EP1090030A1 - Verbindungen von instabilen dp iv-inhibitoren - Google Patents

Verbindungen von instabilen dp iv-inhibitoren

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Withdrawn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)
French (fr)
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/de
Withdrawn legal-status Critical Current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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Molecular Biology (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)
EP99931163A 1998-06-24 1999-06-24 Verbindungen von instabilen dp iv-inhibitoren Withdrawn EP1090030A1 (de)

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 (de) 1998-06-24 1999-06-24 Verbindungen von instabilen dp iv-inhibitoren

Publications (1)

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

Family

ID=7871860

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99931163A Withdrawn EP1090030A1 (de) 1998-06-24 1999-06-24 Verbindungen von instabilen dp iv-inhibitoren

Country Status (17)

Country Link
US (1) US7053055B2 (hu)
EP (1) EP1090030A1 (hu)
JP (1) JP3761781B2 (hu)
KR (1) KR100630254B1 (hu)
CN (1) CN100345866C (hu)
AU (1) AU758843B2 (hu)
BR (1) BR9911415A (hu)
CA (1) CA2335978A1 (hu)
DE (1) DE19828114A1 (hu)
HU (1) HUP0102250A3 (hu)
IL (1) IL140338A0 (hu)
IS (1) IS5739A (hu)
NO (1) NO20006483L (hu)
NZ (1) NZ508721A (hu)
PL (1) PL345060A1 (hu)
RU (1) RU2226195C2 (hu)
WO (1) WO1999067279A1 (hu)

