WO1988010258A1 - Composes inhibiteurs de l'elastase leucocytaire humaine - Google Patents

Composes inhibiteurs de l'elastase leucocytaire humaine Download PDF

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WO1988010258A1
WO1988010258A1 PCT/AU1988/000155 AU8800155W WO8810258A1 WO 1988010258 A1 WO1988010258 A1 WO 1988010258A1 AU 8800155 W AU8800155 W AU 8800155W WO 8810258 A1 WO8810258 A1 WO 8810258A1
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pyrone
carbon atoms
alkyl
hydroxy
compound
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PCT/AU1988/000155
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English (en)
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Bela Ternai
Maria Luisa Cook
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La Trobe University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Definitions

  • This invention provides potent and specific inhibitor compounds for elastase-type enzymes, especially for human leucocytic elastase (HLE), which enzyme is implicated in the growth of tumors, degradation of tissues in arthritis and in the destruction of lung tissues in emphysema, the molecular structure of the inhibitor compounds of the invention being designed to have an expected absence of undesirable side- effects in use.
  • HLE human leucocytic elastase
  • the invention also provides: processes for the preparation of said inhibitor compounds; pharmaceutical/veterinary compositions containing said inhibitor compounds; and methods for the clinical application of said inhibitor compounds and said pharmaceutical/veterinary compositions.
  • Elastase-type enzymes especially human leucocyte elastase (HLE) have been implicated in many inflammatory disease states such as pulmonary emphysema, acute arthritis and the destruction of connective tissue 1-4 .
  • HLE human leucocyte elastase
  • ⁇ 1 -PI is readily inactivated by oxidants such as those present in cigarette smoke or oxidative enzymes (i.e. myeloperoxidase) that normally function in phagocytic cells during inflammatory states.
  • oxidants such as those present in cigarette smoke or oxidative enzymes (i.e. myeloperoxidase) that normally function in phagocytic cells during inflammatory states.
  • myeloperoxidase oxidative enzymes
  • Oleic acid a cis-unsaturated carboxylic acid
  • PPE porcine pancreatic elastase
  • trypsin trypsin
  • chymotrypsin chymotrypsin
  • cathepsin G which has indicated to us that the principal difference between HLE and the other serine proteases could be due to the different hydrophobic character of a site near the active site, noting that HLE has not been fully sequenced, its 3-dimensional structure has not been determined, and its active site-stereochemistry is unknown.
  • Omura et al 5 reported that elasnin (I), an alkylated
  • R 1 is methyl when R is methyl or - CH 2 COPh, and R 1 is hydrogen when R is hydrogen or - CH 2 COPh;
  • R 1 is hydrogen when R is propyl, butyl, pentyl, hexyl or undecyl, and R 1 is alkyl in which the alkyl group is ethyl, propyl, pentyl, undecyl or pentadecyl, when R is methyl.
  • R 1 is pentyl, hexyl, octyl, nonyl or undecyl, when R is pentyl, hexyl, octyl, nonyl or undecyl, respectively, in hindering the growth of bacteria.
  • the present invention provides as potent and specific inhibitors of elastase-type enzymes, especially for HLE, a novel compound of the formula (III):
  • R 1 and R 3 are independently selected from hydrocarbon-chain radicals of 5 to 12 carbon atoms in length which are bonded directly to the pyrone ring or bonded indirectly to the pyrone ring through an oxygen or nitrogen atom, said hydro- carbon-chain radicals being independently unsubstituted or substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes, the total number of carbon atoms of the longest chain length in each of the groups R 1 ana R 3 being 5 to 12; and R 2 is hydrogen or hydrocarbon radical of 1 to 5 carbon atoms unsubstituted or substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes;
  • R 1 when R 1 is oxohexyl and R 2 is hydrogen, then R 3 cannot be pentyl; when R 1 is oxoheptyl and R 2 is hydrogen, then R 3 cannot be hexyl; when R 1 is oxononyl and R 2 is hydrogen, then R 3 cannot be octyl; when R 1 is oxo- decyl and R 2 is hydrogen, then R 3 cannot be nonyl; and when R 1 is oxododecyl and R 2 is hydrogen, then R 3 cannot be undecyl.
