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WO2003007984A1 - Utilisation d'inhibiteurs de la thrombine pour traiter l'arthrite - Google Patents

Utilisation d'inhibiteurs de la thrombine pour traiter l'arthrite Download PDF

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Publication number
WO2003007984A1
WO2003007984A1 PCT/EP2002/007679 EP0207679W WO03007984A1 WO 2003007984 A1 WO2003007984 A1 WO 2003007984A1 EP 0207679 W EP0207679 W EP 0207679W WO 03007984 A1 WO03007984 A1 WO 03007984A1
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WO
WIPO (PCT)
Prior art keywords
thrombin
rheumatic
thrombin inhibitor
bibr
protease
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.)
Ceased
Application number
PCT/EP2002/007679
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German (de)
English (en)
Inventor
Norbert Hauel
Wolfgang Wienen
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of WO2003007984A1 publication Critical patent/WO2003007984A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • thrombin inhibitors which inhibit the catalytic domain of thrombin but do not block the exosite domain of thrombin show favorable effects in a pharmacological arthritis model.
  • throombin inhibitors which additionally inhibit the enzyme trypsin have particularly favorable effects.
  • the present invention thus relates to a method for the prevention and / or treatment of diseases of the rheumatic / arthritic type in humans or in mammals, comprising the administration of an effective amount of a thrombin inhibitor which, although inhibiting the catalytic domain of the protease thrombin, does not blocked the thrombin exosite domain to a patient in need of such treatment.
  • Rheumatic / arthritic diseases include: acute and chronic arthritis, activated arthrosis, rheumatoid arthritis (chronic polyarthritis), osteoarthritis and ankylosing spondylitis (Bmürew-Strümpell-Marie disease).
  • a preferred object of the method according to the invention comprises the administration of an effective amount of a thrombin inhibitor, which additionally inhibits the protease trypsin, to a patient in need of such treatment.
  • thrombin inhibitors which thrombin according to the "Handbook of Proteolytic Enzymes", Eds .: A.J. Barrett, N.D. Rawlings and J.F. Woessner, Academic Press, London 1998, described an enzyme inhibition method with a Ki of less than 200 nM, preferably less than 20 nM, and at the same time trypsin according to the test described in the same publication with a Ki of less than 500 nM, preferably of less than 150 nM, inhibit, for example
  • BIBR 953 prodrug forms likewise described in WO 98/37075, in particular from BIBR 1048 (1-methyl-2- [N- [4- (Nn-hexyloxycarbonylamidino) phenyl] aminomethyl] benzimidazole-5 -yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide)
  • melagatran prodrug form or from a melagatran prodrug form, in particular the orally active prodrug form ximelagatran (H-376/95; JI Weitz, J. Hirsch; New Anticoagulant Drugs, Chest, 2001, Vol. 119, No.1 Suppl., 95S -107S)
  • prodrug forms of BIBR 953 and of melagatran are to be understood as meaning those derivatives of these compounds which contain one or more residues which can be split off in vivo, in particular a group which can be converted into a carboxy group in vivo or / and a residue which can be split off from an imino or amino group in vivo.
  • Prodrug forms which contain two such residues represent so-called double prodrugs.
  • a convertible in vivo into a carboxy group is, for example Hydroxmethyloeuvre, an esterified carboxy group with an alcohol in which the alcoholic moiety is preferably a C 1 6 alkanol, a phenyl-C., 3 -alkanol, a
  • C 1 3 -alkyl groups can be substituted, a C 5 8 -cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by an optionally by a C 1 3 -alkyl, phenyl-C, 3 -alkyl -, Phenyl-C, 3 -alkoxycarbonyl- or C 2 6 -alkanoyl group substituted imino group is replaced and the
  • Cycloalkanol part can additionally be substituted by one or two C, 3 -alkyl groups, a C 4 7 -cycloalkenol, a C 3 5 -alkenol, a phenyl-C 3 5 -alkenol, a C 3 5 -alkinol or phenyl-C 3 5 alkynol with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C 3 -C 8 -cycloalkyl-C, 3- alkanol, a bicycloalkanol with a total of 8 to 10
  • Carbon atoms, which in the bicycloalkyl part can additionally be substituted by one or two C 3 alkyl groups, a 1, 3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula
  • R 1 is a C 8 -alkyl, C 5 7 -cycloalkyl, phenyl or phenyl-C, 3- alkyl group,
  • R 2 is a hydrogen atom, a C 1 3 alkyl, C 5 7 cycloalkyl or phenyl group and
