IL101257A - 2, 4 - and -2,5 - pyridine dicarboxyamides, a process for preparing them, the use thereof and pharmaceutical compositions based on these compounds - Google Patents
2, 4 - and -2,5 - pyridine dicarboxyamides, a process for preparing them, the use thereof and pharmaceutical compositions based on these compoundsInfo
- Publication number
- IL101257A IL101257A IL101257A IL10125792A IL101257A IL 101257 A IL101257 A IL 101257A IL 101257 A IL101257 A IL 101257A IL 10125792 A IL10125792 A IL 10125792A IL 101257 A IL101257 A IL 101257A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- compounds
- collagen
- compound
- pyridine
- Prior art date
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
- 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
- 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
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Transplantation (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pulmonology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Photoreceptors In Electrophotography (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to mixed pyridine-2,4- and -2,5-dicarboxylic acid diamides, the carboxylic acid amide group in position 2 being a primary acid amide. The said compounds are suitable for the inhibition of proline hydroxylase and lysine hydroxylase and are used as fibrosuppressants and immunosuppressants.
Description
MIXED PYRIDINE-2,4- AND -2,5-DICARBOXAMIDES, A PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS BASED ON THESE COMPOUNDS ,ΌΠΠϊϊΡ ΠϋΊϋ3 ,T]',T",TlOTj2iaii?",T-5,2-l -4,2 ΓΤΤ^ "?UJ ΠΙΠΊΙΙΓΙ ϊΐ? mum "?D Ό-ΌΟΠΠΠ mnpn --ταοΓΠ HOECHST A TIEN6ESELLSCHAFT HOE 91/F 079 Dr.FI/pl Description Mixed pyridine-2,4- and -2,5-dicarboxamides, a process for preparing them, the use thereof and pharmaceuticals based on these compounds Compounds which inhibit proline hydroxylase and lysine hydroxylase effect a very selective inhibition of collagen biosynthesis due to influencing collagen-specific hydroxylation reactions. In the course thereof, protein-bound proline or lysine is hydroxylated by the enzymes proline hydroxylase or lysine hydroxylase respectively. If this reaction is suppressed by inhibitors, the resulting collagen molecule is unable to function, is insufficiently hydroxylated and can be released by the cells only in small amounts into the extracellular space. The insufficiently hydroxylated collagen cannot, moreover, be incorporated in the collagen matrix and is very easily broken down by proteolysis. The consequence of these effects is an overall reduction in the amount of collagen deposited in the extracellular space.
It is known that inhibition of proline hydroxylase by known inhibitors such as α , a ' -dipyridyl results in inhibition of Clq biosynthesis by macrophages (W. Muller et al., FEBS Lett. 90 (1978), 218; Immunobiology 155 (1978), 47). This results in the classical pathway of complement activation becoming inoperative. Hence inhibitors of proline hydroxylase act as immunosuppres-sants, for example in immune complex diseases.
It is known that proline hydroxylase can be effectively inhibited by pyridine-2,4- and -2,5-dicarboxylic acids (K. Mayama et al., Eur. J. Biochem. 138 (1984) 239-245). However, in cell culture, these compounds are effective inhibitors only in very high concentrations (Tschank, G. - 2 - 101257/2 et al., Biochem. J. 238 (1987) 625-633).
DE-A 34 32 094 describes pyridine-2,4- and -2,5-dicarboxylic disesters with 1-6 carbon atoms in the ester alkyl moiety as pharmaceuticals for the inhibition of proline hydroxylase and lysine hydroxylase.
These lower alkylated diesters have the disadvantage, however, that they are too rapidly cleaved in the body to the acids and do not reach their site of action in the cell in sufficiently high concentration and thus are less suitable for possible administration as pharmaceuticals.
DE-A 37 03 959 corresponding to IL 85362, DE-A 37 03 362 corresponding to IL 85360 and DE-A 37 03 963 corresponding to IL 85361, described in a general form mixed esters/amides, higher alkylated diesters and diamides of pyridine-2,4- and -2 , 5-dicarboxylic acids which are effective inhibitors of collagen biosynthesis in animal models.
Thus, DE-A 37 03 959 describes, inter alia, the synthesis of Ν,Ν' -bis ( 2-methoxyethyl )pyridine-2 , -dicarboxamide and , ' -bis ( 3-isopropoxypropyl )pyridine-2 , 4-dicarboxamide .
German Patent Applications P 38 26 471.4 corresponding to IL 91185 and P 38 28 140.6 propose an improved process for preparing N, ' -bis ( 2-methoxyethyl ) pyridine-2 , 4-dicarboxamide . German Patent Application P 39 24 093.2 corresponding to IL 95121 proposes novel N, ' -bis ( alkoxyalkyl ) pyridine-2 , 4-dicarboxamides .
