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EP1090030A1 - Composes d'inhibiteurs instables de la dipeptidylpeptidase iv - Google Patents

Composes d'inhibiteurs instables de la dipeptidylpeptidase iv

Info

Publication number
EP1090030A1
EP1090030A1 EP99931163A EP99931163A EP1090030A1 EP 1090030 A1 EP1090030 A1 EP 1090030A1 EP 99931163 A EP99931163 A EP 99931163A EP 99931163 A EP99931163 A EP 99931163A EP 1090030 A1 EP1090030 A1 EP 1090030A1
Authority
EP
European Patent Office
Prior art keywords
compounds
inhibitors
pro
dipeptidyl
unstable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99931163A
Other languages
German (de)
English (en)
Inventor
Hans-Ulrich Demuth
Jörn Schmidt
Torsten Hoffmann
Konrad Glund
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Prosidion Ltd
Original Assignee
Probiodrug AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Probiodrug AG filed Critical Probiodrug AG
Publication of EP1090030A1 publication Critical patent/EP1090030A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 compounds of unstable inhibitors of dipeptidyl peptidase IV (DP IV), which compounds have the general formula A-B-C, wherein
  • B is the chemical bond between A and C or an amino acid
  • C is an unstable inhibitor of DP IV.
  • DP IV CD 26 positive cells
  • DP IV inhibitors cf. WAKSELMAN, M., NGUYEN, C, MAZALEYRAT, J.-P., CALLEBAUT, C, KRUST, B., HOVANESSIAN, AG, Inhibition of HIV-1 infection f CD 26+ but not CD26- cells by a potent cy- clopeptidic inhibitor of the DPP IV activity of CD 26. Abstract P 44 of the 24 th European Peptide Symposium 1996].
  • DP IV can modulate the activity of neuroactive peptides such as neuropeptide Y and CLIP [cf. MENTLEIN, R., DAHMS, P., GRANDT, D., KRUGER, R., Pro teolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul. Pept. 49, 133 (1993); WETZEL, W., WAGNER, T., VOGEL, D., DEMUTH, H.-U., BALSCHUN, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes. Neuropeptides, 31, 41 (1997)].
  • Verbindun ⁇ gene of unstable inhibitors of dipeptidyl peptidase IV (DP IV) is dissolved, said compounds having the general formula ABC, wherein
  • B is the chemical bond between A and C or an amino acid
  • C is an unstable inhibitor of DP IV. If B represents a bond, it is in particular a peptide bond; if B represents an amino acid, this is preferably linked to A and C via peptide bonds.
  • these compounds can be used as inhibitors of DP IV, wherein the site of action, the time of onset of action and duration of action ge ⁇ can be precisely defined:
  • the compounds When administered, the compounds are e.g. cleaved by suitable enzymes and so the unstable inhibitors "C" are released with the cleavage of groups A-B.
  • the inhibitors are released both by chemical and by enzymatic mechanisms.
  • esterases, proteases and peptidases are used for drug release from compounds according to the invention.
  • Such esterases, proteases, etc. are e.g. in WO 97/45117, US 5433955, US 5614379, US 5624894.
  • the released unstable inhibitors can then interact with the DP IV present on site and inhibit it. As a result, e.g. a reduced degradation of the above-mentioned insulinotropic peptides is achieved and the effectiveness of insulin is thereby increased.
  • Inhibitors provided as component C which have only a short duration of action and, after definable half-lives, change into inhibitory inactive chemical compounds.
  • a duration of action of the inhibitors of a few minutes is sufficient, while e.g. suppression of the DP IV-mediated immune response in transplantation requires a long-term effect of the inhibitors.
  • the unstable inhibitors according to the invention cyclize after their release, for example to a piperazine derivative, and are thus inactivated. This reaction occurs spontaneously and is due to the Nucleophilic attack of the N-terminal amino nitrogen can be attributed to the C-terminal carbonyl function of the dipeptide derivative and is facilitated by the cis-trans isomerization around the amino acid imide bond, which is facilitated particularly in proline-containing peptides.
  • this disintegration process only begins when the compound reaches the desired target compartment, for example the bloodstream, and has the desired effect.
  • inhibitors according to the invention can be used according to the invention for the design of different DP IV inhibitors in order to initiate its now desired, time-defined deactivation by intramolecular cyclization after the DP IV inhibitor has been released.
  • C represents a dipeptide derivative with an active carbonyl group at the C-terminus.
  • C is preferably a dipeptidyl chloroalkyl ketone, a dipeptidyl boronic acid or a dipeptidyl cyanide compound or a dipeptidyl-pyridinium methyl keto compound.
  • Such inhibitors have proven to be particularly effective unstable DP IV inhibitors.
  • compounds are used in which B is proline, hydroxyproline, thiazolidinecarboxylic acid, dehydroproline, pipecolic acid, azetidinecarboxylic acid or aziridinecarboxylic acid, proline and hydroxyproline being particularly preferred.
  • the compounds according to the invention have the particular advantage that the inhibitors of DP IV are released depending on the individual needs of the patient: If a compound according to the invention interacts with a DP IV molecule, it is split into groups AB and inhibitor C by the enzyme. The inhibitor C will inhibit the DP IV molecule so that it can no longer break down any further compounds. If further DP IV molecules are present, the compounds are cleaved (if a sufficient amount of the corresponding compounds has been administered) until the last DP IV molecule is inhibited. The other compounds are not decomposed and thus represent an inhibitor depot until the concentration of DP IV molecules rises again or inhibitor molecules are displaced by the DP IV or inhibitor molecules are eliminated or inactivated and the compounds according to the invention and thus there is a release of inhibitors.
  • the invention therefore has the further advantage that each organism will release exactly the amount of inhibitor that is necessary to inhibit the DP IV present individually in different amounts. If there is a patient DP IV e.g. in high concentrations, a large amount of inhibitor is released; if there is only a slightly increased concentration of DP IV, only a small amount of inhibitor is released.
