EP0648209A1 - Agents de contraste pour diagnostic rm - Google Patents

Agents de contraste pour diagnostic rm

Info

Publication number
EP0648209A1
EP0648209A1 EP93915763A EP93915763A EP0648209A1 EP 0648209 A1 EP0648209 A1 EP 0648209A1 EP 93915763 A EP93915763 A EP 93915763A EP 93915763 A EP93915763 A EP 93915763A EP 0648209 A1 EP0648209 A1 EP 0648209A1
Authority
EP
European Patent Office
Prior art keywords
general formula
methyl
salts
radical
different
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Withdrawn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
EP93915763A
Other languages
German (de)
English (en)
Inventor
Bernhard Kohl
Rolf-Peter Hummel
Klaus-Peter Lodemann
Klaus-Dieter Beller
Hildegard Boss
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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 Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0648209A1 publication Critical patent/EP0648209A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to new complexing agents.
  • the object of the present invention is to provide new complexing agents whose complexes with paramagnetic metal ions are characterized by high complex stability, good solubility in water at physiological pH values, strong relaxivity and by a pronounced organ specificity combined with reduced side effects and faster out Mark divorce.
  • the invention relates to complexing agents of the general formula I,
  • R1, R2, R3 and R4 are the same or different and are H, COOH, C (O) NHR5, where R5 is H and C1-C4-alkyl,
  • R6 and R7 in the general formula Ila are identical or different and are H, methyl and benzyl,
  • R7 in the general formula Ilb denotes methyl and benzyl
  • R8 denotes H or C1-C4-alkyl
  • radicals R1, R2, R3 and R4 represents a radical of the general formulas Ila or Ilb
  • R9 denotes H, C1-C4-alkyl and (CH 2 ) n R1,
  • n, q for 1 or 2, where n and q are the same or different, and
  • a preferred subject of the invention are complexing agents of the general formula I above,
  • R1, R2, R3 and R4 are the same or different and for COOH, C (O) NHR5,
  • R5 denotes H, methyl and ethyl, and a radical of the general
  • R6 and R7 are the same or different and are H and methyl
  • radicals R1, R2, R3 and R4 are a radical of the general formula Ila,
  • R9 (CH 2 ) n R1 means
  • a particularly preferred object of the invention are complexing agents of the above general formula I,
  • R1, R2, R3 and R4 are the same or different and are for COOH and a radical of the general formula Ila,
  • R6 and R7 are the same or different and are H and methyl
  • radicals R1, R2, R3 and R4 are a radical of the general formula Ila,
  • R1, R2, R3 and R4 are the same or different and are for COOH and a radical of the general formula Ila,
  • R6 and R7 are the same or different and are H and methyl, with the proviso that at least one of the radicals R1, R2, R3 and R4 is a radical of the general formula Ila,
  • Particularly preferred complexing agents are N, N'-bis - [(3-hydroxy-4-methoxypyridin-2-yl) methyl] ethylenediamine-N, N'-diacetic acid, N, N "- bis - [(3-hydroxy- 4-methoxypyridin-2-yl) methyl] diethylenetriamine-N, N ', N' '- tri-acetic acid, N' - [(3 ⁇ -hydroxy-4-methoxypyridin-2-yl) methyl] diethylenetriamine-N, N, N ' ', N' '- tetraacetic acid N, N "-bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethylenetriamine ⁇ N, N', N" -triacetic acid, N '- [3,4-dimethoxy- 2-pyridinyl) methyl] diethylenetriamine-N, N, N ", N” -tetraacetic acid and their salts with
  • the invention also relates to a process for the preparation of the complexing agents of the general formula I, which is characterized in that a compound of the general formula I in which the 3-hydroxy-4-methoxypyridin-2-yl radicals are substituted by 3-hydroxy -4-methoxypyridin-2-yl radicals, the hydroxyl groups of which are protected by protective groups which are customary for hydroxyl groups, preferably benzyl and methyl, are reacted under conditions which selectively remove protective groups.
  • the complexing agents according to the invention can be prepared starting from the corresponding 3,4-bis-hydroxypyridine-2-aldehydes, in which the hydroxy groups which are to be retained in the end product of the formula I are protected by suitable protective groups, for example methyl or, in particular, benzyl .
  • suitable protective groups for example methyl or, in particular, benzyl .
  • R1 is COOH
  • ⁇ -halogen (CH 2 ) n -R1 compounds can also be used, in which R1 represents a derivative of the carboxyl group, such as a nitrile or ester group which can be converted into the free carboxyl group by hydrolysis.
  • the protective groups have been split off, if necessary, for example by hydrogenation, the complexing agents according to the invention are obtained which, if desired, can be reacted with organic and inorganic acids and bases.
  • Another subject is complexes of paramagnetic metal ions with the complexing agents according to the invention and their salts, with complexes and their salts with gadolinium (III) and manganese (II) being preferred.
  • Possible paramagnetic metal ions are the cations of the transition metals of atomic numbers 21 to 29, 42 and 44 and the cations of the lanthanide elements of atomic numbers 57 to 70, gadolinium being preferred by the lanthanide elements.
  • the sodium and N-methylglucamine salts are preferred as salts of the complexes according to the invention.
  • contrast media for MR diagnostics containing complexes according to the invention and their salts as well as the use of the complexes according to the invention and their salts for the production of contrast media for MR diagnostics.
  • Preferred complexes are the gadolinium (III) and manganese (II) complexes of N, N '' - bis - [(3,4-dimethoxy-2-pyridinyl) methyl] diethyltriamine-N, N ', N "- triacetic acid, N, N '' bis - [(3-hydroxy-4-methoxypyridin-2-yl) methyl] diethylenetriamine-N, N ', N''- triacetic acid and N, N'-bis - [(3- hydroxy-4-methoxypyridin-2-yl) methyl] ethylenediamine-N, N'-diacetic acid.
  • the sodium and methyl glucamine salts are preferred.
  • Another object of the invention is a process for the preparation of complexes, characterized in that compounds of the general formula I, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, m, n, p and q have the meanings given above, are reacted with paramagnetic metal ions and, if desired, the complexes obtained are converted into the salts with the aid of strong bases.
  • the complexes according to the invention result in a very good increase in contrast in MR diagnostics and are distinguished by numerous advantages over the prior art. In the dosages relevant for MR diagnostics, they do not cause a drop in blood pressure and heart rate. They are excreted unchanged and quickly renally. They are not sensitive to hydrolysis.