The object to be achieved was thus to find compounds which are suitable in a much improved manner than those hitherto disclosed for the inhibition of proline hydroxylase and lysine hydroxylase. The object has been achieved by pyridine-2,4- and -2 , 5-dicarboxamides of the formula - - Λ pyridine-2,4- or -2 , 5-dicarboxainide of the formul in which H i and R2 are different, and designate alkoxyalkyl or hydrogen.
The meaningc of haiogon am fluo ino, ohlorino, bromino and iodino.
The invention further relates to the compounds of the formula I for use as pharmaceuticals. The invention additionally relates to the compounds of the formula I for use as fibrosuppressants and immunosuppressants and for the inhibition of proline hydroxylase and lysine hydroxylase and for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of Clq. Inhibitors of proline hydroxylase are suitable tools in the therapy of diseases in which the deposition of collagens makes a crucial contribution to the clinical picture. These include, inter alia, fibroses of the lungs, liver and skin (scleroderma) and atherosclerosis .
The pyridine-2,4- and -2 , 5-dicarboxamides of the formula I which are substituted exclusively in position 4 or 5 in the amide group show a considerable and surprising improved activity in inhibiting proline hydroxylase and lysine hydroxylase in animal experiments compared with the pyridine-2,4-dicarboxamides substituted in position 5 also by carboxamide groups from DE-A-3 707 429 and compared with the pyridine-2,4- and -2, 5-dicarboxamides substituted in both amide groups of DE-A 37 039 59.
The invention further relates to a process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II' with a compound of the formula III where R1 and R2 have the meanings indicated for formula I, and Y is halogen, especially chlorine, and subsequently converting the resulting compound of the formula IV (IV) with H3 into a compound of the formula I 0 J! - N R½2 followed, where appropriate, by conversion into its physiologically tolerated salts.
The following reaction diagram shows the preparation route (stages 5 and 6), including the synthesis of the precursors (1 to 4) Reaction diagram 2 C02H CONR-'-R CO R R' In stage 1, commercially available pyridine-2,4-dicarboxylic acid is converted into its dicarbonyl dihalide, preferably its dichloride, and reacted with an optionally substituted benzyl alcohol to give dibenzyl pyridine-2, 4-dicarboxylate .
In stage 2, the diester is selectively hydrolyzed in position 2, for example in the presence of a copper salt as described by Delarge, J.: Phar. Acta. Helv. 44 (10), 637 (1969).
The free acid functionality in position 2 is subsequently converted in stage 3 into the corresponding acid chloride and reacted with an alcohol such as, for example, methyl or ethyl alcohol to give the corresponding 2-carboxylic ester.
The remaining benzyl protective group in position 4 is eliminated by hydrogenolysis in stage 4 (for example with H2/Pd, Houben-Weyl: Vol. IV/lc (1980), pp. 381 - 82).
The free acid in position 4 (formula II) is converted into its acid halide, preferably chloride. The acid chloride can now be converted with the amine of the formula (III) into the mixed pyridine-4-carboxamide-2-carboxylic ester (IV).
The mixed diamide of the formula (I) is prepared from the 2-carboxylic ester (IV) with alcoholic ammonia solution (for example in methanol).
The said process, which has been described in the reaction diagram for the compounds substituted in position 4, also applies to the compounds correspondingly substituted in position 5.
It is possible where appropriate for the products to be worked up, for example, by extraction or by chromatography, for example on silica gel. The isolated products can be recrystallized and, where appropriate, reacted with a suitable acid to give a physiologically tolerated salt. Examples of suitable acids are: mineral acids such as hydrochloric and hydrobromic acid and sulfuric, phosphoric, nitric or perchloric acid or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, aleic, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1, 5-disulfonic or ascorbic acid.
The starting compounds of the formula (III) which cannot be bought can be synthesized straightforwardly (for example Organikum, Organisch Chemisches Grundpraktikum, 15th edition, VEB Deutscher Verlag der Wissenschaften, 1976; a summary of the various possibilities is to be found in the methods index, p. 822).
The compounds of the formula I according to the invention have valuable pharmacological properties and, in particular, display activity as inhibitors of proline hydroxy-lase and lysine hydroxylase, as fibrosuppressant and immunosuppressant.
The activity of the fibrogenase can be determined by radioimmunological determination of the N-terminal propeptide of collagen type III or of the N- or C-terminal crosslinking domain of collagen type IV (7s collagen or type IV collagen NCX) in serum.
For this purpose, the hydroxyproline, procollagen III peptide, 7s collagen and type IV collagen NCi concentrations were measured in the liver of a) untreated rats (control) b) rats given tetrachloromethane (CC14 control) c) rats give first CC1/, and then a compound according to the invention (this test method is described by Rouiller, C, experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, pp. 335-476, New York, Academic Press, 1964).