  • A-B is a dipeptide of the formula Ile-Pro or Gly-Pro.
  • the present invention thus relates to new compounds of unstable inhibitors of serine peptidase dipeptidyl peptidase IV, which can be used for the treatment of various diseases, in particular metabolic diseases associated with diabetes mellitus.
  • masked inhibitors ge ⁇ genüber unmasked inhibitors in addition a considerably increased effectiveness on identical amounts are used by un- masked inhibitors of DP IV and compounds of the invention, it is used in Wistar rats by the compounds of the invention to a significant glucose tolerance improvement.
  • Another advantage of the compounds according to the invention is that the onset of action and also the duration of action of the DP IV inhibitors can be timed by suitable selection of groups A-B.
  • the release of groups A-B from the compounds according to the invention depends on the nature of the amino acid residue of A: With regard to the definition of group A, the following sequence of release rates of residues A-B from compounds A-B-C by DP IV was found:
  • the rate constants of the corresponding DP IV-catalyzed releases are between 1 s "1 and 100 s " 1 .
  • This provides a means of releasing the DP IV inhibitors in a precisely defined time: If the enzymes are to have an immediate effect, for example when ingesting high-glucose food, a compound ABC is selected which, for example, has the amino acid Gly as group A; if a delayed action of the inhibitor should occur, the amino acid Ile, for example, can be selected as group A.
  • DP IV inhibitors can thus, in particular, be transported through the small intestinal mucosa almost without delay, for example almost simultaneously with ingested foods, by the compounds according to the invention.
  • aminopeptidases such as B. Pyroglutamyl Aminopeptidase and prolyl aminopeptidase.
  • residues AB By suitable selection of the residues AB it can be determined according to the invention by which aminopeptidase the DP IV inhibitor is to be released and thus it can be determined where the effect of the inhibitor is to take place.
  • the compounds according to the invention or corresponding pharmaceutical compositions can therefore also be used for cell, tissue or organ-specific inhibition of DP IV.
  • the groups AB can also be selected in such a way that only those enzymes are addressed which are only vascularly present and which release the inhibitors at a sufficiently high rate.
  • the release of the inhibitors can take place according to the patient's needs
  • the release of the inhibitors from the compounds can be timed
  • the release of the inhibitors from the compounds can be controlled with regard to the release site
  • a depot of DP IV inhibitors can be provided.
  • the duration of action or the end of action of the initiators can be precisely defined from the time of their unmasking.
  • compositions are also provided, in particular for oral administration, which are characterized in that they contain at least one compound according to the invention, optionally in combination with conventional carriers or auxiliaries.
  • the compounds according to the invention or pharmaceutical compositions containing them can be used for the treatment or prophylaxis of diseases of mammals which can be treated by modulating the DP IV activity of a mammal, such as, for example, metabolic diseases of humans.
  • they can be used for the treatment of impaired glucose tolerance, glucosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus, diabetic neuropathy and nephropathy as well as secondary diseases of mammals caused by diabetes mellitus.
  • the preferably short duration of action of the unstable inhibitors according to the invention can in particular minimize or prevent an influence on processes in the human or animal body which would require long-term inhibition of DP IV.
  • the Z-protective group is split off from Z-Val-Pro-CH 2 - (N + C 5 H 4 ) / Cl " by means of HBr / glacial acetic acid in a 5 minute reaction time.
  • 1.0 mmol of Z-protected peptide is mixed with 2 ml of HBr / Glacial acetic acid (33%) and let it stir for about 10 minutes at 23 ° C.
  • the mixture is then concentrated in vacuo, and the peptide is precipitated as a hydrobromide from methanol using diethyl ether, filtered off with suction and dried in vacuo.
  • the Z-protecting group is Z-Phe-Pro-CH 2 - cleaved (N + C 5 H 4) / Cl "according ⁇ in 5 minutes Reakti onszeit 1.0 mmol Z-protected peptide is mixed with 2 ml of HBr /. Glacial acetic acid (33%) and allowed to stir for about 10 minutes at 23 ° C. The mixture was then concentrated in vacuo and the peptide was precipitated as hydrobromide with diethyl ether, filtered off with suction and dried in vacuo.
  • Retention time: 17.7 min, Nucleosil 100 7 C 8 , 220 nm, flow rate 5 ml / min, isochromatic 50% acetonitrile in H 2 0 (0.1% TFA)
  • the Z-protecting group is Z-Phe-Pro-CH 2 - cleaved (N + C 5 H 4) / Cl "according minutes in 5 Reaction Time 1.0 mmol Z-protected ⁇ tes peptide is treated with 2 ml of HBr /. Glacial acetic acid (33%) and allowed to stir for about 10 minutes at 23 ° C. The mixture was then concentrated in vacuo and the peptide was precipitated as hydrobromide with diethyl ether, filtered off with suction and dried in vacuo.
  • the compound of the invention is H-Gly-Pro-Val-Pro-CH 2 proves - (N + C 5 H 5) over 24 hours in a buffered aqueous solution in the Ab ⁇ being an enzyme as stable .
  • the active DP IV inhibitor H-Val-Pro-CH 2 is only released by adding the enzyme DP IV (also used here as an example to release the DP IV inhibitor) with elimination of the N-terminal dipeptide H-Gly-Pro-OH - (N + C 5 H 5 ) released.
  • DP IV also used here as an example to release the DP IV inhibitor
  • Figure 7 are consequently, even after an incubation time of 60 minutes, clearly more than 50% of the incubated compound according to the invention can be seen. Because of this sustained release, in addition to the desired effective inhibition of the target enzyme, a significantly prolonged activity is surprisingly observed with a significantly reduced concentration of the compound according to the invention compared to the unstable DP IV inhibitors ( Figure 8).
  • Figure 1 Structural formula of the product of the intramolecular cyclization of H-Phe-Pro-Pyridinium methyl ketone. The characteristic chemical

