IL42562A - Pharmaceutical compositions containing 3-amino-pyrazol-5-ones - Google Patents

Pharmaceutical compositions containing 3-amino-pyrazol-5-ones

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Publication number
IL42562A
IL42562A IL42562A IL4256273A IL42562A IL 42562 A IL42562 A IL 42562A IL 42562 A IL42562 A IL 42562A IL 4256273 A IL4256273 A IL 4256273A IL 42562 A IL42562 A IL 42562A
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Israel
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amino
pyrazol
compound
active ingredient
salt
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IL42562A
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IL42562A0 (en
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Bayer Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/52—Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

1391052 Pyrazolone derivatives BAYER AG 22 June 1973 [23 June 1972] 29786/73 Heading A5B A pharmaceutical composition contains as an active ingredient a compound which is a 3-amino-pyrazol-5-one of general formula: or its salt in which R is an aryl radical which carries either no substituents or the following substituents, (a) 1, 2 or 3 identical or different substituents selected from halogen, trifluoromethyl, alkyl, phenyl, alkoxy, and alkenoxy groups; or (b) one alkylamino, dialkylamino, trifluoromethoxy, nitro, nitrile, carbonamido, sulphonamido or SO n -Alkyl (n=0, 1 or 2) group and optionally also 1 or 2 substituents selected from alkyl, alkoxy, halogen and trifluoromethyl groups; or (c) an annellated branched or unbranched, saturated or unsaturated 5-, 6- or 7-membered-isocyclic or heterocyclic ring (which latter ring can optionally contain 1 or 2 oxygen andlor sulphur atoms) in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface active agent. The active ingredient may be in the form of its sodium, potassium, ethanolamine, diethanolamine, triethanolamine, amino-tris-hydroxymethyl-methane, glucosamine or N-methyl-glucosamine salt. The compound may be used in the form of a sterile or isotonic solution. It may also be used with or without a diluent, as a medicament and in the form of tablets, pills, dragees, capsules, ampoules or suppositories. Suitable compounds exemplified are 3-aminol-(4-chlorobenzyl)-pyrazole- 5 - one, 3-amino- 1-(4-bromobenzyl)-pyrazol-5-one and 3-amino- 1-(3, 4-dimethylbenzyl)-pyrazol-5-one. [GB1391052A]

Description

42562/2 0»3ii5-5- TNTs-i3,»23K-»3 a* »3»n o»'iiann o'T»©an P arniac eutical eonpceitons containing 3- wiin©* BilYER AETIEHGE3ELLSCHAFT 0· 40590 42562/2 The present invention relates to the medicinal use of certain l-substituted 3-amino-pyrazol-5-one compounds especially as diuretics, saluretics and anti-hypertensive agents. l-Aryl-3-amino-pyrazo-5-ones have already "been disclosed as colour-coupling agents for colour photography (A. Weiss-berger et al. , J. Am. Chem. Soc. 6., 2133 (1942).
Furthermore, some 3-aniinopyrazo-5-ones have also been used as intermediate products in the manufacture of colour coupling agents (British Patent 599,919; U.S. Patent 2,367,523; U.S. Patent 2,376,380; U.S. Patent 2,511,231; U.S. Patent 2,600,788; U.S. Patent 2,619,419; U.S. Patent 2,672,417).
Their use as drugs, especially as diuretics and antihypertensive agents, is new and has not hitherto been disclosed.
The invention thus provides new pharmaceutical compositions containing as active ingredients 3-amino-pyrazol-5-one compounds of the following general formula or salts thereof in which H is a naphthyl radical optionally substituted by halogen or phenyl radical which carries either no substituents or the following substituents: (a) 1, 2 or 3 identical or different substituents selected from halogen, Irifluoromethyl, lower alkyl, lower aUoxy and phenyl; or (b) one trifluoromethoxy, nitro or cyano; or meth lenedioxy group; in admixture with a solid or liquified gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except, in the presence of a surface-active agent.
A preferred form of the pharmaceutical composition according to the invention, especially adapted for parenteral administration, is a pharmaceutical composition containing as an active ingredient a compound as defined above in the form of a sterile or isotonic aqueous solution.
The present invention also provides a medicament in dosage unit form (as defined "below) comprising a compound as defined above either alone or in admixture with a diluent.
Particular forms of the medicament of the invention are •tablets, pills, dragees, capsules, ampoules and suppositories conprising a compound as defined above either atone or in admixture with a diluent.
The invention further provides a method of combatting (including prevention, relief and cure of) circulatory and saline metabolic disturbances in human and non-human animals which comprises administering to the animals a compound of the invention either alone or in admixture with a diluent or in the form of a medicament according to the invention, Details and further preferred features of the pharmaceutical compositions, medicaments in dosage unit form and method according to the invention are given below.
Throughout the remainder of this specification the term "compound of the invention" means a compound which is a 1- subatituted-3-amino-pyrazol-5-one of the general formula I Le A 14 99-RTF. -3- given above or its salt.
The compounds of the invention exhibit tautomeriem. They can exist not only with the preferred structure given above as general formula I but also with the following tautomeric structures: The invention extends to the 3-amino-pyrazol-5-ones defined above in any of these tautomeric forms and in the forms of mixtures of two or more of these forms.
Surprisingly, the compounds of the invention display strong diuretic, saluretic and anti-hypertensive effects.