  • the present invention also provides a pharmaceutical or veterinary composition
  • a pharmaceutical or veterinary composition comprising as active ingredient at least one compound of formula (IV):
  • R 1 and R 3 are independently selected from hydrocarbon-chain radicals of 5 to 12 carbon atoms in length which are bonded directly to the pyrone ring or bonded indirectly to the pyrone ring through an oxygen or nitrogen atom, said hydrocarbon-chain radicals being independently unsubstituted or substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes, the total number of carbon atoms of the longest chain length in each of the groups R 1 , and R 3 being 5 to 12; and
  • R 2 is hydrogen or hydrocarbon radical of 1 to 5 carbon atoms unsubstituted or substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes; in association with a pharmaceutical or veterinary adjuvant or carrier.
  • the present invention further provides the use of an effective amount of at least one compound or physiologi- cally acceptable salt thereof according to formula (III), or a composition according to formula (IV), as an inhibitor for elastase-type enzymes.
  • the present invention still further provides a method for inhibiting the growth of tumors or the degradation of tissues in arthritis or the destruction of lung tissues in emphysema, which comprises administering to an animal suffering from any one or such conditions , a therapeutical ly effective amount of at least one compound or physiologically acceptable salt thereof according to formula (III), or a composition according to formula (IV).
  • the groups R 1 and R 3 of the compounds of general formulae (III) and (IV) above may be independently selected from unsubstituted alkyl, alkenyl, alkynyl or alkoxy, of 5 to 12 carbon atoms, or alkyl, alkenyl, alkynyl or alkoxy, of 5 to 12 carbon atoms, substituted with alkyl, alkenyl, alkynyl, alkoxy, carboxy, oxo, amino, or other such physiologically innocuous substituents which do not interfere with the binding of said compounds with elastase-type enzymes.
  • the groups R 1 and R 3 of the compounds of general formulae (III) and (IV) above may be independently selected from:
  • alkyl, alkenyl or alkynyl of 5 to 12 carbon atoms, unsubstituted or substituted with physiologically innocuous substituents which do not interfere with the binding of said compounds with elastase-type enzymes exemplified by oxoalkyl of 5 to 12 carbon atoms or oxoalkyl of 5 to 12 carbon atoms substituted with said physiologically innocuous substituents exemplified by wherein n is zero or an integer 1 to 11 and R', is hydrogen or alkyl, alkenyl or alkynyl of 1 to 11 carbon atoms unsubstituted or substituted with alkyl, alkenyl, alkoxy, carboxy, oxo, amino, or other such physiologically innocuous substituents which do not interferewith the binding of said compounds with elastase-type enzymes, provided that the total number of carbon atoms of the longest chain length in the groups R 1 and R 3 is 5 to 12
  • n is zero or an integer 1 to 11 and R'' is hydrogen or alkyl, alkenyl or alkynyl of 1 to 11 carbon atoms unsubstituted or substituted with alkyl, alkenyl, alkoxy, carboxy, oxo, amino or other such physiologically innocuous substituents which do not interferewith the binding of said compounds with elastase-type enzymes, provided that the total number of carbon atoms of the longest chain length in the groups R 1 and R 3 is 5 to 12; and
  • hydrocarbon radicals of 5 to 12 carbon atoms bonded to the pyrone ring through a nitrogen atom, unsubstituted or substituted with physiologically innoc- uous substituents which do not interferewith the binding of said compounds with elastase-type enzymes exemplified by wherein n is zero or an integer 1 to 11 and R''' is hydrogen or alkyl, alkenyl or alkynyl of 1 to 11 carbon atoms unsubstituted or substituted with alkyl, alkenyl, alkoxy, carboxy, oxo, amino or other physiologically innocuous substituents which do not interfere with the binding of said compounds with elastase-type enzymes, provided that the total number of carbon atoms of the longest chain length in the groups R 1 . and R 3 is 5 to 12.
