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WO1997005161A1 - Derives d'acides bores - Google Patents

Derives d'acides bores Download PDF

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Publication number
WO1997005161A1
WO1997005161A1 PCT/EP1996/003314 EP9603314W WO9705161A1 WO 1997005161 A1 WO1997005161 A1 WO 1997005161A1 EP 9603314 W EP9603314 W EP 9603314W WO 9705161 A1 WO9705161 A1 WO 9705161A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
residue
pharmaceutically acceptable
compounds
Prior art date
Application number
PCT/EP1996/003314
Other languages
English (en)
Inventor
Anette Wienand
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
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 Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to AU67379/96A priority Critical patent/AU6737996A/en
Publication of WO1997005161A1 publication Critical patent/WO1997005161A1/fr

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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
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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 boronic acid derivatives, a process for their production, their use as a pharmaceutical, e.g. as thrombin inhibitors, and pharmaceutical preparations containing them.
  • Thrombin is a trypsin-like serine protease fulfilling a central role in both haemostasis and thrombosis.
  • thrombin is the final key enzyme, proteolytically cleaving fibrinogen to release fibrinopeptides A and B and generate fibrin, which can then polymerize to form a haemostatic plug leading to occlusion of the vessels.
  • the trimethylsilyl-Ala residue, the Pro residue and the N-substituted Lys residue may each have the L or D configuration.
  • the Pro residue and the N-substituted Lys residue each have the L-configuration and the trimethylsilyl Ala residue the D-configuration.
  • residue of formula (a) may exist in cis or trans configuration.
  • Preferred residue of formula (a) is
  • the present invention embraces all isomers and their mixtures.
  • the compounds of formula I wherein each of Q, and Q 2 is OH may exist e.g. in free or salt form.
  • Salts include acid addition salts with e.g. organic acids, polymeric acids or inorganic acids, for example hydrochloric acid.
  • the compounds of formula I are in free form.
  • the present invention also includes a process for the production of the compounds of formula I, which process comprises a) to produce a compound of formula I wherein Q, and Q 2 form together a residue of formula (a), formylating a compound of formula II
  • R is benzyloxycarbonyl or another amino protecting group and, where required, replacing the amino protecting group R by a benzyloxycarbonyl group, or b) to produce a compound of formula I wherein each of Q. and Q 2 is OH, cleaving a compound of formula I wherein Q, and Q 2 form together a residue of formula (a), and recovering the compounds of formula I thus obtained wherein each of Q, and Q 2 is OH in free form or in salt form.
  • the formylation step a) may conveniently be performed by using mixed anhydride of acetic acid and formic acid.
  • the reaction may advantageously be carried out in an organic solvent, e.g. tetrahydrofuran.
  • R in compound of formula II is preferably benzyloxycarbonyl.
  • R is an amino protecting group other than benzyloxycarbonyl, it may be e.g. tert.-butoxycarbonyl or an amino protecting group as disclosed in "Protective Groups in Organic Synthesis", T.W. Greene, J. Wiley & Sons NY (1981), 219-287.
  • R in the compounds of formula II is other than benzyloxycarbonyl, the formylation may conveniently be carried out before replacement of said protecting group R by benzyloxycarbonyl.
  • the replacement of R by a benzyloxycarbonyl group may be performed in accordance widi methods known and practiced in the art.
  • Process step b) may conveniently be performed by using e.g. NaIO 4 , advantageously in an organic solvent, e.g. acetone.
  • Boc tert.-butoxycarbonyl
  • Boc-D-TMSal-Pro-BoroLys-OPin used as starting material may be prepared as disclosed in WO 94/20526.
  • the compounds of formula I or a pharmaceutically salt thereof when each of Q, and Q 2 is OH exhibit pharmacological activity and are useful as pharmaceuticals.
  • the compounds of formula I show trypsin-like serine protease inhibiting properties, as indicated in the following test methods:
  • Test substance is dissolved in cremophor/ethanol (1:1) or DMSO and diluted with distilled water to yield a 1 mM stock solution. Further dilutions are made into the assay buffer (100 mM sodium phosphate buffer, pH 7.4, containing 100 mM NaCI and 0.1 % bovine serum albumin). Kinetic assays are performed using a
  • each well contains 50 ⁇ l substrate, 100 ⁇ l test compound and 100 ⁇ l enzyme in buffer.
  • Assays are initiated by adding enzyme to solutions containing the substance to be tested and substrate.
  • E, S, P, and I are the enzyme, substrate, product (p-nitroaniline) and inhibiting substance to be tested, respectively, and k on and l ⁇ are the association and dissociaton rate constants for the inhibition (Tapparelli et al.. J. Biol. Chem.,
  • In vitro coagulation assays are performed with pooled citrated human plasma. Substance to be tested or solvent are incubated with plasma for 10 min at 37°C prior to assay. Thrombin time(TT) determinations are performed at a final thrombin concentration of 5 U/ml. Activated partial thromboplastin time (APTT) is determined by incubating 0.1 ml plasma ⁇ substance to be tested with 0.1 ml purified soya bean phospholipid in ellagic acid (Actin-FS) for 4 min at 37°C and followed by the addition of 0.1 ml CaCl 2 (50mM).
