WO1991005763A1 - Inhibiteurs de metalloendopeptidase a base d'analogues dipeptidiques et leurs modes d'emploi - Google Patents

Inhibiteurs de metalloendopeptidase a base d'analogues dipeptidiques et leurs modes d'emploi Download PDF

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Publication number
WO1991005763A1
WO1991005763A1 PCT/US1990/005902 US9005902W WO9105763A1 WO 1991005763 A1 WO1991005763 A1 WO 1991005763A1 US 9005902 W US9005902 W US 9005902W WO 9105763 A1 WO9105763 A1 WO 9105763A1
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group
benzyl
alanine
compound
glycine
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PCT/US1990/005902
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English (en)
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Soumitra Shankar Ghosh
Emil Thomas +Di Kaiser
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The Salk Institute Biotechnology/Industrial Associates, Inc.
Kaiser, Bonnie, Lu +Ef
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Publication of WO1991005763A1 publication Critical patent/WO1991005763A1/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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • 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
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates generally to inhibitors of metalloendopeptidases and more specifically to inhibitors of enkephalinase, angiotensin-converting enzyme, and collagenase and therapeutic uses of said inhibitors.
  • Enkephalins Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), are pentapeptides which specifically bind opiate receptors in the brain and thereby are involved in regulation of nociceptive or pain stimuli.
  • the enkephalins are generally short-lived
  • a variety of peptidases are known which are able to cleave enkephalins, in vitro, into biologically inactive fragments. Cleavage by an aminopeptidase results in release of the N-terminal tyrosine. A dipeptidylamino- peptidase has been implicated in the cleavage of the
  • enkephalinase EC 3.4.24.11, also known as “neutral endopeptidase 24.11" (hereinafter referred to as "enkephalinase") and
  • angiotensin-converting enzyme (EC 3.4.15.1, also known as “angiotensin I converting enzyme”) (hereinafter referred to as “angiotensin- converting enzyme” or "ACE”) cleave the Gly 3 -Phe 4 bond.
  • enkephalinase is the enzyme primarily responsible for the in vivo hydrolytic cleavage of enkephalins and, as such, has a significant role in causing and regulating pain.
  • Competitive inhibitors of enkephalinase are known which are active as ancinociceptive agents (i.e., pain-relievers or "analgesics") in vivo in mammals, including humans. See, e.g., Erdos and Skidgel, FASEB J. 3, 145 (1989); Grazia et al., Eur. J. Pharmacol. 125, 147 (1986).
  • ANF(99-126) of atrial natriuretic factor
  • enkephalinase is thought to have a role in regulation of fluid balance and blood pressure. Indeed, enkephalinase inhibitors, by inhibiting the degradation of ANF(99-126), might be employed in vivo to induce fluid and Na + excretion and reduce blood pressure. Increases in urine volume and Na + secretion are potentiated by, for example, the potent enkephalinase inhibitor thiorphan. See Erdos and Skidgel, supra.
  • ACE cleaves enkephalin at the Gly-Phe bond
  • ACE plays a significant role in blood
  • Collagenases are Zn +2 metalloendopeptidases involved in the turnover, remodeling or degradation of collagen and have been isolated from numerous species, from bacterial to human.
  • the substrate specificities of collagenases vary, although they all proteolytically cleave a peptide bond in a collagen.
  • the collagenases of Clostridium histolyticum (EC 3.4.24.3) catalyze cleavage of the X-Gly bond in the repeating secruence -Gly-Pro-X-Gly-Pro-X- of collagen where X is frequently Ala or Hyp but may be any amino acid.
  • the collagenase of Achromobacter iophagus (EC 3.4.24.8)
  • Mammalian collagenases have a recognition sequence of at least five amino acids and proteolytically cleave the
  • Inhibitors of collagenase are thought to have a number of therapeutic applications, including treatment or
  • Zn +2 -metallopeptidase inhibitors may also find antibacterial application against bacteria whose pathogenicity depends at least in part on Zn +2 -metallo- peptidases produced by the bacteria.
