WO1988000192A1 - PYRAZOLO[4,3-d]PYRIMIDINE-7-ONES SUBSTITUEES EN POSITION 5 - Google Patents

PYRAZOLO[4,3-d]PYRIMIDINE-7-ONES SUBSTITUEES EN POSITION 5 Download PDF

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Publication number
WO1988000192A1
WO1988000192A1 PCT/US1987/001411 US8701411W WO8800192A1 WO 1988000192 A1 WO1988000192 A1 WO 1988000192A1 US 8701411 W US8701411 W US 8701411W WO 8800192 A1 WO8800192 A1 WO 8800192A1
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Prior art keywords
compound
compounds
pyrimidin
formula
hydroxy
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PCT/US1987/001411
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English (en)
Inventor
Harriet Wall Hamilton
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Warner-Lambert Company
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Publication date
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Publication of WO1988000192A1 publication Critical patent/WO1988000192A1/fr

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    • 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

  • the present invention provides novel 5-substituted p ⁇ razolo[4,3-d]pyrimidin-7-one compounds.
  • the invention also relates to novel compositions and methods of use for the novel 5-substituted pyrazolo[4,3-d]pyrimidin-7-one compounds disclosed herein.
  • the compositions are novel compounds have highly advantageous A1 and A2 adenosine receptor affinity and thus function as adenosine antagonists or adenosine receptor agonists.
  • the present invention is also such compounds in pharmaceutical compositions for use in the treatment of cardiovascular disorders, anxiety, asthma, allergy and as cognition activators and methods of treating mammals including humans in need of the treatment by administering an amount of such compounds effective for the treatment.
  • the present invention relates to a novel compound of the formula (I)
  • R 1 and R 3 are the same or different and are lower alkyl, optionally substituted by hydroxy
  • R' and R" may be the same or different and are hydrogen or lower alkyl; or lower alkenyl, optionally substituted by hydroxy, CF 3 , or NR'R" wherein R' and R" is as defined above;
  • R 5 is wherein n is an integer of 2-6 ;
  • g and y are the same or different and are integers of from 0-6 with the proviso that together q and y are of from 3-5;
  • X is oxygen, sulfur or NR 6 .
  • the present invention also relates to a pharmaceutical compositon for treating cardiovascular disorders, anxiety, allergy, asthma, or cerebral insufficiency comprising a cardiotonic, CNS stimulative, antiallergy, antiasthma or cognition activator effective amount of a compound of the above formula I with a pharmaceutically acceptable carrier and to a method of treating mammals, including humans, by administering to such mammals having a need for the treatment an effective amount of a compound of formula I as defined above.
  • lower alkyl is a carbon chain of from one to six carbons, inclusive, and means a straight or branched chain, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, or isomers thereof.
  • lower alkenyl is an unsaturated carbon chain of from two to six carbons, inclusive and means a straight or branched chain, such as, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and isomers thereof.
  • the compounds of formula I are useful both in the free base form, in the form of base salts where possible, and in the form of acid addition salts.
  • the three forms are within the scope of the invention.
  • use of the salt form amounts to use of the base form.
  • Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as methanesulfonic acid, and the like, giving the hydrochloride, sulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, respectively or those derived from bases such as suitable organic and inorganic bases.
  • suitable inorganic bases for the formation of salts of compounds of this invention include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like.
  • Salts may also be formed with suitable organic bases.
  • Bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form such salts. These organic bases form a class whose limits are readily understood by those skilled in the art.
  • the class may be said to include mono-, di-, and trialkyl- amines, such as methylamine, dimethylamine, and triethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine; amino acids such as arginine, and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl)aminomethane; and the like.
  • mono-, di-, and trialkyl- amines such as methylamine, dimethylamine, and triethylamine
  • mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine
  • amino acids such as arginine, and lysine