Families Citing this family (170)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020006899A1 (en) * 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
BR9813233A (pt) * 1997-09-29 2000-08-22 Point Therapeutics Inc Estimulação de células hematopoéticas in vitro
US6979697B1 (en) * 1998-08-21 2005-12-27 Point Therapeutics, Inc. Regulation of substrate activity
US20030176357A1 (en) * 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
US6548529B1 (en) 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
AU1916401A (en) * 1999-11-12 2001-06-06 Guilford Pharmaceuticals Inc. Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors
AU2001233622A1 (en) * 2000-02-25 2001-09-03 Novo-Nordisk A/S Inhibition of beta cell degeneration
US6395767B2 (en) * 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
DE60137216D1 (de) 2000-03-31 2009-02-12 Prosidion Ltd Verbesserung der aktivität der inselzellen bei diabetes mellitus und dessen prävention
EP1891948A1 (en) 2000-10-27 2008-02-27 Probiodrug AG Treatment of neurological and neuropsychological disorders
CA2433090A1 (en) * 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Dipeptidyl peptidase iv inhibitor
CN100408579C (zh) * 2001-02-24 2008-08-06 贝林格尔英格海姆法玛两合公司 黄嘌呤衍生物,其制法及其作为药物组合物的用途
AU2002254567B2 (en) 2001-04-11 2007-10-11 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20030060494A1 (en) * 2001-05-18 2003-03-27 Nobuyuki Yasuda Pharmaceutical use of N-carbamoylazole derivatives
KR20040015298A (ko) 2001-06-27 2004-02-18 스미스클라인 비참 코포레이션 디펩티딜 펩티다제 억제제로서의 플루오로피롤리딘
DE10150203A1 (de) * 2001-10-12 2003-04-17 Probiodrug Ag Peptidylketone als Inhibitoren der DPIV
UA74912C2 (en) * 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
HUP0700151A2 (en) 2001-10-18 2007-05-29 Bristol Myers Squibb Co Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7238671B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7727964B2 (en) 2001-11-26 2010-06-01 Trustees Of Tufts College Peptidomimetic inhibitors of post-proline cleaving enzymes
US7153822B2 (en) * 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
DE60304911D1 (de) 2002-02-25 2006-06-08 Eisai Co Ltd Xanthin-Derivate als DPP-IV-Inhibitoren
US7057046B2 (en) 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
ATE422884T1 (de) * 2002-06-03 2009-03-15 Novartis Pharma Gmbh Verwendung von substituierten cyanopyrrolidinen zur behandlung von hyperlipidämie
JP2006506442A (ja) * 2002-07-09 2006-02-23 ポイント セラピューティクス， インコーポレイテッド ボロプロリン化合物併用療法
ES2306781T3 (es) 2002-08-09 2008-11-16 Prosidion Ltd. Inhibidores de la dipeptidil-peptidasa iv para disminucion de la tasa de aumento cronico de peso.
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
SI1532149T1 (sl) * 2002-08-21 2010-05-31 Boehringer Ingelheim Pharma amino piperidin il ksantini njihova priprava in njihova uporaba kot zdravila
ES2344057T3 (es) 2002-10-23 2010-08-17 Bristol-Myers Squibb Company Inhibidores de la dipeptidil peptidasa iv basados en nitrilos de glicina.
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
TW200504021A (en) 2003-01-24 2005-02-01 Bristol Myers Squibb Co Substituted anilide ligands for the thyroid receptor
DE10308355A1 (de) 2003-02-27 2004-12-23 Aventis Pharma Deutschland Gmbh Aryl-cycloalkyl substituierte Alkansäurederivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE10308351A1 (de) 2003-02-27 2004-11-25 Aventis Pharma Deutschland Gmbh 1,3-substituierte Cycloalkylderivate mit sauren, meist heterocyclischen Gruppen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE10308352A1 (de) 2003-02-27 2004-09-09 Aventis Pharma Deutschland Gmbh Arylcycloalkylderivate mit verzweigten Seitenketten, Verfahren zu ihrer Herstellung und ihre Anwendung als Arzneimittel
DE10308353A1 (de) 2003-02-27 2004-12-02 Aventis Pharma Deutschland Gmbh Diarylcycloalkylderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
US7550590B2 (en) 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP4806628B2 (ja) 2003-05-05 2011-11-02 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤
KR20100106630A (ko) 2003-05-05 2010-10-01 프로비오드룩 아게 글루타미닐 및 글루타메이트 사이클라제의 이펙터의 용도
WO2004098625A2 (en) 2003-05-05 2004-11-18 Probiodrug Ag Medical use of inhibitors of glutaminyl and glutamate cyclases
US7638638B2 (en) 2003-05-14 2009-12-29 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7459474B2 (en) 2003-06-11 2008-12-02 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
US6995183B2 (en) 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
ZA200602051B (en) 2003-08-13 2007-10-31 Takeda Pharmaceutical 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2005026148A1 (en) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
BRPI0415409A (pt) 2003-10-15 2006-12-05 Probiodrug Ag uso de efetuadores de ciclases de glutaminila e glutamato
JP2007509971A (ja) * 2003-10-31 2007-04-19 アルザ・コーポレーシヨン メトホルミンの増加された吸収のための組成物及び投与形態物
EP2338490A3 (en) 2003-11-03 2012-06-06 Probiodrug AG Combinations useful for the treatment of neuronal disorders
EP1824846A2 (en) 2003-11-03 2007-08-29 Probiodrug AG Novel compounds for the treatment of neurological disorders
KR20170005163A (ko) 2003-11-17 2017-01-11 노파르티스 아게 디펩티딜 펩티다제 ⅳ 억제제의 용도
EP2165703A3 (en) 2004-01-20 2012-03-28 Novartis Pharma AG Direct compression formulation and process
US7241787B2 (en) 2004-01-25 2007-07-10 Sanofi-Aventis Deutschland Gmbh Substituted N-cycloexylimidazolinones, process for their preparation and their use as medicaments
BRPI0507485A (pt) 2004-02-05 2007-07-10 Probiodrug Ag inibidores novos de glutaminil ciclase
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CN102127053A (zh) * 2004-03-15 2011-07-20 武田药品工业株式会社 二肽基肽酶抑制剂
DE602004004631D1 (de) 2004-04-01 2007-03-22 Sanofi Aventis Deutschland Oxadiazolone, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Pharmazeutika
US7687638B2 (en) 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7145040B2 (en) 2004-07-02 2006-12-05 Bristol-Myers Squibb Co. Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
TW200611704A (en) 2004-07-02 2006-04-16 Bristol Myers Squibb Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
US7534763B2 (en) 2004-07-02 2009-05-19 Bristol-Myers Squibb Company Sustained release GLP-1 receptor modulators
WO2006019965A2 (en) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
ATE553077T1 (de) * 2004-07-23 2012-04-15 Nuada Llc Peptidaseinhibitoren
US20060063719A1 (en) * 2004-09-21 2006-03-23 Point Therapeutics, Inc. Methods for treating diabetes
AR051446A1 (es) 2004-09-23 2007-01-17 Bristol Myers Squibb Co Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2)
DE102004054054A1 (de) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP5068174B2 (ja) * 2004-12-23 2012-11-07 カンピナ ネーデルランド ホールディング ビー．ブイ． Ｄｐｐ−ｉｖを阻害するペプチド中に濃縮されたタンパク質の加水分解物及びその使用
US7589088B2 (en) 2004-12-29 2009-09-15 Bristol-Myers Squibb Company Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7635699B2 (en) 2004-12-29 2009-12-22 Bristol-Myers Squibb Company Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
DOP2006000008A (es) * 2005-01-10 2006-08-31 Arena Pharm Inc Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1
US7317024B2 (en) 2005-01-13 2008-01-08 Bristol-Myers Squibb Co. Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
EP1879881A2 (en) 2005-04-14 2008-01-23 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type i
US7521557B2 (en) 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US20090317376A1 (en) 2005-06-06 2009-12-24 Georgetown University Medical School Compositions And Methods For Lipo Modeling
DE102005026762A1 (de) 2005-06-09 2006-12-21 Sanofi-Aventis Deutschland Gmbh Azolopyridin-2-on-derivate als Inhibitoren von Lipasen und Phospholipasen
US7888381B2 (en) 2005-06-14 2011-02-15 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof
DE102005035891A1 (de) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
CN101232873A (zh) * 2005-08-11 2008-07-30 霍夫曼-拉罗奇有限公司 含有dpp-iv抑制剂的药物组合物
DK1942898T4 (da) 2005-09-14 2014-06-02 Takeda Pharmaceutical Dipeptidylpeptidase-inhibitorer til behandling af diabetes
KR101368988B1 (ko) 2005-09-16 2014-02-28 다케다 야쿠힌 고교 가부시키가이샤 디펩티딜 펩티다제 억제제