  • Predicting compounds that will be specific inhibitors for a particular type of Zn +2 metalloendopeptidase i.e., enkephalinase or ACE or collagenase, with, in the case of a competitive inhibitor, an inhibition constant, K i , for one type that is at least about two orders of magnitude lower than that for the other types
  • K i an inhibition constant
  • still more uncertain is the design of so-called "mechanism-based" inhibitors or enzymes, including Zn +2 metalloendo-peptidases, as such inhibitors must not only, like competitive inhibitors, physically occupy the active site of an enzyme to block access thereto of substrate but also be positioned with sufficient precision and stability in the active site to undergo chemical reaction(s) there to unmask reactivity of a functional group so that the activated functional group, in turn, can form a covalent bond with a moiety of the enzyme, usually in or near the active site.
  • the known inhibitors for enkephalinase, ACE and collagenases are competitive inhibitors.
  • the inhibitors are only transiently held non-covalently, in the enzyme's active site and are effective in blocking peptidase activity on natural substrates only during the time that they occupy the active site of the enzyme in a way that blocks access thereto in a reactive orientation of such a substrate. Dissociation of the enzyme-inhibitor complex frees the enzyme to act upon its natural substrate.
  • the activity of the enzyme intended to be inhibited is quickly and substantially fully restored, because no enzyme is irreversibly inactivated by competitive inhibitors. Nonetheless, it would be desirable to have additional competitive
  • suicide inhibitor is capable, once it has formed a Michaelis complex through non-covalent interactions in the active site of the enzyme to be inhibited, of chemically interacting with moieties of the enzyme in the active site in a manner which enables a "latent” functional group of the inhibitor to be activated (sometimes referred to as “unmasked") so that the inhibitor then reacts, and forms covalent bonds, with residue(s) of the enzyme in, or very close to, the active site. If, in an encounter of the inhibitor with an active site of the enzyme to be inhibited, stable covalent bonds with the enzyme are formed, the enzyme will be irreversibly
  • Zn +2 metallopeptidase e.g., only enkephalinase, or only ACE, or only collagenase
  • a mammalian, and particularly the human, species e.g., only enkephalinase, or only ACE, or only collagenase
  • the regioisomers, (R)-2-benzyl-5-cyano-4-oxopentanoic acid and (R) -3-benzyl-5-cyano- 4-oxopentanoic acid are mechanism based inhibitors of the zinc exopeptidase
  • CPA carboxypeptidase A
  • the invention entails potent inhibitors of
  • inhibitors of the invention are dipeptide-analog derivatives of
  • inhibitors of the invention are compounds of Formula I
  • metalloendopeptidase at its active site, is capable of abstracting a proton to yield an activated functional group capable of forming a stable, covalent bond with a residue in the active site;
  • z is 0 or 1, wherein, when z is 0, the group -(CR 3 R 4 ) z -(CR 5 R 6 ) ⁇ - is not in the compound and the group X 1 - is bonded directly to the group -(CHR 9 )-;
  • x is 0 if z is 0 or is 0 or 1 if z is 1, wherein, when x is 0 and z is 1, the group -(CR 5 R 6 ) ⁇ - is not in the compound and the group -(CR 3 R 4 )- is bonded directly to the group -(CHR 9 )-;
  • R 3 , R 4 , R 5 , and R 6 are independently hydrogen or alkyl of 1 to 3 carbon atoms;
  • R 9 is benzy
  • X 1 are a group of formula
  • inhibitors of the invention are useful as
  • analgesics i.e., the enkephalinase inhibitors
  • analgesics i.e., the enkephalinase inhibitors
  • antihypertensives i.e., the ACE inhibitors or the
  • the invention encompasses methods of treating pain or hypertension in mammals, including humans, suffering therefrom by administering to such a mammal an effective amount of an analgesic or antihypertensive, respectively, according to the invention.
  • the invention further encompasses 2-benzyl- 5-cyano-4-oxopentanoic acid substantially free (i.e., contaminated with less than about 10 mole %) of its
  • the present invention provides compounds of Formula I, described supra.
  • the discovery which underlies the present invention is that the presence of a functional group X 1 in a compound which is capable of binding in the active site of a Zn +2 metalloendopeptidase provides a mechanism-based inhibitor for the enzyme.
  • the invention provides a method for treating hypertension in a mammal suffering therefrom comprising administering to said mammal an antihyper- tensive-effective amount of a compound of Formula I, wherein X 2 is other than X 3 X 4 ; or a physiologically
  • the invention provides a method for inhibiting collagenase comprising combining with a
  • collagenase a collagenase-inhibiting effective amount of a compound of Formula I, wherein X 2 is X 3 X 4 ; or a
  • the invention provides
  • the invention provides a method of making (R)-2-benzyl-5-cyano-4-oxo-pentanoic acid, substantially free of 3-benzyl-5-cyano-4-oxo-pentanoic acid, which method comprises the steps of:
  • step (c) acidifying the product of step (b) to convert substantially all of said product to the acid form;
  • step (d) reducing the product of step (c) to make
  • the compounds of Formula I of the present invention are inhibitors of enkephalinase or angiotensin-converting enzyme ("ACE") or both of these enzymes from mammals, including humans, or inhibitors of bacterial or mammalian collagenases.
