WO2004002985A1 - Compose peptidique inhibiteur de la thrombine - Google Patents

Compose peptidique inhibiteur de la thrombine Download PDF

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Publication number
WO2004002985A1
WO2004002985A1 PCT/KR2003/001166 KR0301166W WO2004002985A1 WO 2004002985 A1 WO2004002985 A1 WO 2004002985A1 KR 0301166 W KR0301166 W KR 0301166W WO 2004002985 A1 WO2004002985 A1 WO 2004002985A1
Authority
WO
WIPO (PCT)
Prior art keywords
pro
thioph
amd
dpa
cch
Prior art date
Application number
PCT/KR2003/001166
Other languages
English (en)
Inventor
Suk Kyoon Yoon
Bongchan Kim
Sungji Kim
Sangyeul Hwang
Kunhye Nam
Hee Dong Park
Sun Hwa Lee
Aeri Kim
Ho Jun Kim
Su-Kyung Park
Koo Lee
Original Assignee
Lg Life Sciences Ltd.
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 Lg Life Sciences Ltd. filed Critical Lg Life Sciences Ltd.
Priority to AU2003245060A priority Critical patent/AU2003245060A1/en
Publication of WO2004002985A1 publication Critical patent/WO2004002985A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • thrombin inhibitor which can be orally administered as well as absorbed into blood in a high concentration when orally administered, has been published in WO 00/39124.
  • the present invention relates to a composition for the therapeutic and/or prophylactic treatment of thrombosis and hypercoagulabihty in blood and tissues of animals including humans.
  • Triethylamine(2.2 ⁇ n ⁇ , 15.86mmol) was slowly added dropwise thereto and the mixture was stirred for 3 hours at 0°C.
  • the reaction mixture was washed with water(20m- ⁇ ), IN-aqueous sodium hydroxide solution(20m£) and aqueous sodium chloride solution(20m ⁇ ), dried over anhydrous sodium sulfate, and. filtered to give the title compound(1.7g, 8.54mmol) in a yield of 55.6%.
  • step b) Preparation of EtO 2 CCH 2 -D-Dpa-Pro-NH-CH 2 -5-(2-amd)-thioph-C(O)/Pr
  • the compound prepared in step a)(760mg, 3.57mmol) was reacted according to the same procedure as step b) of Example 4 to give the title compound(1.12g, 1.77mmol) in a yield of 50%.
  • thrombin T 6769, Sigma, concentration: 1.4 NIH units/iiu?) in buffer solution (100 _-C, pH 7.4) was added inhibitor solution (lOO ⁇ Jl,), which was then incubated for 1 minute. Pooled normal citrated human plasma (100 £) was then added and the clotting time was measured in an automatic device (Diagnostica Stago. ST ART-4). The clotting time in seconds was plotted against the inhibitor concentration, and the IC 50 TT was determined by interpolation. IC5 0 TT means the concentration of inhibitor that doubles the thrombin clotting time for human plasma.
  • the dissociation constant Ki denotes the degree of dissociation of the enzyme-thrombin inhibitor complex. Accordingly, a low dissociation constant means a high binding property of thrombin inhibitor to enzyme, and therefore, is estimated that the thrombin inhibitor has high inhibitory activity for thrombin.
  • Such dissociation constant can be determined by reacting thrombin with a certain substrate which develops a color when it is hydrolyzed by the action of thrombin, and then measuring the degree of color development as a function of time by means of spectrophotometry.
  • Cmax means the maximum blood concentration
  • Tmax means the time to reach the maximum blood concentration
  • AUC means the integration value under the curve of time versus blood concentration.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé inhibiteur de la thrombine, qui présente un effet inhibiteur efficace contre la thrombose, et peut être administré par voie orale. Elle concerne également une méthode de préparation du composé, et une composition destinée au traitement thérapeutique et/ou prophylactique de diverses maladies associées au mécanisme d'inhibition de la thrombine, ladite composition comprenant le composé de l'invention en tant que principe actif.
PCT/KR2003/001166 2002-06-27 2003-06-13 Compose peptidique inhibiteur de la thrombine WO2004002985A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003245060A AU2003245060A1 (en) 2002-06-27 2003-06-13 Peptidic thrombin inhibitor compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2002-0036219 2002-06-27
KR20020036219 2002-06-27

Publications (1)

Publication Number Publication Date
WO2004002985A1 true WO2004002985A1 (fr) 2004-01-08

Family

ID=29997390

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2003/001166 WO2004002985A1 (fr) 2002-06-27 2003-06-13 Compose peptidique inhibiteur de la thrombine

Country Status (5)

Country Link
KR (1) KR20040002699A (fr)
AR (1) AR039757A1 (fr)
AU (1) AU2003245060A1 (fr)
TW (1) TW200400187A (fr)
WO (1) WO2004002985A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018081513A1 (fr) 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Promédicaments d'inhibiteurs de la kallicréine
US10294189B2 (en) * 2016-09-20 2019-05-21 Uchicago Argonne, Llc Process for producing fluorinated electrolyte solvent

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999037611A1 (fr) * 1998-01-26 1999-07-29 Basf Aktiengesellschaft Amidines heterocycliques utilisees comme inhibiteurs de la kallicreine
WO2000039124A1 (fr) * 1998-12-29 2000-07-06 Lg Ci Ltd. Inhibiteurs de thrombine
WO2000061609A2 (fr) * 1999-04-09 2000-10-19 Basf Aktiengesellschaft Promedicaments d'inhibiteurs de la thrombine
WO2002051445A2 (fr) * 2000-12-22 2002-07-04 Abbott Gmbh & Co. Kg Promédicament de faible poids moléculaire, inhibiteur de la thrombine, en formulation pharmaceutique orale et parentérale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999037611A1 (fr) * 1998-01-26 1999-07-29 Basf Aktiengesellschaft Amidines heterocycliques utilisees comme inhibiteurs de la kallicreine
WO2000039124A1 (fr) * 1998-12-29 2000-07-06 Lg Ci Ltd. Inhibiteurs de thrombine
WO2000061609A2 (fr) * 1999-04-09 2000-10-19 Basf Aktiengesellschaft Promedicaments d'inhibiteurs de la thrombine
WO2002051445A2 (fr) * 2000-12-22 2002-07-04 Abbott Gmbh & Co. Kg Promédicament de faible poids moléculaire, inhibiteur de la thrombine, en formulation pharmaceutique orale et parentérale

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10294189B2 (en) * 2016-09-20 2019-05-21 Uchicago Argonne, Llc Process for producing fluorinated electrolyte solvent
WO2018081513A1 (fr) 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Promédicaments d'inhibiteurs de la kallicréine

Also Published As

Publication number Publication date
AR039757A1 (es) 2005-03-09
AU2003245060A1 (en) 2004-01-19
KR20040002699A (ko) 2004-01-07
TW200400187A (en) 2004-01-01

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