WO2007053819A2 (en) 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase iv and methods
WO2007054577A1 (en) 2005-11-14 2007-05-18 Probiodrug Ag Cyclopropyl-fused pyrrolidine derivatives as dipeptidyl peptidase iv inhibitors
EP1954299B1 (en) 2005-11-30 2016-01-13 Campina Nederland Holding B.V. Use of a protein hydrolysate for enhancing activity of glucagon-like peptide-1
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP2369341A3 (en) * 2006-04-11 2012-01-04 Arena Pharmaceuticals, Inc. Methods of using gpr119 receptor to identify compounds useful for increasing bone mass in an individual
PE20071221A1 (es) 2006-04-11 2007-12-14 Arena Pharm Inc Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas
EP2007734A1 (en) 2006-04-12 2008-12-31 Probiodrug AG Enzyme inhibitors
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
NO347644B1 (no) 2006-05-04 2024-02-12 Boehringer Ingelheim Int Polymorfer
US20100022457A1 (en) 2006-05-26 2010-01-28 Bristol-Myers Squibb Company Sustained release glp-1 receptor modulators
US7919598B2 (en) 2006-06-28 2011-04-05 Bristol-Myers Squibb Company Crystal structures of SGLT2 inhibitors and processes for preparing same
US7910747B2 (en) 2006-07-06 2011-03-22 Bristol-Myers Squibb Company Phosphonate and phosphinate pyrazolylamide glucokinase activators
US7795291B2 (en) 2006-07-07 2010-09-14 Bristol-Myers Squibb Company Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
EP2099767A1 (en) 2006-11-01 2009-09-16 Brystol-Myers Squibb Company Modulators of glucocorticoid receptor, ap-1, and/or nf- b activity and use thereof
WO2008057862A2 (en) 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
ATE554085T1 (de) 2006-11-30 2012-05-15 Probiodrug Ag Neue inhibitoren von glutaminylcyclase
ES2529147T3 (es) 2006-12-26 2015-02-17 Pharmacyclics, Inc. Método para usar los inhibidores de la histona deacetilasa y monitorear biomarcadores en la terapia de combinación
EP2117540A1 (en) 2007-03-01 2009-11-18 Probiodrug AG New use of glutaminyl cyclase inhibitors
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
PE20090185A1 (es) 2007-03-22 2009-02-28 Bristol Myers Squibb Co Formulaciones farmaceuticas que contienen un inhibidor sglt2
JP5667440B2 (ja) 2007-04-18 2015-02-12 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤としてのチオ尿素誘導体
PE20090696A1 (es) 2007-04-20 2009-06-20 Bristol Myers Squibb Co Formas cristalinas de saxagliptina y procesos para preparar las mismas
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
MX354786B (es) 2007-06-04 2018-03-21 Synergy Pharmaceuticals Inc Agonistas de guanilato ciclasa utiles para el tratamiento de trastornos gastrointestinales, inflamacion, cancer y otros trastornos.
JP2010534722A (ja) 2007-07-27 2010-11-11 ブリストル−マイヤーズ スクイブ カンパニー 新規グルコキナーゼ活性化薬およびその使用方法
WO2009024542A2 (en) * 2007-08-17 2009-02-26 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases
ES2448839T3 (es) 2007-11-01 2014-03-17 Bristol-Myers Squibb Company Compuestos no esteroideos útiles como moderadores de la actividad del receptor de glucocorticoides AP-1 y/o NF-kappa b y uso de los mismos
AR071175A1 (es) 2008-04-03 2010-06-02 Boehringer Ingelheim Int Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante
EP2146210A1 (en) 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY
PE20100156A1 (es) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int Tratamiento de nafld
CA2726917C (en) 2008-06-04 2018-06-26 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
CN102149710A (zh) 2008-06-24 2011-08-10 百时美施贵宝公司 糖皮质激素受体、AP-1和/或NF-κB 活性的环戊噻吩调节剂及其用途
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
KR20200118243A (ko) 2008-08-06 2020-10-14 베링거 인겔하임 인터내셔날 게엠베하 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료
UY32030A (es) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
BRPI0917675A2 (pt) * 2008-08-15 2015-12-01 Boehringer Ingelheim Int compostos orgânicos para cura de ferida
MX2011002558A (es) 2008-09-10 2011-04-26 Boehringer Ingelheim Int Terapia de combinacion para el tratamiento de diabetes y estados relacionados.