  • Actin-FS soya bean phospholipid in ellagic acid
  • compounds of formula I significantly increase TT and APTT at a concentration of from 0.1 ⁇ M to 0.5 ⁇ M.
  • prolongation of TT above 300 sec is achieved at 1.0 ⁇ M
  • elevation of APTT to 2x is achieved at 1.8 ⁇ M.
  • the compounds of formula I prevent thrombus formation in a dose dependent manner.
  • thrombus formation is inhibited by 50 % at a dose ( ED JO ) of 0.96 mg/kg i.v. and at a dose of 15.9 mg/kg p.o.
  • the compound of Example 2 has an ED 50 of 0.43 mg/kg i.v.
  • the compounds of Examples 1 and 2 showed an oral effect bioavailability of 35% and 11%, respectively, in conscious aortic catheter rats.
  • the compounds of Ex. 1 and 2 are also administered i.v. and p.o. to the same animals, the oral effect bioavailability is > 15% for both compounds.
  • the method is a modification of that disclosed by Clozel et al. in J. Cardiovasc. Pharmacol., 12, 520-525, 1988.
  • Male wistar rats are anaesthetized and the right jugular vein and the left carotid artery are exposed and cannulated .
  • the cotton thread containing silicone tubing is inserted between ti e vein and the artery. Animals are pretreated with the compound to be tested via the jugular vein 20 min prior to
  • Clot lysis is induced via the carotid artery by a bolus injection of t-PA followed by a 30 min infusion. Clot dissolution is monitored by placing a Nal crystal scintillation detector over the clot containing chamber. In this assay, the compound of Ex. 1 does not affect t-PA induced clot lysis and the compound of Ex. 2 even enhances clot lysis at a dose of 60 ⁇ g/kg/min.
  • the compounds of formula I are therefore useful for preventing or treating thrombosis, for example deep vein thrombosis, pulmonary embolism, in peri-operative antithrombotic cover, arterial thrombosis, unstable angina, disseminated intravascular coagulation (DIC), e.g. induced by sepsis trauma or certain cancers, coronary artery bypass surgery, for the control of coagulation and fibrinolysis, for inhibiting vascular remodelling (proliferation, migration of smooth muscle cells) following venous or arterial surgery or other forms of vascular injuries, e.g. percutaneous transluminal coronary angioplasty, allo- or xenotransplantation surgery, transplant vasculopathies, graft vessel diseases, acute or chronic restenosis and obstructive vascular atherosclerosis, .
  • thrombosis for example deep vein thrombosis, pulmonary embolism, in peri-operative antithrombotic cover, arterial thrombosis, unstable angina, dissemin
  • the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of from about 0.01 to 15 mg/kg animal body weight. Suitable daily dosage rates for larger mammals, for example humans, are of the order of from about 1 to 750 mg/day, conveniently administered once, in divided dosages 2 to 4 x / day, or in sustained release form.
  • Suitable daily dosage rates for larger mammals, for example humans are of the order of from about 1 to 750 mg/day, conveniently administered once, in divided dosages 2 to 4 x / day, or in sustained release form.
  • Compounds of formula I wherein each of Q, and Q 2 is OH may be administered in free form or in pharmaceutically acceptable salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable salt form when each of Q, and Q 2 is OH, in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner.
  • Compounds of formula I may be administered by any conventional route, for example in particular enterally, preferably orally, e.g. in the form of tablets, capsules or drink solutions, or parenterally e.g. in form of injectable solutions or suspensions.
  • the present invention further provides: a) a compound of formula I or a pharmaceutically acceptable salt thereof when each of Q, and Q 2 is OH, for use as a pharmaceutical;
  • the compounds of the invention may be employed as adjunct or adjuvant to other therapy, e.g. a therapy employing an anti-thrombotic agent, a fibrinolytic agent or an immunomodulatory agent, e.g. aspirin, heparin, t-PA, streptokinase, cyclosporins, ascomycins, brequinar, leflunomide or rapamycin or an analog thereof, azathioprine, methotrexate, mizoribine, mycophenolic acid or mycophenolate mofetil.
  • a therapy employing an anti-thrombotic agent, a fibrinolytic agent or an immunomodulatory agent, e.g. aspirin, heparin, t-PA, streptokinase, cyclosporins, ascomycins, brequinar, leflunomide or rapamycin or an analog thereof, azathioprine, methotrexate, mizoribine, mycophenolic acid or my
  • a method for preventing or treating disorders as indicated above in a subject in need of such a treatment comprises administering to said subject an effec ⁇ tive amount of i) a compound of the invention and ii) a second drug substance, said second drug substance being a therapeutic agent as indicated above; and
  • the compounds of formula I particularly the compound of Example 2, have an interesting pharmacological profile, e.g. as disclosed above, as they exhibit an improved selectivity for thrombin and trypsin and a good oral bioavailability.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule (I) dans laquelle Q1 et Q2 sont chacun OH, ou bien Q1 et Q2 forment ensemble un reste représenté par la formule (a), ledit composé possédant d'intéressantes propriétés pharmacologiques.
PCT/EP1996/003314 1995-07-28 1996-07-26 Derives d'acides bores WO1997005161A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67379/96A AU6737996A (en) 1995-07-28 1996-07-26 Boronic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9515489.4A GB9515489D0 (en) 1995-07-28 1995-07-28 Organic compounds
GB9515489.4 1995-07-28