  • R represents a hydrogen atom or a Cj _3-alkyl group, or under a residue which can be split off from an imino or amino group in vivo, for example a hydroxyl group, an acyl group such as a benzoyl or pyridinoyl group optionally substituted by a C 3 alkyl group, for example the benzoyl, p-ethylbenzoyl, p- Isopropyl-benzoyl or nicotinoyl group, or a C, 16 -alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or
  • Hexanoyl group an allyloxycarbonyl group, a C 1 16 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.
  • Phenylpropoxycarbonyl group a C, 3- alkylsulfonyl-C 2 ⁇ -alkoxycarbonyl
  • Preferred prodrug residues for a carboxy group are, for example, a C 6 -alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group or a phenyl -C., 3 -alkoxycarbonyl group such as the benzyloxycarbonyl group.
  • a C 6 -alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group or
  • Preferred radicals which can be split off from an imino or amino group are, for example, the hydroxyl group, a C, g -alkoxycarbonyl group such as that
  • Phenylcarbonyl group such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group such as the nicotinoyl group, a C, 3- alkylsulfonyl-nC 2 3 -alkoxycarbonyl or C 1 3 -alkoxy-C 2 3 -alkoxy-C 2 ⁇ -alkoxycarbonyl group such as the 2-methylsulfonylethoxycarbonyl or 2- (2-ethoxy) ethoxycarbonyl group.
  • the active substance BIBR 953 inhibits thrombin with a Ki value of 4.5 +0.2 nM and trypsin with a Ki value of 50.3 ⁇ 0.3 nM (J.-M. Stassen et al., Identification and in vitro characterization of BIBR 953 ZW, a novel synthetic low molecular weight direct thrombin inhibitor, XVIII congress of The International Society on Thrombosis and Haemostasis, Paris, July 6-12, 2001).
  • the prodrug BIBR 1048 is preferably administered per os, which is cleaved after absorption in the organism and releases the active substance BIBR 953 as the main cleavage product.
  • Another object of the present invention is the use of thrombin inhibitors which, although inhibit the catalytic domain of the protease thrombin, but do not block the composite domain of thrombin, for the production of a medicament for the prevention and / or treatment of diseases of the rheumatic / arthritic type in humans and mammals,
  • thrombin inhibitors which additionally inhibit the protease trypsin
  • thrombin inhibitors the thrombin according to the method described in "Handbook of Proteolytic Enzymes", Eds .: AJ Barrett, ND Rawlings and JF Woessner, Academic Press, London 1998, with a Ki value of less than 200 nM, preferably less than 20 nM, and at the same time inhibit trypsin according to the test described in the same publication with a Ki value of less than 500 nM, preferably less than 150 nM, for example of BIBR 953 or a BIBR 953 prodrug form, in particular the orally active prodrug form BIBR 1048,
  • melagatran or a melagatran prodrug form in particular the orally active prodrug form ximelagatran (H 376/95),
  • the active compounds can be administered orally, buccally, parenterally, by inhalation-atomization, rectally or topically, with oral administration being preferred for the prodrug forms.
  • Parenteral administration can include subcutaneous, intravenous, and intramuscular injections and infusion techniques.
  • the active compounds can also be used in monotherapy or in combination with conventional analgesics / anti-rheumatic drugs known in the art, for example in combination with aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, celecoxib, diciofenac, diflunisal, fenbufen, fenoprofen, ibuprofrofen, flurbrofen, and Indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, meloxicam, naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac or their pharmaceutically acceptable salts.
  • the invention therefore furthermore relates to a product comprising an effective amount of a thrombin inhibitor which, although inhibiting the catalytic domain of the protease thrombin, but not blocking the exosite domain of thrombin, and an effective amount of an analgesic or anti-rheumatic as a combination preparation for simultaneous use , separate or time-graded application in the prevention and / or treatment of diseases of the rheumatic / arthritic type, as well the use of a thrombin inhibitor which, although inhibiting the catalytic domain of the protease thrombin, but not blocking the exosite domain of thrombin, in combination with an effective amount of an analgesic or anti-rheumatic, for the preparation of the combination preparation mentioned above.
  • a thrombin inhibitor which, although inhibiting the catalytic domain of the protease thrombin, but not blocking the exosite domain of thrombin, in combination with an effective amount of an analgesic or anti-
  • thrombin inhibitors or their prodrugs already mentioned above are preferably used in the product according to the invention.