ES2571217T3 (es) * 2008-09-12 2016-05-24 Cadila Pharmaceuticals Ltd Profármacos de sitagliptina
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
TW201036975A (en) 2009-01-07 2010-10-16 Boehringer Ingelheim Int Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy
SG178953A1 (en) 2009-09-11 2012-04-27 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
MX2012005425A (es) 2009-11-13 2012-06-14 Astrazeneca Uk Ltd Formulaciones de metformina de masa reducida.
CA2780941C (en) 2009-11-13 2018-06-12 Bristol-Myers Squibb Company Immediate release tablet formulations
PT2498758T (pt) 2009-11-13 2018-10-23 Astrazeneca Uk Ltd Formulações de comprimido bicamada
AU2010323068B2 (en) 2009-11-27 2015-09-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
TWI562775B (en) 2010-03-02 2016-12-21 Lexicon Pharmaceuticals Inc Methods of using inhibitors of sodium-glucose cotransporters 1 and 2
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
AU2011226074B2 (en) 2010-03-10 2015-01-22 Vivoryon Therapeutics N.V. Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
US8592396B2 (en) 2010-04-14 2013-11-26 Bristol-Myers Squibb Company Glucokinase activators and methods of using same
US8541596B2 (en) 2010-04-21 2013-09-24 Probiodrug Ag Inhibitors
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
KR20190050871A (ko) 2010-06-24 2019-05-13 베링거 인겔하임 인터내셔날 게엠베하 당뇨병 요법
WO2012031124A2 (en) 2010-09-03 2012-03-08 Bristol-Myers Squibb Company Drug formulations using water soluble antioxidants
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
AR083878A1 (es) 2010-11-15 2013-03-27 Boehringer Ingelheim Int Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento
TWI631963B (zh) 2011-01-05 2018-08-11 雷西肯製藥股份有限公司 包含鈉－葡萄糖共同輸送體１與２之抑制劑的組合物與應用方法
EP2670397B1 (en) 2011-02-01 2020-05-13 Bristol-Myers Squibb Company Pharmaceutical formulations including an amine compound
US9580471B2 (en) 2011-03-01 2017-02-28 Synergy Pharmaceuticals, Inc. Process of preparing guanylate cyclase C agonists
ES2570167T3 (es) 2011-03-16 2016-05-17 Probiodrug Ag Derivados de benzimidazol como inhibidores de glutaminil ciclasa
KR101985384B1 (ko) 2011-07-15 2019-06-03 베링거 인겔하임 인터내셔날 게엠베하 치환된 퀴나졸린, 이의 제조 및 약제학적 조성물에서의 이의 용도
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
EP2849755A1 (en) 2012-05-14 2015-03-25 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
CA2891773C (en) 2012-11-20 2021-01-19 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
JP6606491B2 (ja) 2013-06-05 2019-11-13 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼｃの超高純度アゴニスト、その作成および使用方法
WO2015027021A1 (en) 2013-08-22 2015-02-26 Bristol-Myers Squibb Company Imide and acylurea derivatives as modulators of the glucocorticoid receptor
WO2015128453A1 (en) 2014-02-28 2015-09-03 Boehringer Ingelheim International Gmbh Medical use of a dpp-4 inhibitor
AU2016229982B2 (en) 2015-03-09 2020-06-18 Intekrin Therapeutics, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
WO2018162722A1 (en) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Dpp-4 inhibitors for use in treating bone fractures
EP3606527A1 (en) 2017-04-03 2020-02-12 Coherus Biosciences, Inc. Ppar-gamma agonist for treatment of progressive supranuclear palsy
ES2812698T3 (es) 2017-09-29 2021-03-18 Probiodrug Ag Inhibidores de glutaminil ciclasa
AU2019304032B2 (en) 2018-07-19 2021-12-09 Astrazeneca Ab Methods of treating HFpEF employing dapagliflozin and compositions comprising the same
BR112021004839A2 (pt) 2018-09-26 2021-06-08 Lexicon Pharmaceuticals, Inc. formas cristalinas de n-(1-((2-(dimetilamino)etil)amino)-2-metil-1-oxopropan-2-il)-4-(4-(2-metil-5-((2s,3r,4r,5s,6r)-3,4,5-triidróxi-6-(metiltio)tetraidro-2h-piran-2-il)benzil)fenil)butanamida e métodos de sua síntese
EP3871665A1 (en) 2020-02-28 2021-09-01 Martin-Luther-Universität Halle-Wittenberg Inhibitors of rna-binding proteins as anti-cancer drugs
WO2022022865A1 (en) 2020-07-27 2022-02-03 Astrazeneca Ab Methods of treating chronic kidney disease with dapagliflozin
CN118510504A (zh) 2022-01-26 2024-08-16 阿斯利康(瑞典)有限公司 用于在治疗糖尿病前期或降低发展2型糖尿病的风险中使用的达格列净

