EP0077372A1 - NOUVEAUX DERIVES DE LA PYRAZOLO(3,4-d)PYRIMIDINE, PROCEDE DE LEUR PREPARATION ET REMEDE LES CONTENANT - Google Patents

NOUVEAUX DERIVES DE LA PYRAZOLO(3,4-d)PYRIMIDINE, PROCEDE DE LEUR PREPARATION ET REMEDE LES CONTENANT

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Publication number
EP0077372A1
EP0077372A1 EP19820901506 EP82901506A EP0077372A1 EP 0077372 A1 EP0077372 A1 EP 0077372A1 EP 19820901506 EP19820901506 EP 19820901506 EP 82901506 A EP82901506 A EP 82901506A EP 0077372 A1 EP0077372 A1 EP 0077372A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
methyl
pyrazolo
ethyl
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Withdrawn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
EP19820901506
Other languages
German (de)
English (en)
Inventor
Kailash Kumar Gauri
Hans Erbler
Manfrid Eltze
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 EP0077372A1 publication Critical patent/EP0077372A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • New pyrazolo [3,4-d] pyrimidines process for their preparation and medicaments containing them
  • the invention relates to new pyrazolo [3,4-d] pyrimidines, medicaments containing them and processes for their preparation.
  • DE-PS 11 05330 5-alkyl-4,5,6,7-tetrahydro-4,6-dioxo1H-pyrazolo [3,4-d] pyrimidines with caffeine-like activity are known.
  • DE-AS 11 86466 describes a process for the preparation of up to three times N-substituted 4,5,6,7-tetrahydro-4,6-dioxo-1H-pyrazolo [3-4-d] pyrimidines. The process products are generally said to have valuable pharmacological properties. J. Heterocycl Chem.
  • R 1 and R 2 which are the same or different, represent hydrogen or the radicals C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 4 -C 8 alkylcarbonylalkyl, C 3 -C 8 alkylthioalkyl and C 3 -C 8 alkoxyalkyl, which may be substituted by halogen, hydroxy or the di (C 1 -C 2 alkyl) amino radical, but R 1 and R 2 cannot be hydrogen at the same time, and for a group or in which
  • R 3 is hydrogen or C 1 -C 4 alkyl
  • R 4 is hydrogen C 1 -C 4 -alkyl or phenyl, which can be up to triple C 1 -C 2 -alkoxy-substituted,
  • R 5 is hydrogen, C 1 -C 6 -alkyl, hydroxy-C 1 -C 3 -alkyl, di (C 1 - C 2 -alkyl) amino-C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, Phenyl, phenyl-C 1 -C 2 -alkyl or benzoyl, where the phenyl rings of the latter three radicals can be substituted up to three times by CpCoalkoxy, C.-C ⁇ -alkylthio ⁇ -C.alkyl or hydroxy-, amino- or sulfo-C , -C 3 -alkylthioC 2 -C 4 -alkyl, where R 1 , R 2 and R 5 are not simultaneously ethyl, R 1 and R 2 are not both methyl when R 3 or R 5 is butyl or di ( C 1 -C 2 alkyl) aminoethyl mean, and the sum of
  • Chains together is at least 6, or at least 5 if R 2 is isobutyl, have a strong bronchospasmolytic, phosphodiesterase inhibiting and retinotropic effect. They also improve the rheological properties of the blood and thus the peripheral blood flow. They are therefore suitable, for example, for the treatment of obstructive respiratory diseases, cerebral and peripheral circulatory disorders, circulatory disorders of the retina and choroid, deafness of the elderly, buzzing in the ears and otogenic vertigo.
  • the compounds of the invention are not mutagenic.
  • the invention therefore relates to pyrazolo [3,4-d] pyrimidines of the above general formula I, in which A, R 1 and R 2 have the meanings indicated and their use for treating the indicated Ge health disorders and for the production of medicaments, in particular those for the treatment of the stated health disorders and medicaments containing these compounds, if desired in conjunction with suitable carriers or auxiliaries.