Hitherto, pharmaceutical effects, especially diuretic, saluretic and anti-hypertensive effects, have not been disclosed for the 3-amino-pyrazolones known from the state of the art. In respect of these special pharmaceutical effects, the compounds of the invention represent a novel class of substances and are therefore to be regarded as an enrichment of pharmacy.
The 3-amino-pyrazol-5-ones to be used according to the invention are accurately defined by the formula (I).
In the general formula (I), R is preferably a phenyl, naphthyl or halonaphthyl radical, the phenyl radical carrying as subetituent(s) (a) 1 , 2 or 3 straight or branched-chain alkyl radicals with up to 8 carbon atoms each; or 1 , 2 or 3 straight or branched-chain alkoxy radicals with up to 6 carbon atoms; or 1 , 2 or 3 halogen atoms; or 1 or 2 trifluoro- methyl radicals; or (c) an annellated, branched or unbranched, oalurutod or nnnntnrnfd, 5, 6 or 7-membered ring as defined above.
The majority of the active compounds of the invention are" new. They can be produced in a simple manner by reacting a hydrazine of the general formula:- R-CH2-NH- H2 (II) with an acetic acid derivative of the general formula:- CH-COX (III) thermally or in the presence of a basic or acid oondeneatloa catalyst. If in the reaction of (II) with (III) an amidrazone of the formula:- is formed it may be isolated and cyclized in the presence of a basic condensation catalyst.
In the general formulae (II), (III) and (IV) given above R ie as defined above; X is a hydroxyl, alkoxy, aralkoxy, amino or alk lamino radical; and either (a) Y' is a hydrogen atom and Y" is a cyano group; or (b) Y* and Yw together represent the group:- =C £ ^Y [in which Y is an alkoxy, aryloxy, aralkoxy, alkylthio or aralkylthio radical or an amino group].
The reaction can be carried out in one stage [i.e. without intermediate isolation of the amidrazone of general formula (IV)] or in two stages. The single-stage procedure is preferred. The reaction is conveniently carried out in the presence of an inert solvent and an acidic or basic catalyst, at 20-100°C. Suitable acidic catalysts include hydrohalic acids, sulphuric acid, and sulphonic acids; suitable basic catalysts include alkali metal and alkaline earth metal hydroxides and carbonates. For more details of the process, the reader is referred to our copending application of even date, - 42560 /73 (LeA 14440). The principles and reaction conditions for the preparative process described and claimed in this copending application apply generally to the above-described method of preparing the compounds used in the present invention.
The following may be mentioned as examples of the active compounds of the invention: 3-amino-l-benzyl-pyrazol-5-one , -amino-1-( -chlorobenzyl)-pyrazol-5-one, 3-amino-l-(3-chlorobenzyl)-pyrazol-5-one, 3-amino-l-(2-chlorobenzyl)-pyrazol-5-one, 3-amino-l-(3» -dichlorobenzyl)-pyrazol-5-οηβ, 3-amino-l-(2, 4-dichlorobenzyl)-pyrazol-5-one, 3-amino-l-(2 , 5-dichlorobenzyl)-pyrazol-5-one, 3-amino-l-(2 , 6-dichlorobenzyl)-pyrazol-5-one, 3-amino-(3 » 5-dichlorobenzyl)-pyrazol-5-one, 3-amino-l-(3 »4, 5-trichlorobenzyl)-pyrazol-5-one, 3-amino-l-(4-fluorobenzyl)-pyrazol-5-one, 3-amino-l-(4-bromobenzyl)-pyrazol-5-one, 3-amino-l-(4-chloro-3-bromobenzyl)-pyrazol-5-one, 3-amino-l-(4-fluoro-3-chlorobenzyl)-pyrazol-5-one , 3-amino-l-(3» 4-dibromobenzyl)-pyrazol- -one, 3-amino-l-( -bromo-3-chlorobenzyl)-pyrazol-5-one, 3-amino-l-(4-fl oro-3-bromobenzyl)-pyrazol-5-one, 3-amino-l-(4-me hylbenzyl)-pyrazol-5-one, 3-amino-l-(4-methyl-3-chlorobenzyl)-pyrazol-5-one, 3-amino-l-(4-ethylbenzyl)-pyrazol-5-one, 3-amino-l-(4-chloro-3-nieth lbenzyl)-pyrazol-5-one, 3-amino-l-(4-fl oro-3-me hylbenzyl)-pyrazol-5-one , 3-amino-l-(4-t-butylbenzyl)-pyrazol-5-one , 