  • guanidine N-methylglucosamine; N-methylglucamine; L-
  • the acid addition salts of said basic compounds are prepared either by dissolving the free base of compound I in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid or base and isolating the salt by evaporating the solution, or by reacting the free base of compound I with an acid as well as reacting compound I having an acid group thereon with a base such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the compounds of the invention may contain an asymmetric carbon atom.
  • the invention includes the individual stereoisomers, and the mixtures thereof.
  • the individual isomers may be prepared or isolated by methods known in the art.
  • R 1 , R 3 and R 5 are as defined above.
  • the compounds of formula I can be prepared by the following step:
  • the salts of compounds of formula I described above are prepared by reacting the appropriate base with a stoichiometric equivalent of the acid compounds of formula I, or of the appropriate acid with compounds of formula I having a base moiety.
  • the compounds of this invention may also exist in hydrated or solvated form.
  • the compounds of formula I have been found to have advantageous receptor affinities, particularly Al receptor affinities providing activity as bronchodilators, CNS stimulants, antifibrillators and/or cognition activators.
  • the compounds of formula I are useful in treating symptoms in mammals including humans associated with desirable effects recognized as stimulation of the central nervous system, reversing bronchoconstriction, stimulation of the cardiac system, action of cardiotonic agents or treating allergies.
  • a physician or veterinarian of ordinary skill readily determines a subject who is exhibiting symptoms responding to such desirable effects.
  • the compounds of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.
  • the compounds can be administered in such oral unit dosage forms as tablets, capsules, pills, powders, or granules. They also may be administered rectally, vaginally in such forms as suppositories or bougies: they may also be introduced parenterally (e.g., subcutaneously, intravenously, or intramuscularly), using forms known to the pharmaceutical art. They are also introduced directly to an affected area, (e.g., by inhalation). In general, the preferred route of administration is orally. An effective quantity of the compound is employed in treatment.
  • the dosage regimen for preventing or treating the symptoms as described above by the compounds of this invention is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the mammal, the severity of the symptoms, the route of administration, and the particular compound employed. An ordinarily skilled physician or veterinarian will readily determine and prescribe the effective amount to prevent or arrest the progress of the condition having the symptoms as described herein.
  • Daily dosages of the compounds of the invention are ordinarily in the area of 0.1 mg/kg up to at least 100 mg/kg per dose orally, preferably 1 to 50 mg/kg orally and are given from one to four times daily or as needed. When other forms of administration are employed equivalent doses are administered. When dosages beyond 200 mg/kg are employed, care should be taken with each subsequent dose to monitor possible toxic effects.
  • the pellet is resuspended in 20 ml Tris-HCl buffer containing two International Units/ml of adenosine deaminase (Sigma type III from calf intestinal mucosa), incubated at 37°C for 30 minutes, then subsequently at 0°C for ten minutes. The homogenate is again centrifuged, and the final pellet is resuspended in ice-cold 0.05 M Tris-HCl buffer pH 7.7 to a concentration of 20 mg/ml original wet tissue weight and used immediately.
  • Tris-HCl buffer containing two International Units/ml of adenosine deaminase (Sigma type III from calf intestinal mucosa)
  • Tissue homogenate (10 mg/ml) is incubated in 0.05 M Tris-HCl buffer pH 7.7 containing 1.0 nM [ 3 H]-N6-cyclohexyladenosine ([ 3 H]-CHA) with or without test agents in triplicate for one hour at 25°C. Incubation volume was 2 ml. Unbound [ 3 H]-CHA is separated by rapid filtration under reduced pressure through Whatman glass fiber (GF/B) filters. The filters are rinsed three times with 5 ml of ice-cold 0.05 M Tris-HCl buffer pH 7.7.
  • GF/B Whatman glass fiber
  • the radio-labeled ligand retained on the filter is measured by liquid scintillation spectrophotometry after shaking the filters for one hour or longer on a mechanical shaker in 10 ml of Beckman Ready-Solv HP scintillation cocktail.
  • Nonspecific binding is defined as the binding which occurs in the presence of 1 mM theophylline.