  • the group R 1 in the compounds of general formulae (III) and (IV) above is more preferably oxoalkyl of 5 to 12 carbon atoms, most preferably oxoalkyl of 7 to 10 carbon atoms.
  • the group R 3 in the compounds of general formulae (III) and (IV) above is more preferably alkyl of 5 to 12 carbon atoms, most preferably alkyl of 7 to 10 carbon atoms.
  • the group R 2 in the compounds of general formulae (III) and (XV) above is preferably selected from hydrogen or alkyl, alkenyl or alkynyl, inclusive of straight and branched chain radicals and cyclic radicals, exemplified by methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tertiary butyl, and n-butyl.
  • (III) and (IV) above is more preferably selected from hydrogen, C 1-5 alkyl, C 1-5 alkenyl, or C 1-5 alkynyl, most preferably from hydrogen or methyl.
  • Possible salts of compounds of the general formulae (III) and (XV) are all the acid addition salts.
  • the physiologically acceptable salts may be derived from inorganic or organic acids.
  • Physiologically unacceptable salts which may initially be obtained as process products, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into physiologically acceptable salts by processes which are known to the skilled person.
  • physiologically acceptable salts are water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, stearate, tosylate, mesylate and salicylate.
  • water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, stearate, tosylate, mesylate and salicylate.
  • Especially preferred compounds of the present invention are:
  • compounds of the general formula (III) and (IV) above may be prepared by: (A) reacting an appropriate acid imidazolide with an appropriate salt of an alkyl hydrogen malonate to form the corresponding 3-oxocarboxylate ester; hydrolysing said 3-oxocarboxylate ester to afford the corresponding 3-oxocarboxylic acid; and cyclizing said 3-oxocarboxylic acid with carbonyl- diimidazole to afford the corresponding 3-(1 ' -oxoalkyl)-4-hydroxy-6-alkyl-2-pyrones of the formula (V):
  • R 1 and R 3 are independently alkyl of 5 to 12 carbon atoms in length and optionally substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes, the total number of carbon atoms of the longest chain length in each of the groups R 1 and R 3 being 5 to 12; and/or
  • hydrocarbon-chain radicals of 5 to 12 carbon atoms in length which are bonded as required directly to the pyrone ring or bonded indirectly to the pyrone ring through an oxygen or nitrogen atom, said hydrocarbon- chain radicals being independently unsubstituted or substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes, the total number of carbon atoms of the longest chain length in each of the groups R 1 and R 3 being 5 to 12; and/or
  • a further preferred embodiment of the present invention comprises a process for the preparation of a compound of the formula (X):
  • R 1 and R 3 are independently alkyl of 5 to 12 carbon atoms in length, optionally substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes, the total number of carbon atoms of the longest chain length in the groups R 1 , and R 3 being 5 to 12; and
  • R 2 is hydrogen or alkyl of 1 to 5 carbon atoms unsubstituted or substituted with physiologically innocuous substituents which do not interfere with the binding of said compound with elastase-type enzymes;
  • R 1 and R 3 are as defined above, and optionally methylating the 4-hydr ⁇ xy group of the 3-(1'-oxoalkyl)-4- hydroxy-6-alkyl-2-pyrone of the formula (XIII), with dialkyl sulfate to form the corresponding 3-(1'-oxoalkyl)-4- alkyl-6-alkyl-2-pyrone of the formula (X), whereafter, if desired, the compound of 'formula (X) so obtained is converted to a physiologically acceptable salt thereof.
  • the compounds according to the invention are initially obtained either as such or as their salts, depending on the nature of the starting compounds and depending on the reaction conditions.
  • salts are obtained by dissolving the free compounds in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular aliphatic alcohol (ethanol or isopropanol), which contains the desired acid or base, or to which the desired acid or base is subsequently added, if necessary in the precisely calculated stoichio- metric amount.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low-molecular aliphatic alcohol ethanol or isopropanol
  • Resulting salts can be converted into the free compounds by treating with bases or acids, for example, with aqueous sodium bicarbonate or with dilute hydrochloric acid, and the compounds can in turn be converted into their salts.