By reason of these pharmacological properties, the compounds according to the invention are suitable for the treatment of disorders of the metabolism of collagen and collagen-like substances and for the treatment of disorders of the biosynthesis of Cl .
The invention therefore further relates to the use of the compounds of the formula I according to the invention, and of the physiologically tolerated salts thereof, for the treatment of the abovementioned metabolic disorders .
The compounds can be used as pharmaceuticals either alone or mixed with physiologically tolerated auxiliaries or vehicles. They can be administered for this purpose orally in doses of 0.01 - 25.0 mg/kg/day, preferably 0.01 - 5.0 mg/kg/day or parenterally in doses of 0.001 - 5 mg/kg/day, preferably 0.001 - 2.5 mg/kg/day, especially to 0.005 - 1.0 mg/kg/day. It is also possible to increase the dosage in severe cases. However, lower doses also suffice in many cases. These data relate to an adult weighing about 75 kg.
The invention also embraces the use of the compounds according to the invention for preparing pharmaceuticals which are employed for the treatment and prophylaxis of the abovementioned metabolic disorders.
The invention additionally relates to pharmaceuticals which contain one or more compounds of the formula I according to the invention and/or their physiologically tolerated salts.
The pharmaceuticals are producing by processes known per se and familiar to the person skilled in the art. As pharmaceuticals, the pharmacologically active compounds (= active substance) according to the invention are employed either as such or, preferably, in combination with suitable pharmaceutical auxiliaries or vehicles in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, where the content of active substance is up to 95 % advantageously between 10 to 75 %.
Suitable auxiliaries and vehicles for the required pharmaceutical formulation are, for example, besides solvents, gel formers, suppository bases, tableting auxiliaries and other active substance vehicles, also antioxidants, dispersants, emulsifiers, form suppressants, flavorings, preservatives, solubilizers or colorants .
The active substances can be administered orally, parenterally or rectally.
The active compounds are mixed with the additives suitable for this, such as vehicles, stabilizers or iner diluents, and converted by the usual methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. The preparation can be carried out either as dry or as wet granules. Examples of suitable oily vehicles or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds are, if required, converted into a solution, suspension or emulsion with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are physiological saline or alcohols, for example ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
The invention is explained in more detail hereinafter by means of examples .
General procedure for the preparation of the compounds 1 mmol of methyl pyridine-4-carboxamide-2-carboxylate (IV) is dissolved in 30 ml of saturated methanolic ammonia solution and stirred at room temperature for 2 hours. The solution is concentrated and the residue is stirred with diisopropyl ether and filtered off with suction.
Example 1 4-N-Ethylpyridine-2-carboxamide-4-carboxamide Melting point: 197 °C Example 2 4-Morpholinocarbonylpyridine-2-carboxamide Melting point: Example 3 4-N,N-Diethylpyridine-2-carboxamide-4-carboxamide Oil, MS = 222 (M + H+) molecular mass C11H15N302 (221) Example 4 4-N- ( 2-methoxypropyl)pyridine-2-carboxamide-4-carboxamide Melting point: 116 - 120 °C Example 5 4-N- ( 3-methoxypropyl)pyridine-2-carboxamide-4-carboxaraide Melting point: 149 °C Example 6 4-N- ( 3-hydroxypropyl )pyridine-2-carboxamide-4-carboxamide Melting point: 154 - 156 °C Example 7 4-N-alanylpyridine-2-carboxamide-4-carboxamide Melting point: 124 - 125 °C Example 8 4_N-(0-benzylalanyl)pyridine-2-carboxamide-4-carboxamide Melting point: 138 - 140 °C
Claims (9)
1. A pyridine-2,4- or -2 , 5-dicarboxamide of the formula I in which and R2 are different, and designate alkoxyalkyl or hydrogen.
2. A process for the preparation of compounds of the formula I, which comprises reacting a compound of the formula II' with a compound of the formula III H - (III) - 14 - 101257/2 where R1 and Rz have the meanings indicated for formula I, and Y is halogen, especially chlorine, and subsequently converting the resulting compound of the formula IV C02CH with NH3 into a compound of the formula I and into its physiologically tolerated salts. 101257/ 2
3. A compound as claimed in claim 1 for use in a pharmaceutical composition.
4. A compound as claimed in claim 1 for the inhibition of proline hydroxylase and lysine hydroxylase.
5. A compound as claimed in Claim 1 for use as fibrosuppressant and immunosuppressant.
6. A pharmaceutical composition containing a compound of the formula I with compatible pharmaceutical vehicles.
7. The use of compounds of the formula I in the preparation of a composition for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of C19, substantially as described in the specification.
8. The use of compounds of the formula I in the preparation of a composition,for the treatment of disorders of the metabolism of collagen and collagen-like substances and the biosynthesis of C19, substantially as described in the specification.