  • R 1 ' and R 2' which are the same or different, represent hydrogen or the radicals C 1 -C 8 alkyl, C 2 -C 4 alkenyl, C 5 -C 7 alkylcarbonylalkyl, C 5 -C 7 alkylthioalkyl and C 3 -C 7 alkoxyalkyl, which may be substituted by hydroxyl or the dimethylamino radical, but R 1 ' and R 2' cannot simultaneously be hydrogen, and A 'for a group or in which
  • R 3 ' is hydrogen or C 1 -C 3 alkyl
  • R 4' is hydrogen, C 1 -C 3 alkyl or phenyl, which can be up to three times methoxy-substituted
  • R 5 ' is hydrogen, C 1 -C 6 alkyl, hydroxy C 1 -C 3 alkyl
  • R 1 " and R 2" which are the same or different, represent hydrogen, C 1 -C 6 alkyl, 2-hydroxyethyl, allyl, 5-oxo-n-hexyl, hydroxyethoxy methyl, hydroxyethoxy-n-propyl, hydroxyethylthio -n-propyl or 2- (dimethylamino) ethyl, R 1 " and R 2" but cannot simultaneously be hydrogen, and A "for a group"
  • R 3 is hydrogen, methyl or ethyl
  • R 4 " is hydrogen or phenyl and R 5" is hydrogen, C 1 -C 6 alkyl, 2-hydroxyethyl, allyl, trimethoxyphenyl, trimethoxybenzoyl or hydroxyethylthio n-propyl, where R 1 " , R 2" and R 5 " are not simultaneously ethyl, R 1 " and R 2" are not both methyl when R 5 "is butyl and the sum of the carbon, oxygen, nitrogen and sulfur atoms of the chains bonded to ring nitrogen atoms is at least 6, or at least 5 when R 2 " isobutyl, and drugs containing these compounds.
  • Compounds of the general formula I '" are very particularly preferred,
  • radicals R 1 "' and R 2"' for hydrogen, methyl or ethyl, the other for ethyl, butyl, hexyl, 5-oxo-n-hexyl or 2- (dimethylamino) ethyl, and
  • R 3 "' is hydrogen or methyl
  • R 5 is C 1 -C 6 alkyl, 2-hydroxyethyl and trimethoxybenzoyl, the sum of the carbon, oxygen and nitrogen atoms of the chains bonded to ring nitrogen atoms together being at least
  • R isobutyl
  • drugs containing these compounds are drugs containing these compounds.
  • a butyl radical is an n-, i-, sec- or tert. -Butyl rest.
  • a C 4 -C 8 alkylcarbonylalkyl radical is, for example, a 3-oxo-n-butyl-3-oxo-n-pentyl-, 4-oxo-n-pentyl-, 3-oxo-n-hexyl-, 5-oxo -n-hexyl, 6-oxo-n-heptyl or 7-oxo-n-octyl radical, preferably a 5-oxo-n-hexyl radical.
  • a radical C 3 -C 8 -alkylthioalkyl is, for example, a methylthioethyl, methylthiopropyl, ethylthioethyl, n-propylthioethyl, ethylthio-n-butyl, isopropylthio-n-butyl or isobutylthio-n-butyl radical, preferably an ethylthiopropyl radical.
  • a C 3 -C 8 alkoxyalkyl radical is, for example, preferably a methoxyethyl, methoxy propyl, ethoxyethyl, n-propoxyethyl, ethoxy-n-butyl, isopropoxy-m-butyl or isobutoxy-n-butyl radical an ethoxypropyl residue.
  • the radicals C 4 -C 8 or C 5 -C 7 alkylcarbonylalkyl, C 3 -C 8 or C 5 -C 7 alkylthioalkyl and C 3 -C 8 or C 3 -C 7 alkoxyalkyl the specified number of carbon atoms relates to all carbon atoms of the rest.
  • a radical which is substituted by halogen or hydroxy is C 4 -C 8 -alkylcarbonylalkyl, C 3 -C 8 -alkylthioalkyl or C 3 -C 8 -alkoxyalkyl is, for example, a 5-hydroxy-3-oxo-n-pentyl-, hydroxyethylthioethyl-, Hydroxyethoxyethyl, hydroxyethoxy-n-propyl, hydroxyethylthio-n-propyl, 5-chloro-3-oxo-n-pentyl-, (2-chloroethyl) -thioethyl-, (2-chloroethoxy) -ethyl-, (2 Chloroethoxy) n-propyl or ⁇ 2-chloroethyl) thio-n-propyl, preferably a (2-hydroxy) thio-n-propyl, (2-hydroxyethoxy)
  • a residue of amino or sulfo-C 1 -C 3 -alkylthio-C 2 -C 4 -alkyl is, for example, a (2-aminoethyl) thioethyl-, (2-sulfoethyl) -thiopropyl-, (2-aminopropyl) -thio -n-butyl or (3-sulfopropyl) thio-n-propyl radical.