Publications (1)

Publication Number Publication Date
WO1997005161A1 true WO1997005161A1 (fr) 1997-02-13

Family

ID=10778404

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/003314 WO1997005161A1 (fr) 1995-07-28 1996-07-26 Derives d'acides bores

Country Status (5)

Country Link
AU (1) AU6737996A (fr)
CO (1) CO4750837A1 (fr)
GB (1) GB9515489D0 (fr)
WO (1) WO1997005161A1 (fr)
ZA (1) ZA966396B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045912A1 (fr) * 2001-11-29 2003-06-05 Warner-Lambert Company Llc Inhibiteurs du facteur xa et autres serine proteases intervenant dans la cascade de la coagulation
KR20030080810A (ko) * 2002-04-11 2003-10-17 주식회사 엘지생명과학 아미노피리도아릴 그룹을 가진 선택적 트롬빈 억제제
EP1396269A1 (fr) 2002-09-09 2004-03-10 Trigen Limited Sels d'acide boronique des metaux multivalents et leur utilisation dans la préparation de médicaments pour le traitement de la thrombose
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471651A2 (fr) * 1990-08-13 1992-02-19 Sandoz Ltd. Dérivés de l'acide boronique peptidique ayant une activité inhibante de protéase
WO1994020526A1 (fr) * 1993-03-03 1994-09-15 Sandoz Ltd. Derives d'acide bore peptidique a activite d'inhibition des proteases
WO1995020603A1 (fr) * 1994-01-26 1995-08-03 Sandoz Ltd. Inhibiteurs de serine proteases portant un groupe chelateur

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471651A2 (fr) * 1990-08-13 1992-02-19 Sandoz Ltd. Dérivés de l'acide boronique peptidique ayant une activité inhibante de protéase
WO1994020526A1 (fr) * 1993-03-03 1994-09-15 Sandoz Ltd. Derives d'acide bore peptidique a activite d'inhibition des proteases
WO1995020603A1 (fr) * 1994-01-26 1995-08-03 Sandoz Ltd. Inhibiteurs de serine proteases portant un groupe chelateur

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP1744A (en) * 2001-11-29 2007-05-29 Warner Lambert Co Inhibitors of factor XA and other serine proteases involved in the coagulation cascade
KR100688814B1 (ko) * 2001-11-29 2007-03-02 워너-램버트 캄파니 엘엘씨 응고 캐스케이드에 관여되는 인자 Ｘａ 및 기타 세린프로테아제의 억제제
CN1582274B (zh) * 2001-11-29 2011-03-09 沃纳-兰伯特公司 Xa因子以及凝结级联系统中涉及的其他丝氨酸蛋白酶的抑制剂
US7407972B2 (en) 2001-11-29 2008-08-05 Pfizer Inc. Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
US7030141B2 (en) 2001-11-29 2006-04-18 Christopher Franklin Bigge Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
US7407974B2 (en) 2001-11-29 2008-08-05 Pfizer Inc. Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
KR100712782B1 (ko) * 2001-11-29 2007-05-02 워너-램버트 캄파니 엘엘씨 응고 캐스케이드에 관여되는 인자 Ｘａ 및 기타 세린프로테아제의 억제제
WO2003045912A1 (fr) * 2001-11-29 2003-06-05 Warner-Lambert Company Llc Inhibiteurs du facteur xa et autres serine proteases intervenant dans la cascade de la coagulation
EA007579B1 (ru) * 2001-11-29 2006-12-29 Уорнер-Ламберт Компани Ллс ИНГИБИТОРЫ ФАКТОРА Ха И ДРУГИХ СЕРИНОВЫХ ПРОТЕАЗ, ВОВЛЕЧЁННЫХ В КОАГУЛЯЦИОННЫЙ КАСКАД
KR20030080810A (ko) * 2002-04-11 2003-10-17 주식회사 엘지생명과학 아미노피리도아릴 그룹을 가진 선택적 트롬빈 억제제
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
EP1466917A1 (fr) 2002-09-09 2004-10-13 Trigen Limited Procédé der préparation des acides boroniques peptidiques et acides obtenus
EP1396269A1 (fr) 2002-09-09 2004-03-10 Trigen Limited Sels d'acide boronique des metaux multivalents et leur utilisation dans la préparation de médicaments pour le traitement de la thrombose
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

Also Published As

Publication number Publication date
CO4750837A1 (es) 1999-03-31
GB9515489D0 (en) 1995-09-27
AU6737996A (en) 1997-02-26
ZA966396B (en) 1998-01-26

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