3-amino-l-(2-chloro-3-niethylbenzyl)-pyrazol-5-onef 3-amino-l-(3-chloro-5-niethylbenzyl)-pyrazol-5-one, 3-amino-l-(3-bromo-5-methylbenzyl)-pyrazol-5-one, 3-amino-l-(3, -dimethylbenzyl)-pyrazol-5-one, 3-amino-l-(4-propyl-3-chlorobenzyl)-pyrazol-5-one, 3-amino-l-(4-bromo-3-methyl-benzyl)-pyrazol-5-one, 3-amino-l-(3»4i 5-trimeth lbenzyl)-pyrazol-5-one, 3-amino-l-(4-phenylbenzyl)-pyrazol-5-one, 3-amino-l-(3-phenylbenzyl)-pyrazol-5-one, 3-amino-l-(3-phenyl-4-chlorobenzyl)-pyrazol-5-one, 3-amino-l-(4-phenyl-3-meth lbenzyl)-pyrazol-5-one, 3-amino-l-(4-trifluoromethylbenzyl)-pyrazol-5-one, 3-amino-l-(3-trifluoromethylbenzyl)-pyrazol-5-one , 3-amino-l- 4-chloro-3-trifluoromethylbenzyl)-pyrazol-5: one, 3-amino-l- 3-chloro-4-trifluoromethylbenzyl)-pyrazol-5-one, 3-amino-l- 4-fluoro-3-trifluoromethylbenzyl)-pyrazol-5-onef 3-amino-l- 4-bromo-3-trifluoromethylbenzyl)-pyrazol-5-one, 3— min -1- 3-chloro-5-trifluoromethylbenzyl)-pyrazol-5-one, 3-amino-l- 4-trifluoromethyl-3-methylbenzyl)-pyrazol-5-one, 3-amino-1- 4-meth l-3-trifluoromethylbenzyl)-pyrazol-5-one, 3-amino-l- 3.4-dimethylbenzyl)-pyrazol-5-one , 3-amino-l- 2. -dimethylbenzyl) -pyrazol-5-one, 3-amino-l- 3 ,4-trimethylenebenzyl)-pyrazol-5-one, 3-amino-l- 3,4-tetramethylenebenzyl)-pyrazol-5-one, 3-amino-l- 3,4-tetramethylene-5-chlorobenzyl)-pyrazol-5-one, 3-amino-l- 4-methoxybenzyl)-pyrazol-5-one, 3-amino-l- 3 ,4-dimethoxybenzyl)-pyrazol-5-one , 3-amino-l- 314-meth lenedioxybenzyl)-pyrazol-5-one , 3-amino-l- 3-chloro-4-methoxybenzyl)-pyrazol-5-one, 3-amino-l- 4-chloro-3-methoxy-benzyl)-pyrazol-5-one» 3-amino-l- 4-meth 1-3-methoxybenzyl)-pyrazol-5-one, 3-amino-l- 3-methoxybenzyl)-pyrazol-5-one, 3-amino-l- 4-ethoxybenzyl)-pyrazol-5-onet 3-amino-l- 4-propoxybenzyl)-pyrazol-5-one, 3-amino-l- 4-methoxy-3-me hylbenzyl)-pyrazol- -one» 3-amino-l- 4-nitrobenzyl)-pyrazol-5-one , -amino- 1 - ( 4-nitrobenzyl)-pyrazol-5-one> -amino-l-(3-nitrobenzy1)-pyrazol-5-one, -amino-l-(2-methoxybenzyl)-pyrazol- -one , -amino-l-(2-methoxy-6-methylbenzyl)-pyrazol-5-one, -ainino-l-(2-methoxy-6-chlorobenzyl)-pyrazol-5-one, -amino-l-(2-nitro-6-me hylbenzyl)-pyrazol-5-one, -amino-l-(4-cyanobenzyl)-pyrazol-5-one, -amino-1 -(naphthyl-( 1 )-meth l)-pyrazol-5-one , -amino-1 -(naphthyl-(2 )-methyl)-pyrazol-5-one , -amino-l -( 3-chloro-naphthyl-(2)-methyl)-pyrazol-5-one f - - 3-amino-l-(5 ,6-dichloro-nap th l-(2)-methyl)-pyrazol-5-one, 3-amino-l-(6 ,8-dichloro-naphthyl-(2)-me hyl)-p razolone, 3-amino-l-(5-chloro-naphthyl-(2)-me hyl)-pyrazol-5-one, 3-amino-l-(3-ethyIbenzyl)-pyrazol-5-one , 3-amino-l-(3-n-propyIbenzyl)-pyrazol-5-one , 3-amino-l-(4-n-propyIbenzyl)-pyrazol-5-one, 3-amino-l-( 4-isopropyIbenzyl)-pyrazol-5-one, 3-amino-l-(4-n-butylbenzyl)-pyrazol-5-one , 3-amino-l-(3,4-diethyIbenzyl)-pyrazol-5-one, 3-amino-l-(2-phenyIbenzyl)-pyrazol-5-one, 3-amino-l-(8-chloronaphthyl-(2)-methyl)-pyrazol-5-one, 3-amino-l-(4- rifluoromethyl-3-chlorobenzyl)-pyrazol-5- one, 3-amino-l-(4-trifluoromethoxybenzyl)-pyrazol-5-one, 3-amino-l-(3-trifluoromethoxybenzyl)-pyrazol-5-one , 3-amino-l-(3-butoxybenzyl)-pyrazol-5-one, 3-amino-l-(3-chloro-4-butoxybenzyl)-pyrazol.5„onei ^ 42562/2 .For reasons which will appear below, the water-soluble salts of the compounds of the invention are especially useful. Among these, preferred examples are the sodium, potassium, ethanolamine , diethanolamine, triethanolamine , amino-tri-hydroxymethy1-methane, glucosamine and N-methylglucosamine salts.
When administered orally or parenterally the compounds of the invention cause a strong increase in the excretion of water and of salt and can therefore be used i>r the treatment of oedematous and hypertonic conditions and for flushing out toxic substances. In addition, the compounds of the invention can be used in case of acute renal failure.