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés d'inhibiteurs instables de la dipeptidylpeptidase IV (DP IV), qui présentent la formule générale A-B-C, dans laquelle A est un aminoacide, B est la liaison chimique entre A et C ou un aminoacide, et C est un inhibiteur instable de la DP IV. Ces composés s'utilisent pour traiter la tolérance glucidique altérée, la glucosurie, l'hyperlipidémie, les acidoses métaboliques, le diabète sucré, la neuropathie et la néphropathie diabétiques, ainsi que les maladies provoquées par le diabète sucré chez les mammifères.
EP99931163A 1998-06-24 1999-06-24 Composes d'inhibiteurs instables de la dipeptidylpeptidase iv Withdrawn EP1090030A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19828114A DE19828114A1 (de) 1998-06-24 1998-06-24 Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV
DE19828114 1998-06-24
PCT/EP1999/004381 WO1999067279A1 (fr) 1998-06-24 1999-06-24 Composes d'inhibiteurs instables de la dipeptidylpeptidase iv

Publications (1)

Publication Number Publication Date
EP1090030A1 true EP1090030A1 (fr) 2001-04-11

Family

ID=7871860

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99931163A Withdrawn EP1090030A1 (fr) 1998-06-24 1999-06-24 Composes d'inhibiteurs instables de la dipeptidylpeptidase iv

Country Status (17)

Country Link
US (1) US7053055B2 (fr)
EP (1) EP1090030A1 (fr)
JP (1) JP3761781B2 (fr)
KR (1) KR100630254B1 (fr)
CN (1) CN100345866C (fr)
AU (1) AU758843B2 (fr)
BR (1) BR9911415A (fr)
CA (1) CA2335978A1 (fr)
DE (1) DE19828114A1 (fr)
HU (1) HUP0102250A3 (fr)
IL (1) IL140338A0 (fr)
IS (1) IS5739A (fr)
NO (1) NO20006483D0 (fr)
NZ (1) NZ508721A (fr)
PL (1) PL345060A1 (fr)
RU (1) RU2226195C2 (fr)
WO (1) WO1999067279A1 (fr)

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JP2002518518A (ja) 2002-06-25
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US20010020006A1 (en) 2001-09-06
CA2335978A1 (fr) 1999-12-29
RU2226195C2 (ru) 2004-03-27
HUP0102250A2 (hu) 2001-11-28
NZ508721A (en) 2003-06-30
AU4777299A (en) 2000-01-10
AU758843B2 (en) 2003-04-03
CN1306541A (zh) 2001-08-01
US7053055B2 (en) 2006-05-30
JP3761781B2 (ja) 2006-03-29
PL345060A1 (en) 2001-11-19
IS5739A (is) 2000-11-28
NO20006483L (no) 2000-12-19
IL140338A0 (en) 2002-02-10
NO20006483D0 (no) 2000-12-19
DE19828114A1 (de) 2000-01-27
WO1999067279A1 (fr) 1999-12-29
BR9911415A (pt) 2001-03-20
CN100345866C (zh) 2007-10-31
KR20010071563A (ko) 2001-07-28

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