  • ACE angiotensin-converting enzyme
  • amino acid sequences of the human, rat and rabbit enkephalinases have been deduced from cDNAS for the
  • the compounds of Formula I which are mechanism-based inhibitors, are also necessarily substrates of the enzyme.
  • the compound in some encounters between such a compound of the invention and enkephalinase, ACE, or a collagenase, the compound will be changed in a reaction catalyzed by the enzyme and will diffuse away from the active site of the enzyme before a covalent bond with a moiety in the active site can be formed by this changed inhibitor compound.
  • a reaction catalyzed after such a reaction is catalyzed, a
  • the "partition ratio" of inactivation of an enzyme by a mechanism-based enzyme inhibitor with an enzyme is defined as the negative of the time derivative of the concentration of the inhibitor divided by the time derivative of the concentration of inactivated enzyme.
  • the partition ratio is one less than the average number of molecules of inhibitor with which the enzyme must catalyze formation of an activated intermediate before the intermediate will react with and inactivate the enzyme. Measurement of the partition ratio of inactivation of an enzyme by a mechanism-based inhibitor is readily carried out by the skilled, A partition ratio for
  • a measure of the specificity of a mechanism-based inhibitor for one of a set of enzymes is provided by the partition ratios for inactivation of the various enzymes by the inhibitor; if the partition ratio for one of the enzymes is very much lower than those for the other
  • the mechanism-based inhibitor can be said to be specific in mechanism-based inhibition for the one enzyme of the set.
  • inhibiting agents is ascertained by their ability to inhibit purified enkephalinase, ACE or
  • inventions will be administered under the guidance of a physician or veterinarian to relieve pain in a human or other mammal suffering therefrom (in the case of the enkephalinase inhibitors of the invention) or to reduce blood pressure in a human or other mammal suffering from hypertension (in the case of the ACE inhibitors or
  • enkephalinase inhibitors of the invention or for both purposes in the case of inhibitors of the invention which are effective as inhibitors of both enkephalinase and ACE, or for any of a number of therapeutic applications, such as treatment of corneal ulcers or periodontal disease, in the case of inhibitors of the invention which are effective as inhibitors of collagenases.
  • administration will be parenterally, preferably
  • intravenously in unit doses or by continuous infusion, of an inhibitor or a physiologically acceptable salt thereof dissolved in any physiologically acceptable diluent, such as physiological saline, phosphate buffered saline, or the like.
  • physiologically acceptable diluent such as physiological saline, phosphate buffered saline, or the like.
  • route of administration e.g., intravenous, intramuscular, intraperitoneal, subcutaneous
  • mode of administration e.g., by unit doses or continuous
  • dosage regimen will vary somewhat depending on the inhibitor employed, the species, age, weight and general medical condition of the mammal being treated, and the particular condition of the mammal for which the inhibitor is being administered. Determining these factors for a particular mammal being treated for a particular condition with a particular inhibitor will be routine for the pharmacologist, physician or veterinarian of ordinary skill.
  • a dose of inhibitor or physiologically acceptable salt thereof of between about 0.01 mg/kg body weight per day and 100 mg/kg body weight per day, infused continuously, administered in several equal doses per day, or administered in a single dose per day, will be effective to relieve pain (in the case of enkephalinase inhibitors) or reduce hypertension (in the case of ACE inhibitors or enkephalinase inhibitors).
  • administration may be topical in a suitable, physiologically acceptable vehicle (e.g., cream, solution) for application to the eye, in the case of use for treatment of corneal ulceration, or application into the gingival crevice or subgingival space, in the case of use for treatment of periodontal disease.
  • a suitable, physiologically acceptable vehicle e.g., cream, solution
  • the collagenase inhibitors may also be administered parenterally, in unit doses or by continuous infusion, at or near the site on the body of the mammal being treated at which inhibition of collagen degradation is des; red.
  • the inhibitor or a physiologically acceptable salt thereof will, for
  • diluent such as physiological saline, phosphate buffered saline, or the like.