As stated above, the present invention provides pharmaceutical compositions and medicaments in dosage unit form containing compounds of the invention.
"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete coherent portions suitable for medical administration each containing a daily dose or a multiple (up to four times) or sub-multiple (down to a fortieth) of a daily dose of the compound of the invention. Whether the medicament contains a daily dose or, for example, a half, a third, or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical compositions according to the invention ma for example, take the form of ointments els astes creams, sprays (including aerosols), lotions, suspensions, ^ solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders.
The diluents to "be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate ; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols.
The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned diluents.
The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high ester^ [e.g. O-^-alcohol with C^-fatty acid]) or mixtures of these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
The pharmaceu ical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils [for example ground nut oil], glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral use, solutions of the compounds of the invention can be employed, using suitable liquid excipients. A fact which has proved particularly advantageous for the case of parenteral use is that the compounds of the invention are able to form readily water-soluble salts. These salts are obtained if the compounds of the invention, in a suitable selvent, are combined with the equi- ' molecular amount of a non-toxic inorganic or organic base.
As examples of such bases there may be mentioned: sodium hydroxide solution, potassium hydroxide solution, ethanolamine die hanolamine, triethanolamine , amino-tris-hydroxymethyl-methane, glucosamine and N-methylglucosamine. Such salts can also possess increased importance for oral use of the compound according to the invention, in that they accelerate or retard the resorption, as desired. In addition to the salts already mentioned above, magnesium salts, calcium salts, aluminium salts and iron salts may also be mentioned as examples.
For parenteral admi istration, the solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium metahydroxide , bentonite, agar-agar and tragacanth or mixture thereof.
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin) The pharmaceutical compositions according to the invention preferably contain about 0.1 to 99· 5, more preferably from about 0.5 to 90 of the active ingredient by weight of the total composition.
In addition to a compound of the invention, the pharma- ceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.
Any diluent in the medioaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention. Such medicaments may include solvents of molecular weight less than 200 as sole diluent.
The discrete coherent portions constituting the medicament according to the invention (whether in dosage unit form or not) may be, for example, any of the following: tablets, (including lozenges and granules), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The preferred daily dose for parenteral administration of the medicaments of the invention is 0.5 mg - 4.5 g. , preferably 5 mg. - 900 mg. , of active ingredient; the preferred daily dose for peroral administration is 5 m . 45 g. , preferably 25 mg. - 9 g. » of active ingredient.
The production of the above-mentioned . harmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally or intravenously), rectally or locally, preferably parenterall or perorall . Preferred pharmaceutical compositions and medicaments are therefore J those adapted for parenteral and/or peroral administration, such as tablets, injectable solutions, and ampoules of injectable solutions. Administration in the method of the invention is preferably parenteral or peroral.
In general it has proved advantageous to administer amounts of from 0.01 to 50 mg/kg, preferably 0.1 to 10 mg/kg, of body weight per day parenterally, or 0.1 to 500 mg/kg, preferably 0.5 to 100 mg/kg per day perorally, in order to achieve effective results. Nevertheless, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal subject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is administered and the mode in which the administration is carried out, and the point in the progress of the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the above-mentioned minimum dosage rate, whilst other cases the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day.
The above disclosure applies equally to the uses in human and veterinary medicine of the compounds of the invention.
The pharmaceutical effects of some compounds of the invention are given by way of example below. The remaining compounds show comparable properties.
To demonstrate the diuretic and saluretic effect of the compounds, the compounds described below in Examples 1, 7 and 12 were administered to dogs and rats. 1. Experiment on Doge; a) Method Female beagle dogs received, on the day of the experiment, 1 ml/kg of a solution, which contained O.A" of NaCl and 0.2?o of KC1, given every 30 minutes by means of a probang. The urine formed in the first 60 minutes was discarded.
Thereafter the test preparation (containing 3-amino-1 -(4-chlorobenzyl)-pyrazol-5-one as described in Example 1 ) was administered orally in 0.5 mg/kg of 0.1ft strength tragacanth mucin and the urine was collected for 2 hours. The renal excretion in equivalent kg/2 hours was calculated from the volume of urine (ml/kg) and from the measured electrolyte concentration (mmol/l) . Sodium and potassium were determined by flame photometry and chloride was determined potentio-metrically. b) Results The results are shown in Table 1. The renal excretion of sodium and of water is considerably increased after oral administration of the test preparation. The effect depends on the dose. After 10 mg/kg, administered orally, the excretion of sodium is increased ten-fold compared to the treated control animals. On the other hand, the excretion of potassium is only doubled after this dose.
Table I Effect of 3-amino-1-(4-chlorobenzyl)-pyr perorally) on the renal excretion of ele awake dogs. Mean values and scatter fro 2. Experiment on Rate: a) Method Male SPF rats of the Wistar strain received 10 ml/kg of 0.1# strength tragacanth mucin by means of a probang. The test preparation (containing 3-amino-1 -(4-chlorobenzyl)-pyrazol-5-one as described in Example 1 ) was administered in mg/kg with this liquid. The animals were then placed in pairs in diuresis cages. The period of collection of urine lasted 5 hours. The collected urine was filtered and analysed chemically. b) Results.