  • bases or acids for example, with aqueous sodium bicarbonate or with dilute hydrochloric acid
  • the compounds can in turn be converted into their salts.
  • the compounds can be purified, or physiologically unacceptable salts can be converted into physiologically acceptable salts.
  • the substituted 2-pyrones were prepared according to Scheme I.
  • the 3-oxocarboxylate 6 was formed by reacting an acid imidazolide (formed in situ) with the neutral magnesium salt of ethyl hydrogen malonate 7 . Hydrolysis of the ester in 1M NaOH afforded the 3-oxocarboxylic acid, which was cyclized using 1.1 eq. carbonyldiimidazole in THF 8 to afford the 3-(1'-oxoalkyl)-4-hydroxy-6-alkyl-
  • K i and K i ' The inhibitory activity of each compound, reported as K i and K i ', are included in Table 1.
  • K i is of primary interest because it gives a measure of the affinity of I for E; however, for some inhibitors an ESI and not an El complex is formed therefore it is necessary to compare K i ' values.
  • Compounds 14 and 15 are different from compounds 6 and 7 in three ways: they are unable to bind to E; they have greater affinity for ES; and the affinity of I for ES is independent of the number of methylenes at the 6 position. This can be interpreted to mean that because of steric hindrance and the loss of the hydrophilic 4-hydroxy group, the 4-methoxy-2-pyrone is unable to bind to E. A change in conformation when S binds to E would allow I to bind to ES, hydrophobic interactions would be enhanced, resulting in the greater affinity. The independence of K i ' with 6-alkyl chain length indicates that the binding region might be large enough for a heptyl or nonyl residue.
  • the normally accepted nomenclature describes the former class of compounds as pure noncompetitive inhibitors, while the latter are called mixed-type inhibitors.
  • the mechanism of action differs for the two types of compounds, therefore we conclude that there is a specific binding region for the 4-hydroxy-2-pyrone nucleus and for each of the two alkyl fragments at positions 3 and 6.
  • a further point of interest is that for compounds 1-4, the mechanism is not influenced by the number of methylenes, whereas for compounds 5-8 the reverse is true.
  • the long chain homologs, compounds 7 and 8 have K i ⁇ K i ', that is, I has greater affinity for E than for ES.
  • K i ⁇ K i ' that is, I has greater affinity for E than for ES.
  • the inhibitor and substrate binding regions are overlapping, and that the long alkyl chain ( ⁇ nonyl) cannot form as many hydrophobic interactions with E, when S is already bound, hence the decreased affinity for ES.
  • the shorter homologs, (compounds 5 and 6) the reverse is true, (K i ' ⁇ K i ) that is they have greater affinity for ES. Binding of S would create a srraller hydrophobic pocket, and consequently hydrophobic inter- actions would be increased, leading to the enhanced affinity.
  • the 3,6-dialkyl-2-pyrones, compounds 9-13 would by comparison with the 6-alkyl 2-pyrones, compounds 5-8, be expected to be mixed-type inhibitors. This result was observed, although for the latter the ESI complex is active.
  • the 4-methoxy-6- alkyl-2-pyrones, compounds 14 and 15, are uncompetitive inhibitors, which can be considered to be an extreme form of mixed-type inhibition, where K i >> K i ' ind binding of I to ES is not favourable, presumably because of the loss of the hydrophilic group and the increased bulk of the 4-methoxy group.
  • hydrophobic compounds None of the hydrophobic compounds were found to have inhibitory activity when tested against three related serine proteases, porcine pancreatic elastase, bovine ⁇ - chymotrypsin and bovine trypsin, when they were tested at the approximate limit of their solubility (25 ⁇ M for compounds 9-12, 10 ⁇ M for compound 13, 1000 ⁇ M for compound
  • HLE has an unusually hydrophobic binding cleft and that better inhibitors can be developed by increasing the hydrophobicity of the substituents.