  • R 3 , R 3 ' , R 3 " or R 3"' and R 5 , R 5 ' , R 5 “ or R 5"' have the meanings given above and R 4 , R 4 ' , R 4 " or R 4" is hydrogen, are prepared by using a 4-hydrazinouracil de general formula II or Ha,
  • R 1 , R 1 ' , R 1 " or R 1"' , R 2 , R 2 ' , R 2 " or R 2"' , R 3 , R 3 ' , R 3 " or R 3"' and R 5 , R 5' , R 5 " and R 5"' have the meanings given above, with phosphorus oxychloride and dimethylformamide in a manner known per se, for example by the process specified in DE-AS 11 8646. It is advantageous to enter the 4-hydrazinouracil in a cooled mixture of phosphorus oxychloride and dimethylformamide. After the addition of the 4-hydrazinouracil has ended, the reaction mixture is allowed to warm to room temperature.
  • thermolytic dehydration of the hydrazone is expediently carried out at the melting temperature of the hydrazone up to 30 ° C. above the melting temperature of the hydrazone, preferably at 5 to 20 ° C. above the melting temperature of the hydrazone, in particular about 10 ° C. above the melting temperature of the hydrazone.
  • a temperature range of 180 to 220 ° C has proven to be favorable in most cases.
  • a temperature of approximately 200 ° C. is particularly favorable.
  • the reaction time is generally 2 to 40 minutes, preferably 5 to 20 minutes.
  • the reaction mass is recrystallized from a suitable solvent, such as ethanol
  • an alkylcarbonylalkyl radical can be obtained by reacting the corresponding 4,5,6,7-tetrahydro-4,6-dioxopyrazolo [3,4-d] pyrimidine, preferably in the form of its sodium salt, with an alkylcarbonylalkyl halide, preferably chloride .
  • an alkylcarbonylalkyl halide preferably chloride .
  • 1-chlorohexanone-5 is suitable for the introduction of a 5-oxo-n-hexyl radical.
  • the invention further relates to the above-mentioned process variants and the processes for producing the new compounds defined in the patent claims.
  • the medicaments are produced by methods known per se, the new compounds being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredients, the active ingredient content of these mixtures is 0.5 to 95, preferably 15 to 75 percent by weight of the total mixture.
  • the active substances are used in any suitable formulation, provided that the formation or maintenance of sufficient active substance levels is ensured.
  • This can be done, for example, through oral, rectal or parenteral administration can be achieved in suitable doses, usually the pharmaceutical preparation of the active ingredient is in the form of unit doses which are tailored to the desired administration.
  • a unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.
  • unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or multiples of a single therapeutic dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score line.
  • compositions according to the invention when in unit doses and for application e.g. intended for humans, contain about 10 to 500 mg, advantageously 50 to 300 mg and in particular 100 to 300 mg of active ingredient.
  • Parenteral preparations can contain about 2 to 40 mg, advantageously 4 to 30 mg and in particular 10 to 25 mg of active ingredient.
  • the active ingredient (s) when administered orally in a daily dose of 0.1 to 12, preferably 1 to 8, in particular 2 to 4 mg / kg body weight, optionally in the form of several, preferably 1 up to 3 individuals administered to achieve the desired results.
  • a single dose contains the active ingredient (s) in amounts of 0.1 to 6, preferably 0.5 to 4, in particular 1 to 3 mg / kg body weight.
  • Preparations for intravenous administration are particularly useful for emergency treatment.
  • the therapeutic administration of the pharmaceutical preparation can take place 1 to 4 times a day at fixed or varying times, e.g. before meals and / or in the evening. However, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individual to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. In acute cases, a higher dose is given at the start of treatment. After the desired effect occurs, the dose is reduced to a lower dose.
  • the optimum dosage and type of application of the active ingredients required in each case can be determined by any specialist on the basis of his specialist knowledge.
  • the pharmaceutical preparations generally consist of the active substances according to the invention and non-toxic, pharmaceutically acceptable medicinal products which are used as admixtures or diluents in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a sachet or another container , are used for the therapeutically active ingredient.
  • a carrier can e.g. serve as a mediator for the medication ingestion by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.
  • tablets, coated tablets, hard and soft capsules for example as gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups
  • Tablets can contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose;
  • Granulating and distributing agents for example corn starch or alginates;
  • Binders for example starch, gelatin or acacia; and lubricants, for example aluminum or magnesium stearate, talc or silicone oil.
  • Gelatin capsules can contain the drug mixed with a solid, for example calcium carbonate or kaolin, or an oily, for example olive, peanut or paraffin oil, diluent.