The results of the experiments are shown in Table II. In rats, again, a dosage-dependent increase in the excretion of NaCl and water occurs after oral administration of the test preparation. As in the case of dogs, the excretion of sodium is substantially more strongly affected than the excretion of potassium.
Table II Effect of peroral administration of 3-amino-1-(4-chl 5-one on excretion of electrolyte and water by rats. scatter of groups of 16 animals. 3. Experiment on Rats: The effects of the compounds of Preparative Examples 7 and 12 (3-amino-1-(4-bromobenzyl)-pyrazol-5-one and 3-amino- 1-(3,4-dimethylbenzyl)-pyrazol-5-one respectively) were also tested on rats, using the method described in the preceding Experiment on Rats (2). The results of this test, carried out as illustration only, are shown in Tables HI and IV which follow.
Analogously to the test results of the compound of Preparative Example 1 , it must be assumed that the compounds of Examples 7 and 12 also show a distinctly stronger effect in dogs.
Table III Excretion of electrolyte and of water by rats after stration of the compound of Example 12. Mean values groups of 10 animals .
Table IV Excretion of electrolyte and of water by rats afte stration of the compound of Example 7. Mean value groups of 10 animals.
Preparative Examples Example 1 -Amino-1 -( -chlorobeiizyl)-pyrazol-5-one 174 g (10#excess) of P-amino^-ethoxyacrylic acid ethyl ester are introduced into 500 ml of ethanol. 156 g of 4-chlorobenzylhydrazine are added thereto whilst stirring.
In the course thereof, the temperature rises to 30 - 40°. The reaction mixture is stirred for a further 2 hours and is then left for 12 hours. Crystals which have separated out are filtered off, the solvent is driven off and the residue is taken up in water and rendered alkaline with 2 N NaOH. The aqueous alkaline phase is extracted with ether and the ether is discarded. The crystals already obtained from the reaction solution are dissolved in the phase containing sodium hydroxide and the solution is stirred for 30 minutes with animal charcoal and filtered. Introduction of C02 or acidification with dilute acetic acid yields the reaction product which is further purified by reprecipitating it once more or recrystallising it from alcohol. 138 g of the compound identified above as felted colourless needles of melting point 1 4° are obtained. (Yield: 62$ of theory) Example 2 3-Amino-1-(3-chlorobenzyl)-pyrazol -5-one CI 35 g ( 10 excess) of P-amino-P-ethoxyacrylic acid ethyl ester are introduced into 100 ml of ethanol. 32 g of 3-chlorobenzylhydrazine in 50 ml of ethanol are added whilst stirring. The mixture is worked up as above. 8.9 g of the compound identified above, as colourless felted needles of melting point 132° , are obtained.
(Yield: 2 of theory) Example 3 5-Amino- -( 2-chlorobenzyl)-pyrazol-5-one 35 g of p-amino-p-ethoxyacrylic acid ethyl ester and 32 g of 2-chlorobenzylhydrazine when reacted as described in Example 1 yield 17.5 g of the compound identified above as colourless crystals of melting point 153°.
(Yield: 40$ of theory) Example 4 3~Amino-1-(216-dichlorobenzyl)-pyrazol-5-one 35 g of p-amino-p-ethoxyacrylic acid ethyl ester and 8 g of 2 ,6-dichlorobenzylhydrazine when reacted as described in Example 1 yield 24 g of the compound identified above as colourless crystals, corresponding to 46?-· of theory, of melting point 225°.
Example 5 3-Amino-1 -(3.4-dichlorobenzyl)-pyrazol-5-one 1 4 g (10^ excess) of P-amino-p-methoxyacrylic acid methyl ester are introduced into 500 ml of dioxane. 191 g of 3,4-dichlorobenzylhydrazine are introduced into the reaction mixture whilst flushing with nitrogen. The mixture is stirred for 2 hours at 60°, the solvent is driven off on a rotary evaporator, the residue is worked with 600 ml of 2 N NaOH and extracted with1 ether, and the aqueous phase is stirred with animal charcoal for ■£· hour. After filtration, the mixture is adjusted to pH 5 with dilute acetic acid. The product which initially is obtained as an oil becomes crystalline on rubbing and is finally purified by recrystallising it again from alcohol. 139 g> corresponding to about 54$ of theory, of the compound identified above, as felted colourless needles of melting point 1 9° are obtained.
Example 6 3-Amino-1 -(4-bromobenzyl)-pyrazol-5-one 9.2 g of metallic sodium are dissolved in 200 ml of ethanol. A mixture of 25 g of cyanoacetic acid ethyl ester and 35 g of js-bromobenzylhydrazine in 50 ml of ethanol is then added at room temperature. The mixture is warmed to 60° for 2 hours, the substance which has precipitated is filtered off, and the filtrate is evaporated. The residue is taken up in water, the solution is thoroughly shaken with ether and the aqueous phase is acidified with dilute acetic acid. The crude product is purified by recrystallising it twice from alcohol. 17 g of the compound identified above as felted needles of melting point 139°, corresponding to 36$ of theory, are obtained .
Example 7 3-Amino-1 -(4-bromobenzyl)-pyrazol-5-one 17.5 g of -amino--ethoxyacrylic acid ethyl ester and 20 g of 4-bromobenzylhydrazine, on stirring for 5 hours in alcohol at 50° and working up as described in Example 1 , yield 15.6 g, corresponding to 58% of theory, of the compound identified above as colourless crystals of melting point 139°.
