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WO2000078749A1 - Derives de sulfonamide comme inhibiteur du facteur xa - Google Patents

Derives de sulfonamide comme inhibiteur du facteur xa Download PDF

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Publication number
WO2000078749A1
WO2000078749A1 PCT/GB2000/002319 GB0002319W WO0078749A1 WO 2000078749 A1 WO2000078749 A1 WO 2000078749A1 GB 0002319 W GB0002319 W GB 0002319W WO 0078749 A1 WO0078749 A1 WO 0078749A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically
factor
acceptable salt
solvate
Prior art date
Application number
PCT/GB2000/002319
Other languages
English (en)
Inventor
Roger James
Original Assignee
Astrazeneca Uk Limited
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 Astrazeneca Uk Limited filed Critical Astrazeneca Uk Limited
Priority to AU55466/00A priority Critical patent/AU5546600A/en
Publication of WO2000078749A1 publication Critical patent/WO2000078749A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the invention relates to 4- ⁇ 4-[4-(5-chloroindol-2-ylsulfonyl) piperazine-1- carbonyl]phenyl ⁇ pyridine-l -oxide, or pharmaceutically-acceptable salts thereof or a solvate of either thereof, which possesses antithrombotic and anticoagulant properties and is accordingly useful in methods of treatment of humans or animals.
  • the invention also relates to pharmaceutical compositions containing the above compound or a pharmaceutically- acceptable salt thereof.
  • Factor Xa is one of a cascade of proteases involved in the complex process of blood coagulation.
  • the protease known as thrombin is the final protease in the cascade and Factor Xa is the preceding protease which cleaves prothrombin to generate thrombin.
  • Certain compounds are known to possess Factor Xa inhibitory properties and the field has been reviewed by R.B. Wallis, Current Opinion in Therapeutic Patents, 1993, 1173-1179.
  • TRIP tick anticoagulant protein
  • the compound of the present invention possesses activity in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery and cerebro- vascular disease.
  • cardiovascular and cerebrovascular conditions such as myocardial infarction, the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery, thrombus formation after the application of blood vessel operative techniques or after general surgery such as hip replacement surgery, the introduction of artificial heart valves or on the recirculation of blood, cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischaemia and angina (including unstable angina).
  • myocardial infarction the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes
  • vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery
  • thrombus formation after the application of blood vessel operative techniques or after general surgery such as hip replacement surgery
  • the compound of the invention is also useful as an inhibitor of blood coagulation in an ex-vivo situation such as, for example, the storage of whole blood or other biological samples suspected to contain Factor Xa and in which coagulation is detrimental.
  • the compound of the invention 4- ⁇ 4- [4- (5-chloroindol-2-ylsulfonyl) piperazine-1-carbonyl] phenyl ⁇ pyridine 1 -oxide (hereinafter called the compound of formula I), or a pharmaceutically-acceptable salt thereof or solvate of either thereof.
  • the compound of formula I or a pharmaceutically- acceptable salt thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess Factor Xa inhibitory activity.
  • a pharmaceutically-acceptable salt of the compound of formula I it may be obtained, for example, by reaction of the compound of formula I with a suitable acid or base using a conventional procedure.
  • the compound of formula I is an inhibitor of the enzyme Factor Xa.
  • the effects of this inhibition may be demonstrated using one or more of the standard procedures set out hereinafter:-
  • test compound is administered intravenously or orally to a group of Alderley Park Wistar rats. At various times thereafter animals are anaesthetised, blood is collected and PT coagulation assays analogous to those described hereinbefore are conducted.
  • e) An in vivo Measurement of Antithrombotic Activity Thrombus formation is induced using an analogous method to that described by Vogel et al., Thromb. Research, 1989, 54, 399-410.
  • a group of Alderley Park Wistar rats is anaesthetised and surgery is performed to expose the vena cava. Collateral veins are ligated and two loose sutures are located, 0.7 cm apart, round the inferior vena cava. Test compound is administered intravenously or orally.
  • tissue thromboplastin (30 ⁇ l/kg) is administered via the jugular vein and, after 10 seconds, the two sutures are tightened to induce stasis within the ligated portion of vena cava. After 10 minutes the ligated tissue is excised and the thrombus therein is isolated, blotted and weighed.
  • Fasted male Alderley Park rats 300-450 g are pre-dosed by oral gavage (5 mls/kg) with compound or vehicle (5% DMSO/PEG200) at various times before being anaesthetised with Intraval® (120 mg/kg i.p.).
  • Intraval® 120 mg/kg i.p.
  • the left jugular vein and the right carotid artery are exposed and cannulated.
  • a 1 mL blood sample is taken from the carotid canular into 3.2% trisodium citrate.
  • 0.5 mL of the whole blood is then treated with EDTA and used for platelet count determination whilst the remainder is centrifuged (5 mins, 20000g) and the resultant plasma frozen for subsequent drug level, fibrinogen or thrombin antithrombin (TAT) complex determinations.