  • route of administration, mode of administration (e.g., by unit doses or continuous infusion), and dosage regimen will vary somewhat depending on the inhibitor employed, the species, age, weight and general medical condition of the mammal being treated, and the particular condition of the mammal for which the inhibitor is being administered. Determining these factors for a particular mammal being treated for a particular condition with a particular inhibitor will be routine for the pharmacologist, physician or veterinarian of ordinary skill.
  • a dose of inhibitor or physiologically acceptable salt thereof of between about 0.1 mg per day and 100 mg per day, infused continuously, or administered by any route, including topically or by injection into or near the site at which collagenase inhibition is desired, in several equal doses per day, or a single dose per day, will be effective to achieve the desired inhibition of collagen degradation.
  • collagenases and mammalian collagenases may be employed in combination.
  • (R) -4-benzyl-2-cyanomethyl-(R,S)-2-hydroxytetra- hydrofuran is subjected to Jones oxidation by adding said solution slowly to a solution of acetic, chromic, and sulfuric acids to give (R)-2-benzyl-5-cyano-4-oxopentanoic acid.
  • 2-alkyl-5-cyano-4-oxo-pentanoic acids and 5-cyano-4- oxo-pentanoic acid may be synthesized from the
  • the synthesis of 3-methyl-3-carbomethoxy propionic acid is known in the art. Cushman et al. Biochemistry 16, 5484 (1977).
  • 3-iso-butyl- 3-carbomethoxy propionic acid is prepared by Arndt-Eistert homologation of the commercially available monomethyl ester of 2-iso-butyl-malonic acid.
  • 2-alkyl-5-cyano-4-oxo-pentanoic acid and 5-cyano- 4-oxo-pentanoic acid are employed as described above to make inhibitors according to the invention.
  • inhibitors of the invention which are derivatives based on 2-alkyl-6-cyano-5-oxo-hexanoic acid and 6-cyano-5-oxo- hexanoic acid may be synthesized by starting from
  • a 4-alkyl-4-carbomethoxy-butanoic acid is conveniently obtained by homologation of the corresponding 3-alkyl-3- carbomethoxy propionic acid using the Arndt-Eistert
  • reaction of the latter compound with oxalyl chloride in the presence of a catalytic amount of dimethylformamide followed by treatment of the resulting acid chloride with etherial diazomethane provides the diazolactone derivative.
  • Exposure to Ag 2 O and then acidic treatment affords the 4-alkyl-4-carbomethoxy-butanoic acid.
  • the method of Cushman et al., supra can be used employing fractional crystallization of the
  • diastereomers can be separated employing reverse phase chromatography.
  • the dipeptide-analogs derivatized with the methyl ester of L-leucine, L-phenylalanine, or glycine were synthesized analogously to the method as described for the L-alanine methyl ester derivative.
  • the dipeptide-analogs derivatized with L-leucine, L-phenylalanine, and glycine were synthesized in the same manner as the L-alanine derivative by hydrolysis of their methyl esters.
  • Enkepalinase from rabbit kidney cortex was purified by immunoaffinity chromatography using a monoclonal antibody. Biochem. Biophys. Res. Commun. 131, 255 (1985). The assay for enkephalinase is carried out in vitro usi ng the fluorescent substrate,
  • DAGNPG dansyl-D-Ala-Gly-Phe-(p-NO 2 )-Gly
  • Angiotensin converting enzyme from frozen rabbit lung is purified according to the procedure of Das and Soffer, J. Biol. Chem. 250, 6762 (1975).
  • the enzyme is assayed using hippuryl-L-histidyl- L-leucine according to the procedure of Cheung and Ondetti, Biochim. Biphys. Acta 293, 451 (1973), by following the release of histidyl-leucine in 100 mM potassium phosphate, 300 mM NaCl, pH 8.3 and a single 30 minute time point.
  • the reaction is initiated by the addition of enzyme and
  • the fluorometric assay of the released histidyl-leucine is then performed using o-pthaldialdehyde in methanol, followed by addition of 3 M Hcl, and measuring the fluorescence at 500 nm, using excitation at 365 nm.
  • the inactivation assay is carried out as follows: ACE and various amounts of inhibitor in 50 mM potassium
  • Collagenase A obtained from Sigma Chemical Co.