  • Aqueous suspensions may include suspending agents, e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth or acacia; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monoleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxy benzoate; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
  • suspending agents e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth or acacia
  • Dispersing and wetting agents
  • suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickening agents, e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavorings and antioxidants.
  • Powders and granules dispersible in water can be admixed with the drugs in admixture with dispersing, wetting and suspending agents, e.g. the above, as well as with sweeteners, flavorings and colorants.
  • Emulsions can contain, for example, olive, peanut or paraffin oil in addition to emulsifiers, such as, for example, acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
  • emulsifiers such as, for example, acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
  • Suppositories are used for rectal application of the medicinal products, which are produced with the aid of binders melting at rectal temperature, for example cocoa butter or polyethylene glycol.
  • sterile injectable if necessary short-term, aqueous suspensions, isotonic salt solutions or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents, e.g. Propylene or butylene glycol.
  • the inhalative application of the compounds according to the invention is also preferred. These are administered either directly as a powder or by atomizing solutions or suspensions containing the compounds according to the invention.
  • the nebulization can be done in a conventional manner, for example by compressed air nebulizer or ultrasonic nebulizer. Administration from spray cans, in particular those with a conventional metering valve (metering aerosols), is particularly advantageous. Dosing aerosols make it possible to provide a defined amount of active ingredient per spray. So-called synchronous inhalers are of particular advantage here, with which the release of nitrogen can take place synchronously with the inhalation. Suitable synchronous inhalation devices are e.g. in DE-PS 1945 257, DE-PS 19 17 911 and DE-OS 2055 734.
  • the active ingredients are preferably used in micronized form, particle sizes of less than 10 ⁇ m being advantageous.
  • the active ingredients are dispersed in customary blowing agents, preferably with the aid of a dispersing agent.
  • Mixtures of trichlorofluoromethane (Frigen ® 11) and dichlorodifluoromethane (Frigen ® 12) are particularly suitable as blowing agents, and trichlorofluoromethane can be replaced in whole or in part by 1,1,2-trichlorotrifluoromethane (Frigen ® 113).
  • Particularly suitable dispersants are the sorbitan esters (Spane ® from Atlas GmbH) and lecithin which are customary for this purpose.
  • the dispersant is in the Heavily volatile excipient component, refrigerated, dissolved.
  • the micronized active ingredient or the micronized active ingredients are stirred into the solution.
  • the dispersion is poured into spray cans. After crimping, the more volatile propellant component is pressed on.
  • the active ingredient (s) can optionally also be formulated in microencapsulated form with one or more of the specified excipients or additives.
  • the compounds of the invention show, inter alia, a strong inhibition of phosphodiesterase and antagonize the damage to the retina caused by methanol.
  • Table 1 shows the values found for the inhibition of phosphodiesterase (PDE).
  • PDE phosphodiesterase
  • Table 2 shows the retinotropic effect, measured on the mouse electroretinogram, for compounds according to the invention.
  • the research methodology is described by K.K. Gauri and W.Hohl, Der Augenaptapt, 1979 (No. 9), and the references given therein.
  • the compounds according to the invention antagonize the retina damage caused by methanol (retinotropic action), while theophylline and pentoxifyll do not yet show any retinotropic action in at least the dose range in which the compounds according to the invention were investigated.
  • mol / l relaxation is carried out, with a constant relaxation response being waited for after each individual dose of the test substance before the next higher concentration is applied, so that a complete dose response is achieved over a period of 20 to 30 minutes
  • the respective relaxation is expressed as a percentage of the maximum relaxation that can be achieved by (-) isoprenal in (10 mol / l).
  • Table 3 shows the ED 50 (dose of the half-maximum possible relaxation) and the relative power compared to theophyll in for compounds according to the invention.
  • Example 2 2.5 g of the product of Example 1 are suspended in about 20 ml of acetone and mixed with an excess of ethyl bromide. Potassium carbonate is added to bind the hydrogen halide acid liberated, and the whole is boiled under reflux for a few hours until the reaction is complete. The excess alkylating agent and the solvent are then distilled off and the residue is recrystallized in an ethanol-water mixture. The title compound obtained melts at 107 to 108 ° C.
  • 1-Hexyl-4-hydrazino-3-methyluracil is reacted in chloroform / pyridine for 12 hours at 60 ° C. with 3,4,5-trimethoxybenzoyl chloride.