Example 8 -Amino-1 -( - luorobenzyl)-pyrazol-5-one 17.5 g of -amino--ethoxyacrylic acid ethyl ester and 13 g of 4-fluorobenzylhydrazine, on stirring for 5 hours in ethanol at 60° and working up as described in Example 1 yield 13.2 g of the compound identified above, as colourless crystals of melting point 148°, corresponding to 63 of theory.
Example 9 5-Amlno-1 -(3-fluorobenzyl)-pyrazol-5-one 17.5 g of β-aiTi ηο-β-ethoxyacrylic acid ethyl ester and 135 g of 3-fluorobenzylhydrazine , on stirring for 5 hours in ethanol at 60° and working up as described in Example 1 yield 11.3 g» corresponding to 55$ of theory, of the compound identified above, as colourless crystals of melting point 129° Example 10 3-Amino-1 -(4-methylbenzyl)-pyrazol-5-one 17.5 g of p-ajiiino-p-etholxyacrylic acid ethyl ester and 13.6 g of 4-methylbenzylhydrazlne are introduced into 75 ml of pyridine. The mixture is stirred for 8 hours at room temperature and the pyridine is driven off under reduced pressure. The residue is treated with a solution of 4.6 g of Na in 100 ml of ethanol and the mixture is warmed to 60° for 1 hour. The alcohol is driven off and the residue is taken up in 100 ml of water. The aqueous phase is extracted with ether clarified with charcoal and acidified. A yellow-coloured precipitate, which melts at 149° after recrystallisation from alcohol, is obtained. The yield is 7.3 g of the compound identified above, corresponding to 36 of theory.
Example 11 CH 4.6 g of Na are dissolved in 100 ml of ethanol. A mixture of 12 g of cyanoacetic acid ethyl ester and 13.6 g of 3-methylbenzylhydrazine is added to this solution. The mixture is heated to the boil for 5 hours whilst stirring and introducing Ν2· After driving off the solvent, taking up in water, extracting with ether, clarifying with animal charcoal and acidifying with acetic acid, the compound identified above is obtained as colourless crystals, which after a further re-crystallisation from ethanol melt at 92°. The yield is 10.3 g» corresponding to 5 $ of theory.
Example 12 3-Amino-1 -( .4-dimethylbenzyl)-pyrazol-5-one 17.5 g of p-amino-P-ethoryacrylic acid ethyl ester and 15 g of 314-dimethylbenzylhydrazine yield, analogously to the procedure described in Example 1 , 16 g of the compound identified above as colourless small needles of melting point 160°, corresponding to 74$ of theory.
Example 13 3-Amino-1 -(2.4-dimethylbenzyl)-pyrazol-5-one 17.5 g of ^-amino^-ethoxyacrylic acid ethyl ester and 15 g of 2,4-dimethylbenzylhydrazine yield, analogously to the procedure described in Example 1, 14.3 g of the compound identified above, corresponding to 66$ of theory, of melting point 151°.
Le A 14 199-RTF - 29 - Example 14 5-Amino- -(4-nitrobenzyl)-pyrazol-5-on 17.5 g of p-amino-P-ethoxyacrylic acid ethyl ester and 16.7 g of 4-nitrobenzylhydrazine yield, analogously to the procedure described in Example 1, 17.3 g of the compound identified above, as yellowish crystals of melting point 182°, corresponding to 74$ of theory.
Example 15 3-Amino-1 -( -nitrobenzyl)^pyrazol-5-one 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 16.7 g of 3-nitrobenzylhydrazine yield, analogously to the procedure described in Example 1, 12.3 g of the compound identified above, as yellow crystals of melting point 163°, corresponding to ¾6 of theory.
Example 16 3-Amino-1 -( -cyanobenzyl)-pyrazol-5-one NC-^CH^N^ ^ -H.0 17.5 g of p-amino--ethoxyacrylic acid ethyl ester and 4.7 g of 4-cyanobenzylhydrazine yield, analogously to the procedure described in Example 1, 11.3 g» corresponding to 49$ of theory, of colourless crystals which melt at 187° after drying in a drying tube. On reprecipitation or recrystallisa-tion from aqueous solvents, the compound identified above crystallises with one mol of water of crystallisation.
Example 17 3-Amino-1 -(3-trifluoromethylbenzyl)-pyrazol-5-one 4.6 g of Na are dissolved in 200 ml of ethanol. 42 g of β-aII-ino-β-et ylmerca toacrylic acid ethyl ester, as the hydrochloride, are introduced in the cold. 38 g of 4-tri-fluorobenzylhydrazine are then introduced into the mixture. The batch is stirred for 2 hours at 60° and is left to stand for 12 hours at room temperature. The solvent is distilled off, 200 ml of water and 200 ml of ether are added, the ether phase is separated off and the aqueous phase is acidified. The crude product is further purified by recrystallisatxon from alcohol. 33 g of the compound identified above, as felted needles of melting point 130° , corresponding to 63# of theory, are obtained.
Example 18 3-Amino-1 -(2.5-dichlorobenzyl)-pyrazol-5-one 32.8 g of β-εϋηηο-β-ethoxyacrylic acid ethyl ester and 1 g of j2-toluenesulphonic acid were dissolved in 120 ml of ethanol and 39 g of 2,5-dichorobenzylhydrazine were added under nitrogen. After stirring for 2 hours the mixture was left to stand overnight and the compound identified above, which precipitated, was filtered off and recrystallised from ethanol. Melting point: 195-196°C; yield: 23 g (43#).