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE296075C (hu)
US2961377A (en) 1957-08-05 1960-11-22 Us Vitamin Pharm Corp Oral anti-diabetic compositions and methods
US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
DE1961686B2 (de) * 1969-12-02 1979-05-31 Siemens Ag, 1000 Berlin Und 8000 Muenchen UEberstromschutzrelais fuer Wechselstromnetze
US3879541A (en) 1970-03-03 1975-04-22 Bayer Ag Antihyperglycemic methods and compositions
DE2009743A1 (de) 1970-03-03 1971-09-16 Farbenfabriken Bayer Ag, 5090 Leverkusen Substituierte Biguanide mit antihyperglykämischer Wirkung
US3960949A (en) 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
CH602612A5 (hu) 1974-10-11 1978-07-31 Hoffmann La Roche
US4935493A (en) 1987-10-06 1990-06-19 E. I. Du Pont De Nemours And Company Protease inhibitors
US5433955A (en) 1989-01-23 1995-07-18 Akzo N.V. Site specific in vivo activation of therapeutic drugs
ES2113879T3 (es) 1990-01-24 1998-05-16 Douglas I Buckley Analogos de glp-1 utiles para el tratamiento de diabetes.
ES2099158T3 (es) 1990-04-14 1997-05-16 New England Medical Center Inc Tratamiento del rechazo de trasplantes o de enfermedades autoinmunitarias y complejo de la formula general x-pro-y-boropro asociada al mismo.
US5462928A (en) 1990-04-14 1995-10-31 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type IV
WO1991017767A1 (en) 1990-05-21 1991-11-28 New England Medical Center Hospitals, Inc. Method of treating inhibition of dipeptidyl aminopeptidase type iv
JPH0819154B2 (ja) 1991-03-14 1996-02-28 江崎グリコ株式会社 ジペプチジルカルボキシペプチダーゼを阻害するペプチド
JPH04334357A (ja) 1991-05-02 1992-11-20 Fujirebio Inc 酵素阻害作用を有するアシル誘導体
CA2121369C (en) * 1991-10-22 2003-04-29 William W. Bachovchin Inhibitors of dipeptidyl-aminopeptidase type iv
IL106998A0 (en) 1992-09-17 1993-12-28 Univ Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
FR2696740B1 (fr) 1992-10-13 1994-12-30 Dospharma Sa Dérivés prodrogués de la diméthylbiguanide et applications comme médicaments.
WO1995011689A1 (en) * 1993-10-29 1995-05-04 Trustees Of Tufts College Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells
IL111785A0 (en) 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
CA2137206A1 (en) 1993-12-09 1995-06-10 John A. Galloway Glucagon-like insulinotropic peptides, compositions and methods
US5543396A (en) 1994-04-28 1996-08-06 Georgia Tech Research Corp. Proline phosphonate derivatives
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5614379A (en) 1995-04-26 1997-03-25 Eli Lilly And Company Process for preparing anti-obesity protein
DE19616486C5 (de) * 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Verfahren zur Senkung des Blutglukosespiegels in Säugern
CA2256669A1 (en) 1996-05-29 1997-12-04 Prototek, Inc. Prodrugs of thalidomide and methods for using same as modulators of t-cell function
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
AR016751A1 (es) 1996-11-22 2001-08-01 Athena Neurosciences Inc Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo
AU4854999A (en) 1998-07-02 2000-01-24 Invitro Diagnostics, Inc. Methods, compositions and apparatus for making nucleic acid molecules having a selected affinity to a target molecule
DE19834591A1 (de) 1998-07-31 2000-02-03 Probiodrug Ges Fuer Arzneim Verfahren zur Steigerung des Blutglukosespiegels in Säugern
WO2000053171A1 (en) 1999-03-05 2000-09-14 Molteni L. E C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. Use of metformin in the preparation of pharmaceutical compositions capable of inhibiting the enzyme dipeptidyl peptidase iv
AU2001233622A1 (en) 2000-02-25 2001-09-03 Novo-Nordisk A/S Inhibition of beta cell degeneration