  • Analgesics / anti-rheumatic drugs are given, for example, in Physician's Desk Reference, 35th Edition, 1981; The Merck Index on CD-ROM, version 12: 3, Merck & Co. Inc., Whitehouse Station, NJ, USA, published on CD-ROM by Chapman & Hall / CRC, 1999; Cutting's Handbook of Pharmacology, 6th Edition, Ed. TZ Csacky, MD, Appleton-Century-Crofts, New York, 1979, Chapter 49: 538-550; and Rote Liste ® 1999, Editio Cantor Verlag Aulendorf.
  • the dosage of the above-mentioned thrombin inhibitors required to achieve a corresponding effect in monotherapy is expediently 0.01 to 3.0 mg / kg, preferably 0.03 to 1.0 mg / kg in the case of intravenous administration, and 0.03 to 30 mg / kg in the case of oral administration of the aforementioned prodrugs, preferably 0.1 to 10 mg / kg, each 1 to 4 times a day.
  • a dosage unit can be, for example, for the following analgesics / anti-rheumatics in combination with thrombin inhibitors: 100 - 500 mg diflunisal, 100 - 400 mg fenbufen, 50 - 100 mg fenoprofen, 25 - 100 mg flurbiprofen, 50 - 400 mg ibuprofen, 125 - 500 mg naproxen, 10 - 20 mg piroxicam, 5 - 20 mg meloxicam, 125 - 250 mg mefenamic acid, 25 - 50 mg ketoprofen, 25 - 100 mg zomepirac sodium.
  • thrombin inhibitors can optionally be used in combination with other active substances, together with one or more inert customary carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or suitable substances containing fat such as hard fat , work into common galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.
  • inert customary carriers and / or diluents e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water
  • the active ingredients can be administered orally in a wide variety of different dosage forms, for example together with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, cookies, hard candies, powders, atomizers, aqueous suspensions, elixirs, syrups and the like be formulated.
  • Such carriers include, for example, solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • such oral formulations can be sweetened and / or flavored in a suitable manner with the aid of various agents usually used for this purpose.
  • the active ingredients are present in such oral dosage forms with concentration levels whose range, based on the total composition, ranges from about 0.5% by weight to about 90% by weight in amounts sufficient to give the desired dosage units.
  • Other suitable dosage forms for the active ingredients include controlled release formulations and devices that are well known to those skilled in the art.
  • solutions of the active ingredients in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts can be used.
  • Such aqueous solutions should, if necessary, be suitably buffered and the liquid diluent made isotonic with sufficient salt or glucose.
  • aqueous solutions are particularly suitable for the purpose of intravenous, intramuscular and subcutaneous injections.
  • the sterile aqueous media used are easy to obtain using common techniques well known to those skilled in the art.
  • distilled water is commonly used as the liquid thinner, and the final preparation is passed through a suitable bacterial filter, such as a sintered glass or diatomaceous earth or unglazed porcelain filter.
  • Preferred filters of this type include the Berkefeld, Chamberland and asbestos disk metal Seitz filters, in which the fluid is sucked into a sterile container with the aid of a suction pump.
  • the necessary procedural steps should be taken to ensure that the end products are preserved in a sterile condition.
  • the dosage form of the particular compound or compounds may include, for example, solutions, lotions, ointments, creams, gels, suppositories, sustained rate release formulations and devices therefor.
  • Such dosage forms include the particular compound or compounds and may include ethanol, water, penetrants and inert carriers such as gel generators, mineral oil, emulsifiers, benzyl alcohol and the like.
  • Test animals Female mice (170 B10.RIII; Jackson Laboratory) were used as test animals. The animals were 10 to 12 weeks old at the start of the experiment.
  • Lyophilized native collagen type II (Cll) from pigs was dissolved overnight at 4 ° C in 0.01 N acetic acid to a concentration of 2 mg / ml. This collagen solution was then emulsified in a 1: 1 ratio with Freund 's adjuvant containing 2 mg / ml Mycobacterium tuberculosis (strain H37Ra). On day 0, all test animals received an intradermal injection of 100 ⁇ l of this emulsion in the tail. Beginning on day 12 after immunization, all animals showed clinical signs of arthritis (limb erythema and edema). The test substance was then administered to the animals in various doses per os for a period of several weeks.