  • the mechanism of action and a possible binding site have been established and based on these results it would be unlikely that these compounds were irreversible inhibitors.
  • a further point in favour of reversible action is that the interaction is very rapid, as measured by UV spectroscopy, and is not dependent on incubation time of E and I, unlike the 6-chloropyrones 24 .
  • Spencer et al 18 used UV difference spectra to show that ⁇ -chymo- trypsin was not acylated, and hence they concluded that the interaction was reversible. We chose dialysis to study this problem.
  • Inhibitors in accordance with the present invention as set out above have been found not only to be very effective inhibitors of HLE but also to be relatively non-toxic, the LD 50 values of the inhibitors being of the order greater than 3g/Kg of body weight in both mice and rats.
  • LD 50 values of the inhibitors of the present invention have been found to be as set out immediately below, where the LD 50 value is in g of compound per Kg of body weight:
  • the inhibitor compounds and salts of the invention can be expected to be useful in the treatment of HLE implicated diseases such as arthritis, tumor growth and emphysema.
  • HLE implicated diseases such as arthritis, tumor growth and emphysema.
  • the invention thus also relates to a method of treating animals suffering from any one of the above-mentioned diseases.
  • the method is characterized in that a therapeutically active and physiologically acceptable amount of one or more of the inhibitors defined above is administered to the animal.
  • the invention also relates to pharmaceutical/ veterinary compositions which contain one or more of the inhibitors defined by the general formula (IV) and/or their physiologically acceptable salts.
  • compositions are produced by processes which are known per se and with which the skilled person is familiar.
  • physiologically active compounds according to the invention are used either as such or, preferably, in combination with suitable pharmaceutical auxiliaries, in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions.
  • auxiliaries which are suitable for the desired pharmaceutical formulations.
  • auxiliaries which are suitable for the desired pharmaceutical formulations.
  • solvents, gelling agents, suppository bases, tableting auxiliaries and other excipients for active ingredients it is also possible to use, for example, antioxidents, dispersing agents, emulsifiers, anti-foaming agents, flavor correctants, preservatives, solubilizing agents and colorants.
  • antioxidents for example, antioxidents, dispersing agents, emulsifiers, anti-foaming agents, flavor correctants, preservatives, solubilizing agents and colorants.
  • the optimum dosage and method of administration of the active compound required in each particular case can easily be determined by any skilled person.
  • the pharmaceutical formulations can also contain one or more physiologically active members of other groups of medicaments, such as steroidal and/or non-steroidal anti-inflamatory agents, immunosuppressants, sulfated glycosamines/glycans and other sulfated carbohydrates, analgesics and antipyretics.
  • physiologically active members of other groups of medicaments such as steroidal and/or non-steroidal anti-inflamatory agents, immunosuppressants, sulfated glycosamines/glycans and other sulfated carbohydrates, analgesics and antipyretics.
  • the inhibitor compounds/salts or compositions of the present invention may be administered orally, rectally or by injection, for example, by transdermal application for the treatment of arthritis, in the form of pharmaceutical preparations comprising at least one active compound or salt thereof in association with a pharmaceutically acceptable carrier, which may be a solid or semi-solid or liquid diluent or capsule or aerosol applicator.
  • a pharmaceutically acceptable carrier which may be a solid or semi-solid or liquid diluent or capsule or aerosol applicator.
  • the active substance will constitute between 0.1 and 99% by weight of a solid/semi-solid/liquid preparation, more particularly, between 0.5 and 20% by weight for preparations intended for injection, and between 2 and 50% by weight for preparations suitable for oral administration.
  • Dosage unit pharmaceutical preparations containing at least one compound or salt thereof in accordance with the invention for oral application may be prepared by mixing the selected compound or salt with a solid pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate, polyethlene glycol waxes, then compressed to form tablets.
  • a solid pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine
  • a lubricant such as magnesium stearate, calcium stearate, polyethlene glycol waxes
  • Coated tablets can be prepared by coating the tablets prepared as described above, with a concentrated sugar solution which may contain components such as gum arabic, gelatine, talcum, titanium dioxide, or the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture or organic solvents.