Le A 14 199-RTP - 31 - Example 19 -Amino-1 -(3.5-dichlorobenzyl)-pyrazol-5-one After adding 1 g of jj-toluenesuiphonic acid to a solution of 49.6 g of p-amino-p-ethoxyacrylic acid ethyl ester in 220 ml of ethanol, 59 g of 3 , 5-dichlorobenzylhydrazine were added dropwise under nitrogen. The solution was left to stand overnight and the solids which precipitated melted at 175-176°C after recrystallisation from ethanol. Yield: 40 g (48$) of the compound identified above.
Example 20 3-Amino-1 -( 2.3-dichlorobenzyl)-pyrazol-5-one 16.7 g of β-amino-P-ethoxyacr lic acid ethyl ester and 1 g of jg-toluenesulphonic acid were dissolved in 100 ml of ethanol and 20.2 g of 2,3-dichlorobenzylhydrazine were added. After standing overnight at room temperature, the precipitate which had formed was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was again extracted with ether and subsequently slightly acidified with dilute acetic acid. Hereupon the compound identified above precipitated and after recrystallisation from ethanol the melting point was 161-162°C. Yield: 11 g (40#) .
Example 21 -Amino-1 -(2-bromobenzyl)-pyrazol-5-one 42.4 g of 2-bromobenzylhydrazine were added dropwise, under nitrogen, to a solution of 33.4 g of β-βπιΐηο-β- ethoxyacrylic acid methyl ester and 1 g of jg-tolueneaulphonic acid in 250 ml of ethanol. After stirring for 15 hours at room temperature the solution was concentrated in vacuo and the precipitate which had formed was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was again extracted with ether and subsequently slightly acidified with dilute acetic acid, whereupon the compound identified above precipitated. After recrystalllsa- tion from ethanol, the compound melted at 168-169°. Yield: 49 g of -amino-^-ethoxyacrylic acid ethyl ester and 2 g of jD-toluenesulphonic acid were dissolved in 225 ml of ethanol and 72 g of 3-bromo-4-chlorobenzylhydrazine were added under nitrogen. After standing overnight, the compound identified above had separated out as a precipitate, and was filtered off and twice recrystallised from ethanol. Melting point: 171-172°C; yield: 40 g (43#).
Example 23 . 3-Ainino-1-(3-chloro-4-bromobenzyl)-pyrazol-5-one 0 48.8 g of 4-bromo-3-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 33.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of toluene-sulphonic acid in 150 ml of ethanol. After stirring for a further two hours the mixture was left to stand and the compound identified above began to crystallise out after four hours. It was filtered off and twice recrystallised from ethanol. Melting point: 145-146°; yield 23 g (37 ).
Example 24 3-Amino-1 -(214.5-trichlorobenzyl)-pyrazol-5-one 54.7 g of p-amino-p-ethoxyacrylic acid ethyl ester and of £-toluenesulphonic acid were dissolved in 400 ml of ethanol. A solution of 77.6 g of 2,4,5-trichlorobenzyl-hydrazine in 200 ml of ethanol was added dropwise thereto, under nitorgen. After stirring for a further two hours, the mixture was left to stand overnight and the precipitate which had separated out was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was repeatedly extracted with ether and thereafter slightly acidified with dilute acetic acid, whereupon the compound identified above precipitated. After recrystallisation from ethanol, this product melted at 195-196°. Yield: 38 g (38 ).
Example 25 3-Amino-1 -( 4-methyl-3-chlorobenzyl)-pyrazol--5-one 0 50 g of 4-methyl--3-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 46.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p_-toluene-sulphonic acid in 200 ml of ethanol. After stirring for a further two hours, the compound identified above precipitated. It was filtered off and recrystallised from ethanol.
Melting point: 130-131°. Yield: 35 g.(50g).
Example 26 3-Amino-1- (4-phenylbenzyl)-pyrazol-5-one A solution of 29 g of 4-phenylbenzylhydrazine in 60 ml of ethanol was added dropwise, under nitrogen, to a solution of 23.4 g (0.147 mol) of β-amino-p-ethoxyacrylic acid ethyl ester and 1 g of £-toluenesulphonic acid in 100 ml of ethanol.
Meanwhile, the temperature rose from 22° to 32°C. After standing overnight, the reaction solution was concentrated in vacuo, the precipitate which separated out was dissolved in 2 N sodium hydroxide solution and the alkaline solution was repeatedly extracted with ether. Addition of dilute acetic acid until a weakly acid reaction was obtained yielded the compound identified above, which after recrystallisation from ethanol melted at 185-186°C. Yield: 13 g (33 ).
Example 27 3-Amino-1 -(naphthyl-(2 )-methyl)-pyrazol-5-one Δ solution of 40.5 g of β-hydrazinomethylnaphthalene was added dropwise, under nitrogen, to a solution of 37.5 g of -ami o-β-ethox acr lic acid ethyl ester and 1 g of p_-toluene-sulphonic acid in 100 ml of ethanol. The mixture was stirred for a further two hours. After two hours longer, the compound identified above precipitated and was filtered off and recrystallised from ethanol. Melting point: 156-157°. Yield: 26.6 g of 2 , -dime hylbenzylhydrazine were added drop-wise to a solution of 28.2 g of p-amino-p-ethoxyacrylic acid ethyl ester and 1 g of p_-toluenesulphonic acid in 130 ml of ethanol, in the course of which addition the temperature rose from 25 to 35°C After stirring overnight, the compound identified above, which had separated out as a precipitate, and was filtered off and recrystallised from ethanol.