  • concentration of test agent which inhibited 50% of the specific binding (IC 50 ) is determined by nonlinear computer curve fit.
  • the Scatchard plot is calculated by linear regression of the line obtained by plotting the amount of radioligand bound (pmoles/gram of tissue) versus
  • free radioligand is defined as the concentration of (nM) of radioligand added to the incubation mixture.
  • the Hill coefficient is calculated by linear regression of the line obtained by plotting the log of the bound radioligand vs the log of the
  • Brains from 200-500 g mixed sex Sprague-Dawley rats are purchased from Pel-Freez (Rogers, Arkansas). Fresh brains from male Long-Evans hooded rats (Blue Spruce Farms, Altamont, NY) give essentially identical results. Brains are thawed and then kept on ice while the striata are dissected out. Striata are disrupted in 10 vol of ice-cold 50 mM Tris.HCl (pH 7.7 at 25°C, pH 8.26 at 5°C) (Tris) for 30 seconds in a Polytron PT-10 (Brinkman) at setting 5.
  • Tris.HCl pH 7.7 at 25°C, pH 8.26 at 5°C
  • the suspension is centrifuged at 50,000 x g for ten minutes, the supernatant discarded, the pellet resuspended in 10 vol ice-cold Tris as above, recentrifuged, resuspended at 1 g/5 ml, and stored in plastic vials at -70°C (stable for at least six months).
  • tissue is thawed at room temperature, disrupted in a Polytron, and kept on ice until used.
  • N6-cyclopentyl- adenosine can be stored at -20°C for several months.
  • Test compounds are dissolved at 10 mM in dimethylsulfoxide on the same day as the experiment, and diluted in dimethylsulfoxide to 100x the final incubation concentration.
  • Control incubations receive an equal volume (10 ⁇ l) of dimethylsulfoxide; the resulting concentration of dimethylsulfoxide does not affect binding.
  • [ 3 H]NECA is diluted to 40 nM in Tris.
  • the membrane suspension (5 mg/0.79 ml) contained sufficient MgCl 2 and adenosine deaminase to give 10 mM and 0.1 units/ml, respectively, final concentration in the incubation.
  • test compounds with IC 50 values less than 1 ⁇ M the order of additions is test compound (10 ⁇ l), N6-cyclopentyl- adenosine (100 ⁇ l), [ 3 H]NECA (100 ⁇ l), and membranes (0.79 ml).
  • test compounds with IC 50 values greater than 1 ⁇ M and limited water solubility the order of additions (same volumes) is test compound, membranes, N6-cyclopentyladenosine, and [ 3 H]NECA.
  • the rack of tubes is vortexed, and the tubes are then incubated for 60 min at 25°C in a shaking water bath. The rack of tubes is vortexed an additional time halfway through the incubation.
  • Incubations are terminated by filtration through 2.5 cm GF/B filters under reduced pressure.
  • Each tube is filtered as follows: the contents of the tube are poured on the filter, 4 ml of ice-cold Tris are added to the tube and the contents poured onto the filter, and the filter is washed twice with 4 ml of ice-cold Tris. The filtration is complete in about twelve seconds. Filters are put in scintillation vials, 8 ml of Formula 947 scintillation fluid added, and the vials left overnight, shaken, and counted in a liquid scintillation counter at 40% efficiency.
  • Nonspecific binding is defined as binding in the presence of 100 ⁇ M N6-cyclopentyladenosine, and specific binding is defined as total binding minus nonspecific binding.
  • the IC 50 is calculated by weighted nonlinear least squares curve-fitting to the mass-action equation.
  • T is cpm total binding without drug
  • Weighting factors are calculated under the assumption that the standard deviation was proportional to the predicted value of Y. Nonspecific binding is treated as a very large (infinite) concentration of drug in the computer analysis.
  • IC 50 values (nM) for adenosine A 1 and A 2 receptor affinity are reported in the Table I.
  • the above compounds may be compared to theophyline which binds the A 1 receptor at an IC 50 of 15000 nM and the A 2 receptor at an IC 50 of 32000 nM.
  • the purpose of this test is to identify drugs which antagonize the locomotor suppressant effects of A 1 and A 2 selective adenosine agonists in mice.
  • Adenosine agonists produce inhibition of spontaneous exploratory activity in mice. This response has been demonstrated with the A 1 selective adenosine agonist CPA and the A 2 selective agonist CV-1808.
  • the standard adenosine antagonist theophylline is active in this procedure by reversing the suppressant effects of both adenosine agonists.
  • the procedure employs naive animals obviating the need for extensive training and precluding possible cumulative drug effects.
  • Animals Male Swiss-Webster mice are used for this procedure. A minimum of 12 animals are used per dose including vehicle treated controls.