  • Soft gelatine capsules can be prepared by enclosing the selected compound or salt, mixed with a vegetable oil, in a soft gelatine shell.
  • Hard gelatine capsules may contain the selected compound or salt in admixture with solid , pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches. such as potato starch or corn starch or amylopectin, cellulose derivatives or gelatine.
  • Dosage unit preparations for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application can be in the form of syrups or suspensions, such as solutions containing from about 0.2% to about 20% by weight of the selected compound, the balance being sugar and a mixture or ethanol, water, glycerol and propylene glycol.
  • Solutions for parenteral application by injection can be prepared as an aqueous solution of the selected compound or the selected compounds preferably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
  • Suitable transdermal daily-dose administration of the selected compounds or salts in accordance with the invention can be 100-500 mg, preferably 200-300 mg, whilst weekly-dose administration can be in dosage of 25-2000 mg every 1 to 3 weeks.
  • Andrews et al 26 Viscarello et al 27 and Martodam et al 28 .
  • N-t-Boc-L-ala-p-nitrophenyl ester (BAN), N-(2-hydroxy- ethyl)-piperazine-N'-ethanesulfonic acid (HEPES), porcine pancreatic elastase, ⁇ -chymotrypsin and trypsin were purchased from Sigma Co. Spectrophotometric grade dimethyl sulfoxide (DMSO) was purchased from Aldrich. The 1H NMR spectra were recorded on a Perkin-Elmer R-32 spectrophotometer at 90 MHz using tetramethylsilane. (TMS) as internal standard.
  • TMS tetramethylsilane.
  • HLE (1.8 ⁇ g/50 ⁇ l) was made up in 50mM sodium acetate, 0.5M NaCl and 0.1% brij-35 at pH 5.5.
  • the assay conditions were 0.1M HEPES, 0.5M NaCl and 14.8% DMSO at pH 7.5 and 37oC. All inhibitor and substrate solutions were made up in 5% aq. DMSO to retard hydrolysis.
  • HLE 50 ⁇ l
  • DMSO/inhibitor 100 ⁇ l
  • buffer 800 ⁇ l
  • the reference cell contained DMSO/inhibitor (100 ⁇ l) and buffer (850 ⁇ l).
  • BAN 50 ul, final concentration 50-1000 ⁇ M was added to each cuvette.
  • the assay conditions were identical to the HLE assays, except that each inhibitor was tested at one concentration with one concentration of substrate. Inhibitors were tested at their approximate limit of solubility:
  • Solid magnesium methoxide (0.49g, 5mmol) was added to a solution of ethyl hydrogen malonate (1.2g, lOmmol) in THF aiid stirred for 1 h. The solvent was removed under reduced pressure to give a white slightly hygroscopic salt, Mg (OOCOCH 2 COOEt), which was used directly. Carbonyldiimidazole was added to a solution of carboxylic acid (10 mmol) in. THF. After stirring at room temperature for six h the prepared Mg (OOCCH 2 COOEt) 2 was added. The mixture was stirred for 18 h at 25oC, the solvent was then removed at reduced pressure. The residue was partitioned between ether and aq.
  • the 2-pyrone was added to 5 equivalents (by weight) of 90% H 2 SO 4 and heated at 130°C for 15 min. Ice was added to the cooled black solution with vigorous stirring. Recrystallisation from MeOH 2 :O(1:1 ) yielded white needles.