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9967279A1 *

Also Published As

Publication number Publication date
AU758843B2 (en) 2003-04-03
CN100345866C (zh) 2007-10-31
JP3761781B2 (ja) 2006-03-29
WO1999067279A1 (de) 1999-12-29
NO20006483D0 (no) 2000-12-19
RU2226195C2 (ru) 2004-03-27
US20010020006A1 (en) 2001-09-06
BR9911415A (pt) 2001-03-20
CA2335978A1 (en) 1999-12-29
KR20010071563A (ko) 2001-07-28
NO20006483L (no) 2000-12-19
JP2002518518A (ja) 2002-06-25
HUP0102250A3 (en) 2001-12-28
CN1306541A (zh) 2001-08-01
KR100630254B1 (ko) 2006-10-02
HUP0102250A2 (hu) 2001-11-28
NZ508721A (en) 2003-06-30
IS5739A (is) 2000-11-28
AU4777299A (en) 2000-01-10
IL140338A0 (en) 2002-02-10
US7053055B2 (en) 2006-05-30
DE19828114A1 (de) 2000-01-27
PL345060A1 (en) 2001-11-19

Similar Documents

Publication Publication Date Title
EP1090030A1 (de) Verbindungen von instabilen dp iv-inhibitoren
EP1087991B1 (de) Prodrugs von dipeptidylpeptidase iv-inhibitoren
EP1304327B1 (de) Glutamin-Thiazolidide und -Pyrrolidide sowie ihre Verwendung als Dipeptidylpeptidase IV Inhibitoren
DE3505555A1 (de) Neue oligopeptidylargininolderivate und deren homologe, verfahren zu deren herstellung, deren verwendung und diese enthaltende mittel
DE20220238U1 (de) Glutaminyl basierte DPIV Inhibitoren
EP0140084B1 (de) Verfahren zur Herstellung von Insulin-Derivaten, deren B-Kette C-terminal verlängert ist, neue basisch modifizierte Insulin-Derivate, diese enthaltende Mittel und ihre Verwendung
EP1206485A2 (de) Neue effektoren der dipeptidyl peptidase iv zur topischen anwendung
EP0513543A1 (de) Amidinophenylalaninderivate, Verfahren zu deren Herstellung, deren Verwendung und diese enthaltende Mittel als Antikoagulantien
DE60114362T2 (de) Verwendung eines zyklischen ethers zur herstellung von mitteln, die die glukosetoleranz beeinflussen
WO2003016259A2 (de) Milchsäureelemente enthaltende verbindungen, deren herstellung sowie deren verwendung als pharmazeutische wirkstoffe
DE69307414T2 (de) Dipeptidderivate und diese als aktive Bestandteile enthaltendes prophylaktisches oder therapeutisches Mittel gegen Knochenkrankheiten
DE69606552T2 (de) Acylierte enolderivate von alpha-ketoestern und alpha-ketoamiden
EP1023282A1 (de) Neue pharmazeutische wirksame verbindungen, ihre herstellung und verwendung als ece-inhibitoren
DD294176A5 (de) Neue inhibitoren zur hemmung der katalytischen aktivitaet von prolinspezifischen und anderen proteolytischen enzymen und verfahren zu ihrer herstellung
MXPA00012215A (en) Compounds of unstable dipeptidyl peptidase iv inhibitors
CZ20004796A3 (cs) Sloučeniny nestabilních DP IV-inhibitorů
DE2900926A1 (de) Therapeutisch wirksame pseudopeptide, diese enthaltende zusammensetzungen und verfahren zu deren herstellung
CH532024A (fr) Procédé de préparation de dérivés de l'insuline

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20001120

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20001120;LT PAYMENT 20001120;LV PAYMENT 20001120;MK PAYMENT 20001120;RO PAYMENT 20001120;SI PAYMENT 20001120

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: PROBIODRUG AG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: PROSIDION LIMITED

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1033326

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20091229