  • the complexing agents according to the invention give more stable complexes than those according to the prior art which, instead of a radical of the general formula II, have carboxyl groups or -CONHR5.
  • neutral complexes of particularly high complex stability can be prepared by choosing the number and type of the radical of the general formula II, depending on the charge of the central atom. Their preparation is simple and inexpensive and solutions with a physiological pH and low osmolality can be produced.
  • Contrast agents according to the invention for MR diagnostics contain one or more of the complexes of paramagnetic metal ions with complexing agents of the general formula I and, if desired, customary additives.
  • the complexes are prepared in a manner known per se by dissolving salts of the paramagnetic metals in water and / or an alcohol, such as methanol, ethanol, etc., and with the appropriate amount of the complexing agent, if necessary with heating to 50 ° C. to 120 ° C as long as stir until the implementation is complete.
  • an alcohol such as methanol, ethanol, etc.
  • complexes of the paramagnetic metal ions can also be used, for example the corresponding acetylacetonato complexes, the ligands of which are exchangeable by the complexing agents according to the invention. If the complex formed is insoluble in the solvent used, it crystallizes and can be filtered off.
  • the complex is soluble in the solvent used, it can be isolated by evaporating the solution to dryness or precipitated by adding another organic solvent.
  • the complex compound obtained is then dissolved or suspended in water and mixed with the desired inorganic or organic base or acid until the neutral point is reached. After filtration of undissolved portions, the solution is evaporated and the desired complex salt is obtained as a residue or the complex salt is precipitated from an aqueous solution with an organic solvent.
  • the salts of the complexes are obtained, for example, by reaction with strong bases.
  • the complexes can also be prepared in a manner known per se by adding an aqueous solution of the salt of the paramagnetic metal to a solution of the appropriate amount of the complexing agent plus the appropriate amount of base, e.g. Sodium hydroxide, or added dropwise to a salt (e.g. sodium salt) of the complexing agent and sterile filtering the aqueous solution of the salt of the complex or its sodium salt.
  • a salt e.g. sodium salt
  • the complexes can be lyophilized in the form of their salts or precipitated by adding a non-polar, water-miscible solvent (e.g. acetone, isopropanol).
  • a non-polar, water-miscible solvent e.g. acetone, isopropanol.
  • the separation of inorganic salts can also be carried out by precipitation of the complexes by means of mineral acid (e.g. aqueous hydrochloric acid) at pH 2.5-4 and filtration or in a manner known per se using ion exchangers or by chromatography, e.g. on silica gel.
  • mineral acid e.g. aqueous hydrochloric acid
  • chromatography e.g. on silica gel.
  • the aqueous solution or a suspension of the precipitated complex compound eluted from the ion exchanger is converted into the desired form (eg sodium salt or meglumine salt) which is soluble at physiological pH values dung in water with the appropriate amount of strong base (eg sodium hydroxide solution or N-methylglucamine).
  • the desired form eg sodium salt or meglumine salt
  • strong base eg sodium hydroxide solution or N-methylglucamine
  • the new contrast media are prepared in a manner known per se by dissolving the complexes and / or their salts in water or physiological salt solution and, if desired, adding additives customary in galenics, such as, for example, physiologically compatible buffer solutions (e.g. sodium dihydrogen phosphate solution), albumin and the like and sterilized the solution.
  • physiologically compatible buffer solutions e.g. sodium dihydrogen phosphate solution
  • albumin e.g., albumin and the like
  • the solutions can be filled into ampoules or freeze-dried to a soluble powder.
  • the aqueous solutions are adjusted to a pH with sufficient local tissue tolerance, for example to a pH of 7 to 9.
  • the aqueous solutions are administered orally or parenterally, in particular intravascularly.
  • aqueous solutions which contain the paramagnetic complex in a concentration of 30 to 500 mmol / liter. Approximately 1 to 300 ⁇ mol of the complex per kg body weight are administered per application. For an adult, a dose of 1 to 100 mmol proves to be appropriate for an iv application.
  • Example 3.D 8.0 g of the title compound of melting point 72-74 ° C. is obtained from 20 g of 3-benzyloxy-2-hydroxymethyl-4-methoxypyridine in 200 ml of dioxane with 30 g of manganese dioxide.
  • Table 1 summarizes the results of the presentation of the liver of rats. The specified intensity values are standardized to the value 100 before contrast medium administration (KM).
  • Table 2 shows the results of the illustration of brain abscesses produced by bacterial injection in rabbits.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Pyridine Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Agents complexants, de formule générale (I) dans laquelle R1, R2, R3 et R4 sont identiques ou différents et désignent H, COOH, C(O)NHR5, où R5 désigne H et un alkyle en C1-C4, PO3H2, SO3H et un reste de formule générale (IIa) ou (IIb) où R6 et R7 dans la formule générale (IIa) sont identiques ou différents et désignent H, un méthyle et un benzyle, R7 dans la formule générale (IIb) désigne un méthyle et un benzyle, et R8 désigne un H ou un alkyle en C1-C4, à la condition qu'au moins l'un des restes R1, R2, R3 et R4 désigne un reste de formule générale (IIa) ou (IIb), X désigne une liaison simple et NR9, où R9 désigne H, un alkyle en C1-C4 et (CH2)nR1; n, q valent 1 ou 2 et peuvent être identiques ou différents, et p vaut 1 ou 2, mais ne vaut pas 1 lorsque X désigne NR9, ainsi que leurs sels avec des bases et des acides organiques et inorganiques. Ces produits conviennent pour la fabrication de complexes paramagnétiques qui sont utilisés avantageusement comme agents de contraste pour diagnostic RM.
EP93915763A 1992-07-01 1993-07-01 Agents de contraste pour diagnostic rm Withdrawn EP0648209A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH2046/92 1992-07-01
CH204692 1992-07-01
PCT/EP1993/001698 WO1994001406A1 (fr) 1992-07-01 1993-07-01 Agents de contraste pour diagnostic rm