  • Recombinant human tissue factor (Dade Innovin Cat.B4212-50), reconstituted to the manufacturers specification, is infused (2 mL/kg/hr) into the venous canular for 60 minutes.
  • a 2 mL blood sample is taken and platelet count, drug level, plasma fibrinogen concentration and TAT complex are determined as before. Platelet counting is performed using at Coulter T540 blood analyser.
  • Plasma fibrinogen and TAT levels are determining using a clotting assay (Sigma Cat.880-B) and TAT ELISA (Behring) respectively.
  • the plasma concentration of the compound is bioassayed using human Factor Xa and a chromogenic substrate S2765 (Kabi), extrapolated from a standard curve (Fragmin) and expressed in Anti-Factor Xa units.
  • the data is analysed as follows; tissue factor-induced reductions in platelet count are normalised with respect to pre-dose platelet count and drug activity expressed as a percent inhibition of tissue factor- induced thrombocytopenia when compared to vehicle treated animals.
  • Compounds are active if there is statistically significant (p ⁇ 0.05) inhibition of TF-induced thrombocytopenia.
  • the compound of formula I has an IC50 (Factor Xa) of 0.008 ⁇ M as measured in test a).
  • a pharmaceutical composition which comprises the compound of formula I, or a pharmaceutically-acceptable salt thereof or a solvate of either thereof, in association with a pharmaceutically-acceptable diluent or carrier.
  • the composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or
  • the amount of active ingredient (that is the compound of formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the compound of formula I or a pharmaceutically-acceptable salt thereof or a solvate of either thereof, for use in medical therapy.
  • the invention also includes the use of the compound of formula I, or a pharmaceutically-acceptable salt thereof or a solvate of either thereof, in the production of a medicament for use in:-
  • the invention also includes a method of producing an effect as defined hereinbefore or treating a disease or disorder as defined hereinbefore which comprises administering to a warm-blooded animal requiring such treatment an effective amount of the compound of formula I, or a pharmaceutically-acceptable salt thereof or a solvate of either thereof.
  • the size of the dose for therapeutic or prophylactic treatment with the compound of formula I, or a pharmaceutically-acceptable salt thereof will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to well known principles of medicine.
  • the compound of the invention, or a pharmaceutically-acceptable salt thereof is useful in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated.
  • it will generally be administered so that a daily dose in the range, for example, 0.5 to 500 mg/kg body weight is received, given if required in divided doses.
  • lower doses will be administered when a parenteral route is employed, for example a dose for intravenous administration in the range, for example, 0.5 to 50 mg/kg body weight will generally be used.
  • lower doses will be employed, for example a daily dose in the range, for example, 0.5 to 10 mg/kg body weight.
  • the compound of formula I, or a pharmaceutically-acceptable salt thereof or a solvate of either thereof is primarily of value as therapeutic or prophylactic agents for use in warm-blooded animals including man, they are also useful whenever it is required to produce an anticoagulant effect, for example during the ex-vivo storage of whole blood or in the development of biological tests for compounds having anticoagulant properties.
  • the compound of formula I may be administered as a sole therapy or they may be administered in conjunction with other pharmacologically active agents such as a thrombolytic agent, for example tissue plasminogen activator or derivatives thereof or strep tokinase.
  • a thrombolytic agent for example tissue plasminogen activator or derivatives thereof or strep tokinase.
  • the compound of formula I may also be administered with, for example, a known platelet aggregation inhibitor (for example aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a known hypolipidaemic agent or a known anti-hypertensive agent.
  • Illustrative pharmaceutical dosage forms suitable for presenting a compound of formula I, or a pharmaceutically-acceptable salt thereof, for therapeutic or prophylactic use include the following tablet and capsule formulations, which may be obtained by conventional procedures well known in the art of pharmacy and are suitable for therapeutic use in humans:
  • the active ingredient Compound Z is a compound of formula I, as described above.
  • the tablet compositions (a)-(c) may be enteric coated by conventional means, for example, with cellulose acetate phthalate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne 4-{4-[4-(5-chloroindol-2-ylsulfonyl)pipérazine-1-carbonyl]phényl}pyridine-1-oxyde, ou leurs sels acceptables sur le plan pharmaceutique ou un de leurs solvants, possédant des propriétés antithrombotique et anticoagulante et qui, par conséquent, sont utiles dans des procédés de traitement destinés à l'homme ou aux animaux. Cette invention concerne également des compositions pharmaceutiques contenant les composés susmentionnés ou un de leurs sels acceptables sur le plan pharmaceutique.
PCT/GB2000/002319 1999-06-19 2000-06-14 Derives de sulfonamide comme inhibiteur du facteur xa WO2000078749A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55466/00A AU5546600A (en) 1999-06-19 2000-06-14 Sulfonamide derivative as factor xa inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9914342.2 1999-06-19
GBGB9914342.2A GB9914342D0 (en) 1999-06-19 1999-06-19 Compound