9. A process for the production of pharmaceutical compositions for influencing the metabolism of collagen and collagen-like substances and the biosynthesis of C19, which comprises incorporating a compound of the formula 1 in the pharmaceutical. \
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4108824 | 1991-03-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL101257A0 IL101257A0 (en) | 1992-11-15 |
| IL101257A true IL101257A (en) | 1998-03-10 |
Family
ID=6427597
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL101257A IL101257A (en) | 1991-03-18 | 1992-03-16 | 2, 4 - and -2,5 - pyridine dicarboxyamides, a process for preparing them, the use thereof and pharmaceutical compositions based on these compounds |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0504799B1 (en) |
| JP (1) | JP3121428B2 (en) |
| KR (1) | KR100243959B1 (en) |
| AT (1) | ATE154929T1 (en) |
| AU (1) | AU645668B2 (en) |
| CA (1) | CA2063177A1 (en) |
| CZ (1) | CZ282298B6 (en) |
| DE (1) | DE59208651D1 (en) |
| DK (1) | DK0504799T3 (en) |
| ES (1) | ES2104758T3 (en) |
| FI (1) | FI101701B1 (en) |
| GR (1) | GR3024309T3 (en) |
| HR (1) | HRP940835A2 (en) |
| HU (1) | HU217809B (en) |
| IE (1) | IE920843A1 (en) |
| IL (1) | IL101257A (en) |
| MX (1) | MX9201156A (en) |
| NO (1) | NO178859C (en) |
| NZ (1) | NZ241968A (en) |
| TW (1) | TW199147B (en) |
| YU (1) | YU48156B (en) |
| ZA (1) | ZA921945B (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3703959A1 (en) * | 1987-02-10 | 1988-08-18 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| ATE113036T1 (en) * | 1988-08-04 | 1994-11-15 | Hoechst Ag | IMPROVED PROCESS FOR THE PRODUCTION OF N,N-BIS(ALKOXYALKYL)-PYRIDINE-2,4-DICARBONIC DIAMIDES. |
| DE3924093A1 (en) * | 1989-07-20 | 1991-02-07 | Hoechst Ag | N, N'-BIS (ALKOXY-ALKYL) -PYRIDINE-2,4-DICARBONESAUREDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3928144A1 (en) * | 1989-08-25 | 1991-02-28 | Hoechst Ag | CYCLIC PYRIDINE-2,4- AND -2,5-DICARBONIC ACIDEDIAMIDES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE3938805A1 (en) * | 1989-11-23 | 1991-05-29 | Hoechst Ag | PYRIDINE-2,4- AND 2,5-DICARBONIC ACID DIAMOND, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE4030999A1 (en) * | 1990-10-01 | 1992-04-09 | Hoechst Ag | 4- OR 5-SUBSTITUTED PYRIDINE-2-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
-
1991
- 1991-09-20 TW TW080107458A patent/TW199147B/zh active
-
1992
- 1992-03-12 YU YU24692A patent/YU48156B/en unknown
- 1992-03-16 IE IE084392A patent/IE920843A1/en unknown
- 1992-03-16 NZ NZ241968A patent/NZ241968A/en unknown
- 1992-03-16 IL IL101257A patent/IL101257A/en not_active IP Right Cessation
- 1992-03-16 FI FI921119A patent/FI101701B1/en active
- 1992-03-17 EP EP92104584A patent/EP0504799B1/en not_active Expired - Lifetime
- 1992-03-17 HU HU9200891A patent/HU217809B/en not_active IP Right Cessation
- 1992-03-17 DE DE59208651T patent/DE59208651D1/en not_active Expired - Fee Related
- 1992-03-17 KR KR1019920004320A patent/KR100243959B1/en not_active IP Right Cessation
- 1992-03-17 AU AU12967/92A patent/AU645668B2/en not_active Ceased
- 1992-03-17 DK DK92104584.5T patent/DK0504799T3/en active
- 1992-03-17 ZA ZA921945A patent/ZA921945B/en unknown
- 1992-03-17 MX MX9201156A patent/MX9201156A/en unknown
- 1992-03-17 ES ES92104584T patent/ES2104758T3/en not_active Expired - Lifetime
- 1992-03-17 CA CA002063177A patent/CA2063177A1/en not_active Abandoned
- 1992-03-17 JP JP04060053A patent/JP3121428B2/en not_active Expired - Fee Related
- 1992-03-17 NO NO921025A patent/NO178859C/en not_active IP Right Cessation
- 1992-03-17 AT AT92104584T patent/ATE154929T1/en not_active IP Right Cessation
- 1992-03-17 CZ CS92803A patent/CZ282298B6/en unknown
-
1994
- 1994-10-26 HR HRP-246/92A patent/HRP940835A2/en not_active Application Discontinuation
-
1997
- 1997-07-30 GR GR970401958T patent/GR3024309T3/en unknown
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