  • Mixed-type hyperbolic inhibition K i ⁇ K i ' , K s ⁇ k s , ⁇ 0

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Abstract

La présente invention se rapporte à un composé représenté par la formule (III) ou à des sels physiologiquement acceptables dudit composé, où: Z représente une liaison, -O- ou -NH-; R1 et R3 sont choisis séparément parmi des radicaux d'hydrocarbures substitués ou non substitués de 5 à 12 atomes de carbone; R2 représente un hydrogène ou un radical d'hydrocarbures substitués ou non substitués de 1 à 5 atomes de carbone; lesdits radicaux d'hydrocarbures substitués étant substitués par des substituants physiologiquement inoffensifs qui ne perturbent pas la liaison entre ledit composé et les enzymes du type élastase; à condition que: lorsque R1 représente un oxohexyle et R2 un hydrogène, alors R3 ne peut pas être un pentyle; lorsque R1 représente un oxoheptyle et R2 un hydrogène, alors R3 ne peut pas être un hexyle; lorsque R1 représente un oxononyle et R2 un hydrogène, alors R3 ne peut pas être un octyle; lorsque R1 un oxodécyle et R2 un hydrogène, alors R3 ne peut pas être un nonyle; et lorsque R1 représente un oxodécyle et R2 un hydrogène, alors R3 nepeut pas être un undécyle. Ces composés constituent des composés inhibiteurs puissants et spécifiques pour les enzymes du type élastase, tel que notamment l'élastase leucocytaire humaine, (HLE) et on peut prévoir que ces composés ont une utilité dans le traitement des maladies dans lesquelles sont impliquées des enzymes du type élastase, tel que l'arthrite, la croissance des tumeurs et les emphysèmes. La production et le procédé d'utilisation de ces composés ainsi que des compositions pharmaceutiques les contenant sont également décrits.
PCT/AU1988/000155 1987-06-17 1988-05-24 Composes inhibiteurs de l'elastase leucocytaire humaine WO1988010258A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5245056A (en) * 1990-02-23 1993-09-14 Hoffmann-La Roche Inc. Production of oxetanones
US5260310A (en) * 1990-02-26 1993-11-09 Hoffmann-La Roche Inc. Oxetanone compounds and pharmaceutical compositions containing them
WO1997035565A1 (fr) * 1996-03-27 1997-10-02 Toray Industries, Inc. Derives de cetone et usage medicinal
WO1999014211A1 (fr) * 1997-09-19 1999-03-25 Millennium Pharmaceuticals, Inc. α-PYRONES POUR TRAITEMENT D'ETATS SENSIBLES A UN α-PYRONE
US6448289B1 (en) 2000-08-31 2002-09-10 Sumitomo Chemical Co,. Ltd. Method for repelling arthropods
US6509298B2 (en) 2001-04-04 2003-01-21 Sumitomo Chemical Company, Limited Arthropod-controlling composition
US6627654B2 (en) 2000-04-25 2003-09-30 Sumitomo Chemical Company, Limited Anthropod-controlling composition
CN100348591C (zh) * 2004-07-15 2007-11-14 浙江海正集团有限公司 取代亚甲基吡喃酮类衍生物及其制备方法和用途
CN1990478B (zh) * 2005-12-26 2011-08-31 浙江海正药业股份有限公司 6-芳基-3-取代亚甲基吡喃酮类化合物及其制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6271373A (en) * 1972-11-24 1975-05-22 Nippon Soda Co Oxime pyrones
US3973945A (en) * 1973-12-05 1976-08-10 Nippon Soda Company Ltd. Pyran-2,4-dione derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1055556A (fr) * 1954-02-19
CH309838A (de) * 1950-03-02 1955-09-15 Hoffmann La Roche Verfahren zur Herstellung eines Pyranabkömmlings.
CH309839A (de) * 1950-03-02 1955-09-15 Hoffmann La Roche Verfahren zur Herstellung eines Pyranabkömmlings.
CH299536A (de) * 1950-03-02 1954-06-15 Hoffmann La Roche Verfahren zur Herstellung eines Pyranabkömmlings.