  • FLGPA 2-furanacryloyl-L-leucylglycyl-L-prolyl-L- alanine
  • inhibitors of the invention which are collagenase inhibitors (i.e., dipeptide-analogs
  • the derivatized with a dipeptide or dipeptide ester are carried out in a manner similar to that employed for the other analogs.
  • the methyl ester of the dipeptide to be added to the (e.g., pentanoic acid) dipeptide-analog is coupled to the analog using mixed anhydride and then the derivative of the invention is made by alkaline hydrolysis of the resulting methyl ester.
  • the alkyl ester of the dipeptide to b e a dded t o the ( e. g., pentanoic acid ) dispeptide - analog is simply coupled to the analog using mixed anhydride,

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Abstract

Inhibiteurs de Zn+2-métalloendopeptidases d'enképhalinase, d'enzyme de conversion d'angiotensine, et de collagénase. Les inhibiteurs d'enképhalinase de l'invention sont utiles comme analgésiques ou anti-hypertenseurs. Les inhibiteurs d'enzyme de conversion d'angiotensine de l'invention sont utiles en tant qu'anti-hypertenseurs. Les inhibiteurs de collagénase de l'invention sont utiles dans le traitement de maladies, telles que l'ulcération de la cornée, la paradontolyse, et l'arthrite, lesquelles impliquent une activité indésirable de collagénases bactériennes ou mammifères. Les inhibiteurs de l'invention sont des dérivés peptidiques ou d'esters peptidiques d'analogues dipeptidiques de la formule X¿1?-(CR3R4)z-(CR5R6)x-CHR9CO2H, dans laquelle X1- représente un groupe fonctionnel, tel que (N|||C) (CH2) (C=O)-, duquel une Zn?+2¿ métalloendopeptidase, au niveau de son site actif, est capable de soustraire un proton afin de produire un groupe fonctionnel activé capable de former une liaison covalente stable avec un résidu se trouvant dans le site actif; z représente 0 ou 1, dans laquelle, lorsque z représente 0, le groupe -(CR¿3?R4)z- (CR5R6)x- ne représente pas le composé et le groupe X1- est lié directement au groupe -(CHR9)-; x représente 0 si z représente 0, ou il représente 0 ou 1 si z représente 1, dans laquelle, lorsque x représente 0 et z représente 1, le groupe -(CR5R6)x- ne représente pas le composé et le groupe -(CR3R4)- est lié directement au groupe -(CHR9)-; R3, R4, R5 et R6 représentent indépendamment hydrogène ou alkyle contenant 1 à 3 atomes de carbone; et R9 représente benzyl, alkyl contenant 1 à 5 atomes de carbone, ou hydrogène. Parmi les analogues dipeptidique transformés par dérivation à l'aide de peptides ou d'esters peptidiques selon l'invention, se trouve l'acide 2-benzyl-5-cyano-4-oxopentanoïque, que l'invention produit exempt de son régioisomère de 3-benzyl.
PCT/US1990/005902 1989-10-13 1990-10-15 Inhibiteurs de metalloendopeptidase a base d'analogues dipeptidiques et leurs modes d'emploi WO1991005763A1 (fr)

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Cited By (4)

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EP0520573A1 (fr) * 1991-06-27 1992-12-30 Glaxo Inc. Dérivés d'imides cycliques
US5646167A (en) * 1993-01-06 1997-07-08 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamix acids
EP1541545A1 (fr) * 2003-12-08 2005-06-15 Daicel Chemical Industries, Ltd. Dérivés monométhyliques d'acide malonique et procédé de leur préparation
US6916946B2 (en) 2003-08-20 2005-07-12 Daicel Chemical Industries, Ltd. Acid halide derivatives, their production, and production of indanonecarboxylic acid esters using the same

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520573A1 (fr) * 1991-06-27 1992-12-30 Glaxo Inc. Dérivés d'imides cycliques
US5646167A (en) * 1993-01-06 1997-07-08 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamix acids
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EP1541545A1 (fr) * 2003-12-08 2005-06-15 Daicel Chemical Industries, Ltd. Dérivés monométhyliques d'acide malonique et procédé de leur préparation
US7109369B2 (en) 2003-12-08 2006-09-19 Daicel Chemical Industries, Ltd. Malonic acid monomethyl derivatives and production process thereof
US7208621B2 (en) 2003-12-08 2007-04-24 Daicel Chemical Industries, Ltd. Malonic acid monomethyl derivatives and production process thereof

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