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Abstract

La présente invention concerne un procédé pour prévenir et/ou traiter des maladies rhumatismales/arthritiques chez l'homme ou les mammifères. Ce procédé consiste à administrer un inhibiteur de la thrombine inhibant le domaine catalytique de la protéase thrombine, sans bloquer le domaine exosite de la thrombine, et inhibant de préférence également la protéase trypsine. L'invention concerne en outre l'utilisation d'inhibiteurs de la thrombine de ce type pour produire des médicaments correspondants, des produits comprenant ces inhibiteurs en combinaison avec un analgésique ou un antirhumatismal, ainsi que leur production.
PCT/EP2002/007679 2001-07-16 2002-07-10 Utilisation d'inhibiteurs de la thrombine pour traiter l'arthrite Ceased WO2003007984A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10133786A DE10133786A1 (de) 2001-07-16 2001-07-16 Verwendung von Thrombin-Inhibitoren zur Behandlung von Arthritis
DE10133786.8 2001-07-16

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WO2003007984A1 true WO2003007984A1 (fr) 2003-01-30

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074056A1 (fr) * 2002-03-07 2003-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Forme de presentation a administrer par voie orale pour l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique et ses sels
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
WO2005023249A1 (fr) * 2003-09-03 2005-03-17 Boehringer Ingelheim International Gmbh Nouvelle forme galenique orale pour ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyle)-phenylamino]-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino]propionique et ses sels
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7932273B2 (en) 2003-08-29 2011-04-26 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
CN102875529A (zh) * 2011-07-15 2013-01-16 天津药物研究院 达比加群的酯衍生物及其制备方法
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10337697A1 (de) * 2003-08-16 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tablette enthaltend 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenyl-amino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester oder dessen Salze

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074056A1 (fr) * 2002-03-07 2003-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Forme de presentation a administrer par voie orale pour l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique et ses sels
EA009664B1 (ru) * 2002-03-07 2008-02-28 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Предназначенная для перорального применения лекарственная форма для этилового эфира 3-[(2-{[4-(гексилоксикарбониламиноиминометил)фениламино]метил}-1-метил-1h-бензимидазол-5-карбонил)пиридин-2-иламино]пропионовой кислоты и его солей
HRP20040807B1 (hr) * 2002-03-07 2014-11-21 Boehringer Ingelheim International Gmbh Oblik etil estera 3-[(2-{[4-(heksiloksikarbonilamino-imino-metil)-fenilamino]-metil}-1-metil-1h-benzimidazol-5-karbonil)-piridin-2-il-amino]-propionske kiseline i njegovih soli za oralnu aplikaciju
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
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
EP1466917A1 (fr) 2002-09-09 2004-10-13 Trigen Limited Procédé der préparation des acides boroniques peptidiques et acides obtenus
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations
US7932273B2 (en) 2003-08-29 2011-04-26 Boehringer Ingelheim International Gmbh 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl) phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as a medicament
WO2005023249A1 (fr) * 2003-09-03 2005-03-17 Boehringer Ingelheim International Gmbh Nouvelle forme galenique orale pour ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyle)-phenylamino]-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino]propionique et ses sels
CN102875529A (zh) * 2011-07-15 2013-01-16 天津药物研究院 达比加群的酯衍生物及其制备方法

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