Publications (1)

Publication Number Publication Date
WO2000078749A1 true WO2000078749A1 (fr) 2000-12-28

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/002319 WO2000078749A1 (fr) 1999-06-19 2000-06-14 Derives de sulfonamide comme inhibiteur du facteur xa

Country Status (3)

Country Link
AU (1) AU5546600A (fr)
GB (1) GB9914342D0 (fr)
WO (1) WO2000078749A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007008145A1 (fr) * 2005-07-08 2007-01-18 Astrazeneca Ab Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa
US7192968B2 (en) 2000-04-05 2007-03-20 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
US7342014B2 (en) 2001-06-20 2008-03-11 Daiichi Pharmaceutical Co., Ltd. Diamine derivatives
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021188A1 (fr) * 1996-11-08 1998-05-22 Zeneca Limited DERIVES HETEROCYCLIQUES INHIBANT LE FACTEUR Xa
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
WO2000009480A1 (fr) * 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021188A1 (fr) * 1996-11-08 1998-05-22 Zeneca Limited DERIVES HETEROCYCLIQUES INHIBANT LE FACTEUR Xa
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
WO2000009480A1 (fr) * 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200020, Derwent World Patents Index; AN 2000-237442, XP002146911 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7192968B2 (en) 2000-04-05 2007-03-20 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
US7935824B2 (en) 2000-04-05 2011-05-03 Daiichi Pharmaceutical Co., Ltd. Ethylenediamine derivatives
US7342014B2 (en) 2001-06-20 2008-03-11 Daiichi Pharmaceutical Co., Ltd. Diamine derivatives
US7365205B2 (en) 2001-06-20 2008-04-29 Daiichi Sankyo Company, Limited Diamine derivatives
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques
WO2007008145A1 (fr) * 2005-07-08 2007-01-18 Astrazeneca Ab Dérivés de sulfonamides hétérocycliques en tant qu'inhibiteurs du facteur xa

Also Published As

Publication number Publication date
AU5546600A (en) 2001-01-09
GB9914342D0 (en) 1999-08-18

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