  • Drugs Compounds are dissolved or suspended in physiological saline containing Emulphor, 2 - 5%.
  • Suspensions are ultrasonicated for 3 minutes. Drug doses are expressed as the active moiety and are administered intraperitoneally (IP) to mice in volumes of 10 ml/kg.
  • IP intraperitoneally
  • a 1 agonist and CV-1808, 2-anilinoadenosine, (A 2 agonist), are injected IP one hour before locomotor testing in respective doses of 2 and 8 mg/kg.
  • the potential adenosine antagonist is injected 30 minutes before testing at the maximum dose which by itself has little or no effect on mouse locomotor activity.
  • mice treated mice used as an indication of base level locomotion
  • a reference control a group of mice dosed with the antagonist alone to confirm the lack of locomotor response
  • a positive control a group of mice dosed with the agonist alone to demonstrate the inhibition of locomotion.
  • Data Analysis Drug effects on locomotor activity are expressed as percent suppression relative to the vehicle treated (placebo) controls.
  • the locomotor effect produced by the combination of agonist and antagonist (C) substrated from the locomotor suppressant effect of the agonist alone (B) is divided by the value for the agonist (B) and then multiplied by 100 to express the percent reversal.
  • C Theophylline, 10 mg/kg, alone produced locomotor stimulation (160% of placebo controls or -60% suppression).
  • CPA 2 mg/kg, alone produced 94% suppression of locomotion.
  • the dose of theophylline selected produced a significant effect on locomotion (160% relative to control). This dose was selected on the basis of previous results which indicated little or no effect of 10 mg/kg. It is not uncommon to see variation in the locomotor effect of doses which are bordering on profound pharmacological responses, e.g., 30 mg/kg of theophylline on previous testing had produced marked stimulation (200% of control) while 10 mg/kg had produced 118% of control. In light of this possible variation in the locomotor response to the antagonist it is deemed important that the effect of the antagonist alone is shown in order to facilitate understanding how a reversal effect can be more than 100%.
  • the present invention also includes a pharmaceutical composition for treating hypertension and a method for treating hypertension comprising administering to mammals, including humans, suffering therefrom either orally or parenterally the corresponding pharmaceutical composition.
  • the composition contains a compound of the formula I or the formula Ila each as defined above in appropriate unit dosage form.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium sterate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternately, sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon, or other volumetric container. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition.
  • the solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the liquid utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol, and the like as well as mixtures thereof. Naturally, the liquid utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these in packaged form.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from 0.1 mg to 500 mg preferably to 1 to 100 mg according to the particular application and the potency of the active ingredient.
  • the compositions can, if desired, also contain other compatible therapeutic agents.
  • the mammalian dosage range for a 70 kg subject is from 0.1 to 150 mg/kg of body weight per day or preferably 1 to 100 mg/kg of body weight per day.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.
  • Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The operation of this invention is further elaborated, but not limited, by the representative example below.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouvelles pyrazolo(4,3-d)pyrimidine-7-ones substituées en position 5 de formule (I) dans laquelle R1 et R3 représentent un alkyle éventuellement substitué par hydroxy, CF3 ou NR'R''; un alkényl inférieur éventuellement substitué par hydroxy, CF3, ou NR'R''; et R5 est représenté par la formule (2) dans laquelle n est un nombre entier compris entre 2 et 6; ou la formule (3) dans laquelle q et y sont des nombres entiers compris entre 0 et 6 à condition que leur somme soit comprise entre 3 et 5; et X représente l'oxygène, le soufre ou NR6. Procédés et compositions pharmaceutiques ayant une activité comme agents cardiotoniques, anti-allergiques, de stimulation CNS, anti-asthmes ou d'activation de la connaissance.
PCT/US1987/001411 1986-06-26 1987-06-08 PYRAZOLO[4,3-d]PYRIMIDINE-7-ONES SUBSTITUEES EN POSITION 5 WO1988000192A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87924086A 1986-06-26 1986-06-26
US879,240 1986-06-26