CH309837A (de) * 1950-03-02 1955-09-15 Hoffmann La Roche Verfahren zur Herstellung eines Pyranabkömmlings.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6271373A (en) * 1972-11-24 1975-05-22 Nippon Soda Co Oxime pyrones
US3973945A (en) * 1973-12-05 1976-08-10 Nippon Soda Company Ltd. Pyran-2,4-dione derivatives

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 100, No. 1, issued 1984, January 2 (Columbus, Ohio, U.S.A.) W.KOHL, et. al. "Antibiotics from Gliding Bacteria, XVII. Myxopyronin A and B - Two Novel Antibiotics from Myxococcus Fulvux Strain Mxf50.", see page 3140, Column 1, Abstract No. 3141r. *
CHEMICAL ABSTRACTS, Volume 100, No. 15, issued 1984 April 9. (Columbus, Ohio U.S.A.) KULRSCHIK, et. al., "Antibiotics from Gliding Bacteria. 16. The Myxopyronins, New Inhibitors of Bacterial RNA Synthesis from Myxococcus Fulvus (Myxobacterales)." see page 287, column 2, Abstract No. 117513u. *
CHEMICAL ABSTRACTS, Volume 101, No 11, issued 1984, September 10 (Columbus, Ohio, U.S.A.) W. KOHL, et. al., "Antibiotics from Gliding Bacteria", XXII. Biosynthesis of Myxopyronin A an antibiotic from Myxococcus Fulvus Strain Mxf50", see page 335, column 2, Abstract No. 87146c. *
CHEMICAL ABSTRACTS, Volume 103, No. 5, issued 1985, August 5, (Columbus, Ohio, U.S.A.) W. GROUTAS, "Substituted 2-Pyrones, 2-Pyridones, and Other Cogeners of Elasnin as Potential Agents for the Treatment of Chronic Obstructive Lung Diseases". see page 31962, column 1 - Abstract No. 31964s. *
PATENTS ABSTRACTS OF JAPAN, C-116, page 26, JP,A, 57-62273 (Nippon Soda K.K.) 28 July 1982 (28.07.82) *
PATENTS ABSTRACTS OF JAPAN, C-78, page 979, JP,A, 53-34776 (Nippon Soda K.K.) 16 June 1978 (16.06.78) *
See also references of EP0365539A4 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5245056A (en) * 1990-02-23 1993-09-14 Hoffmann-La Roche Inc. Production of oxetanones
US5399720A (en) * 1990-02-23 1995-03-21 Hoffmann-La Roche Inc. Production of oxetanones
US5260310A (en) * 1990-02-26 1993-11-09 Hoffmann-La Roche Inc. Oxetanone compounds and pharmaceutical compositions containing them
US5376674A (en) * 1990-02-26 1994-12-27 Hoffman-La Roche Inc. Oxetanone compounds containing proline and pharmaceutical compositions thereof
US5466708A (en) * 1990-02-26 1995-11-14 Hoffmann-La Roche Inc. Oxetanones
WO1997035565A1 (fr) * 1996-03-27 1997-10-02 Toray Industries, Inc. Derives de cetone et usage medicinal
WO1999014211A1 (fr) * 1997-09-19 1999-03-25 Millennium Pharmaceuticals, Inc. α-PYRONES POUR TRAITEMENT D'ETATS SENSIBLES A UN α-PYRONE
US5981496A (en) * 1997-09-19 1999-11-09 Millennium Pharmaceutical, Inc. α-pyrones for treating α-pyrone responsive states
US6469048B2 (en) 1997-09-19 2002-10-22 Millennium Pharmaceuticals, Inc. α-pyrones for treating α-pyrone responsive states
US6627654B2 (en) 2000-04-25 2003-09-30 Sumitomo Chemical Company, Limited Anthropod-controlling composition
US6448289B1 (en) 2000-08-31 2002-09-10 Sumitomo Chemical Co,. Ltd. Method for repelling arthropods
US6509298B2 (en) 2001-04-04 2003-01-21 Sumitomo Chemical Company, Limited Arthropod-controlling composition
CN100348591C (zh) * 2004-07-15 2007-11-14 浙江海正集团有限公司 取代亚甲基吡喃酮类衍生物及其制备方法和用途
CN1990478B (zh) * 2005-12-26 2011-08-31 浙江海正药业股份有限公司 6-芳基-3-取代亚甲基吡喃酮类化合物及其制备方法和用途

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EP0365539A4 (en) 1990-12-05

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