharma 4 Limited Inhibiteurs de l'élastase neutrophile utilisés dans le traitement de la fibrose

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AU4077193A (en) 1993-11-18
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EP0636144A1 (fr) 1995-02-01

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