  • 2.5 g of the reaction product are reacted with 10 ml of dimethylformamide and 4 g of POC l 3 . Ice is added to the solution obtained and then neutralized with sodium carbonate.
  • the solution obtained is extracted with chloroform.
  • the organic phase is concentrated. The residue is recrystallized from a methanol / water mixture. 7.
  • 1-n-Hexyl-3-methyl-4- (1-methylhydrazino) uracil is reacted with 3,4,5-trimethoxybenzaldehyde at room temperature with stirring in ethanol.
  • the precipitated product is filtered off and heated to 200 ° C. for about half an hour. After cooling, it is recrystallized from ethanol.
  • the compounds substituted in the 3-position by ethyl or phenyl are prepared by using propionaldehyde or benzaldehyde.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composes de formule generale I (FORMULE) dans laquelle R1 et R2, qui peuvent etre identiques ou differents signifient l'hydrogene ou les restes C1-C8-alkyle, C2-C8-alkenyle, C4-C8-alkyle-carbonyle-alkyle, C3-C8-alkyle-thio-alkyle et C3-C8-alkoxy-alkyle, qui peuvent etre substitues par halogene, hydroxy ou par le groupe di(C1-C2-alkyle)-amino, les symboles R1 et R2 ne pouvant cependant signifier en meme temps l'hydrogene; dans laquelle A signifie l'un des groupes (FORMULE) OU (FORMULE) dans lequel R3 signifie hydrogene ou C1-C4-alkyle, R4 signifie hydrogene, C1-C4-alkyle ou phenyle, qui peut etre substitue jusqu'a trois fois par C1-C2-alkoxy, R5 signifie l'hydrogene, C1-C6-alkyle, hydroxy-C1-C3-alkyle, di(C1-C2-alkyle)-amino-C1-C4-alkyle, C2-C6-alkenyle, phenyle, phenyle-C1-C2-alkyle ou benzoyle, les cycles phenyliques des trois derniers restes pouvant etre substitues jusqu'a trois fois par C1-C2-alkoxy, R5 signifiant par ailleurs C1-C3-alkyle-thio-C2-C4-alkyle ou alors hydroxy-, amino ou sulfo-C1-C3-alkyle-thio-C2-C4 alkyle; avec les conditions que R1, R2 et R5 ne peuvent simultanement signifier ethyle, R1 et R2 ne peuvent signifier en meme temps methyle, lorsque R3 ou R5 signifie butyle ou di(C1-C2-alkyle)-amino-ethyle, et la somme des atomes de carbone, d'oxygene, d'azote et de soufre des chaines laterales liees aux atomes d'azote de l'heterocycle etant au total au moins 6, ou au moins 5, lorsque R2 signifie isobutyle. Ces composes presentent une forte activite bronchospasmolytique, un effet inhibiteur sur la phosphodiesterase et un effet retinotrope. Ces composes ameliorent les proprietes rheologiques du sang et en fait la circulation sanguine peripherique. Ces composes se pretent donc a la preparation de medicaments. L'on decrit, par ailleurs, des procede de preparation de ces nouveaux composes.
EP19820901506 1981-04-22 1982-04-20 NOUVEAUX DERIVES DE LA PYRAZOLO(3,4-d)PYRIMIDINE, PROCEDE DE LEUR PREPARATION ET REMEDE LES CONTENANT Withdrawn EP0077372A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH2621/81 1981-04-22
CH262181 1981-04-22
CH187282 1982-03-26
CH1872/82 1982-03-26

Publications (1)

Publication Number Publication Date
EP0077372A1 true EP0077372A1 (fr) 1983-04-27

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EP19820901506 Withdrawn EP0077372A1 (fr) 1981-04-22 1982-04-20 NOUVEAUX DERIVES DE LA PYRAZOLO(3,4-d)PYRIMIDINE, PROCEDE DE LEUR PREPARATION ET REMEDE LES CONTENANT
EP82103302A Withdrawn EP0063381A1 (fr) 1981-04-22 1982-04-20 Pyrazolo(3,4-d) pyrimidines, procédé pour leur préparation et compositions pharmaceutiques les contenant

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EP (2) EP0077372A1 (fr)
JP (1) JPS58500966A (fr)
WO (1) WO1982003626A1 (fr)

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IL130968A (en) * 1999-07-15 2002-12-01 Shmuel Simon Pharmaceutical composition comprising sildenafil or its analogs, useful for the treatment of tinnitus and hearing loss
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JP6549040B2 (ja) 2013-02-17 2019-07-24 イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． 新規使用
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