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WO1988000192A1 true WO1988000192A1 (fr) 1988-01-14

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294612A (en) * 1992-03-30 1994-03-15 Sterling Winthrop Inc. 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof
US5565566A (en) * 1987-04-24 1996-10-15 Discovery Therapeutics, Inc. N6 -substituted 9-methyladenines: a new class of adenosine receptor antagonists
US5656629A (en) * 1995-03-10 1997-08-12 Sanofi Winthrop, Inc. 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
US5736548A (en) * 1995-03-10 1998-04-07 Sanofi 6-aryl pyrazolo 3,4-D! pyrimidin-4-ones and compositions and method of use thereof
WO1999067243A1 (fr) * 1998-06-22 1999-12-29 Arzneimittelwerk Dresden Gmbh Pyrazolo(3,4-d)pyrimidines a action anticonvulsive et antiallergique/antiasthmatique
EP2668102B2 (fr) † 2011-01-27 2022-12-14 GEA Food Solutions Germany GmbH Machine d'emballage pour la preparation du conditionnements évacués

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3939161A (en) * 1973-10-29 1976-02-17 Abbott Laboratories 1,3-Dimethyl- 1H-pyrazolo(4,3-D) pyrimidine-7 (6H)-ones
EP0095289A2 (fr) * 1982-05-24 1983-11-30 Warner-Lambert Company Imidazo(1,2-c)pyrazolo(3,4-e)pyrimidines et leur préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3939161A (en) * 1973-10-29 1976-02-17 Abbott Laboratories 1,3-Dimethyl- 1H-pyrazolo(4,3-D) pyrimidine-7 (6H)-ones
EP0095289A2 (fr) * 1982-05-24 1983-11-30 Warner-Lambert Company Imidazo(1,2-c)pyrazolo(3,4-e)pyrimidines et leur préparation

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565566A (en) * 1987-04-24 1996-10-15 Discovery Therapeutics, Inc. N6 -substituted 9-methyladenines: a new class of adenosine receptor antagonists
US5294612A (en) * 1992-03-30 1994-03-15 Sterling Winthrop Inc. 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof
US5541187A (en) * 1992-03-30 1996-07-30 Sterling Winthrop Inc. 6-heterocycyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compositions and method of use thereof
US5656629A (en) * 1995-03-10 1997-08-12 Sanofi Winthrop, Inc. 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof
US5736548A (en) * 1995-03-10 1998-04-07 Sanofi 6-aryl pyrazolo 3,4-D! pyrimidin-4-ones and compositions and method of use thereof
US5958929A (en) * 1995-03-10 1999-09-28 Sanofi 6-aryl pyrazolo 3,4-d! pyrimidin-4-ones and compositions and methods of use thereof
WO1999067243A1 (fr) * 1998-06-22 1999-12-29 Arzneimittelwerk Dresden Gmbh Pyrazolo(3,4-d)pyrimidines a action anticonvulsive et antiallergique/antiasthmatique
US6054460A (en) * 1998-06-22 2000-04-25 Arzneimittelwerk Dresden Gmbh Anticonvulsive and antiallergic/antiasthmatic pyrazolo-[3,4-d]pyrimidines, and process for preparing
EP2668102B2 (fr) † 2011-01-27 2022-12-14 GEA Food Solutions Germany GmbH Machine d'emballage pour la preparation du conditionnements évacués

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