Publications (1)

Publication Number Publication Date
EP0648209A1 true EP0648209A1 (fr) 1995-04-19

Family

ID=4224675

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93915763A Withdrawn EP0648209A1 (fr) 1992-07-01 1993-07-01 Agents de contraste pour diagnostic rm

Country Status (4)

Country Link
EP (1) EP0648209A1 (fr)
JP (1) JPH07508527A (fr)
AU (1) AU4562693A (fr)
WO (1) WO1994001406A1 (fr)

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US9012450B2 (en) 2011-12-28 2015-04-21 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
SI2797416T1 (sl) 2011-12-28 2017-12-29 Global Blood Therapeutics, Inc. Substituirane spojine benzaldehida in metode njihove uporabe pri povečanju oksigenacije tkiva
US20140274961A1 (en) 2013-03-15 2014-09-18 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9458139B2 (en) 2013-03-15 2016-10-04 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
AP2015008721A0 (en) 2013-03-15 2015-09-30 Global Blood Therapeutics Inc Compounds and uses thereof for the modulation of hemoglobin
BR112015021982B1 (pt) 2013-03-15 2022-12-13 Global Blood Therapeutics, Inc Compostos e seus usos para a modulação de hemoglobina
EP2968299B1 (fr) 2013-03-15 2021-01-20 Global Blood Therapeutics, Inc. Composés et leurs utilisations pour la modulation de l'hémoglobine
US9422279B2 (en) 2013-03-15 2016-08-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
WO2014145040A1 (fr) 2013-03-15 2014-09-18 Global Blood Therapeutics, Inc. Composés aldéhydes substitués et leurs procédés d'utilisation pour accroître l'oxygénation tissulaire
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
EA202092627A1 (ru) 2013-11-18 2021-09-30 Глобал Блад Терапьютикс, Инк. Соединения и их применения для модуляции гемоглобина
CN114181195A (zh) 2014-02-07 2022-03-15 全球血液疗法股份有限公司 一种化合物的结晶多晶型物
MA41841A (fr) 2015-03-30 2018-02-06 Global Blood Therapeutics Inc Composés aldéhyde pour le traitement de la fibrose pulmonaire, de l'hypoxie, et de maladies auto-immunes et des tissus conjonctifs
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Also Published As

Publication number Publication date
AU4562693A (en) 1994-01-31
WO1994001406A1 (fr) 1994-01-20
JPH07508527A (ja) 1995-09-21

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