Melting point: 124°. Yield: 20 g (52 ).
Example 29 3-Amino-1- (3-1rifluoromethylbenzyl)-pyrazol-5-one -RT]? - From 1 7.5 g of p-amino^-ethoxyacrylic acid ethyl ester and 1 9 g of 3-trifluorobenzylhydrazine analogously to the procedure described in Example 1 . 9 g of the compound identified above, as colourless crystals of melting point 144°, corresponding to 33% of theory, are obtained.
EXAMPLE 30 3-Amino-1 -( 4-trifluoromethoxybenzyl)-pyrazol-5-one From 1 7.5 g of -amino- -ethoxyacrylic acid ethyl ester and 20. 6 g of 4-trifluoromethoxybenzylhydrazine, analogously to the procedure described in Example 1 , 8.7 g of the compound identified above, as colourless crystals of melting point 99° » corresponding to 3 of theory, are obtained.
Example 31 3-Amino-1 - ( 4-methoxybenzyl)-pyrazol-5-one From 1 7.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 1 5 .2 g of 4-methoxybenzylhydrazine, analogously to the procedure described in Example 1 , 9.7 g of the compound identified above, as colourless crystals of melting point 1 61 °, corresponding to 4% of theory, are obtained.
Le A 1 4 1 994ITF - 37 - Example 32 5-Amino-1 -( .4-methylenedioxybenzyl)-pyrazol-5-one From 17.5 g of p)amino-a--ethoxyacrylic acid ethyl ester and 16.6 g of 3, 4-methylenedioxybenzylhydrazine , analogously to the procedure described in Example 1, 12.1 g of the compound identified above, as colourless crystals of melting point 218°, corresponding to 5 of theory, are obtained.
Example 33 3-Amino-1-» (314-tetramethylenebenzyl)-pyrazol~5~one From 17.5 g of -amino- -ethoxyacrylic acid ethyl ester and 17.6 g of 3,4-tetramethylenebenzylhydrazine analogously to the procedure described in Example 1 , and after re-crystallisation from alcohol, 15.6 g of the compound identified above, as colourless crystals of melting point 103°, are obtained. The compound crystallises with one mol of alcohol of crystallisation. The yield is of theory.
Example 34 3-Amino-1-(214-dichlorobenzyl)-pyrazole-5-one From 17.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 20.2 g of 2, 4-dichloro'benzylhydrazine analogously to the procedure described in Example 1 , 11 g of the compound identified above, as colourless crystals of melting point 189°, corresponding to 40# of theory, are obtained.
Example 35 3-Amino-1 -( aphthyl-( 1 )-methyl)-pyrazol-5-one 37.5 g of p-amino-p-ethoxyacrylic acid ethyl ester and 40.5 g of a-hydrazinomethyl-naphthalene yield, analogously to the procedure described in Example 1 , 24 g of the compound identified above, as colourless crystals of melting point 180°, corresponding to 0 of theory.
Example 36 3-Amino-1 -( 2-methylbenzyl)-pyrazol-5-one 27.5 g of o-methylbenzylhydrazine, dissolved in 100 ml of ethanol, were added dropwise, at room temperature, to a solution of 32 g of p-amino-p-ethoxyacrylic acid ethyl ester and 1.5 g of £-toluenesulphonic acid in 300 ml of ethanol.
After standing overnight , the reaction solution was concentrated in vacuo and the compoundidentified above, which separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 138°. Yieldi 15 g (31%).
Le A 14 199-RT - 39 - Example 37 3-Amino-1- (3-bromobenz.yl)-pyrazol-5-one 20.5 g of p-amino^-ethoxyacrylic acid ethyl ester were dissolved together with 1.5 g of £-toluenesulphonic acid in 200 ml of ethanol. 26 g of m-bromobenzylhydrazine were added dropwise to this solution, under nitrogen. After stirring for two hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 160°. Yield: 12 g (35%).
Example 38 3-Amino-1-(3-iodobenzyl)-pyrazol-5-one A solution of 45 g of m-iodobenzylhydrazine in 70 ml of ethanol was added dropwise to a solution of 28.6 g of β-amino-^-ethoxyacrylic acid ethyl ester and 1.5 g of p_-toluenesulphonic acid in 350 ml of ethanol. After stirring overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Meltin point: 186°. Yield: 16 g (28j£).
Example 39 3^Amino-1-(4-iodobenzyl)-pyrazol-5-one A solution of 25.5 S of ^--iodobenzylhydrazine in 100 ml of ethanol was added dropwise, under nitrogen, to a solution of 16.2 g of β-amino-β-e hoxyacΓ lic acid ethyl ester and 1 g of j-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue was recrystallised from ethanol. Yield: 15 g (47$) of the compound identified above. Melting point: 1 8°.
Example 40 3-^Amino-1--(2-fluorobenzyl)-pyrazol-5-one 30.2 g of -amino-p-ethoxyacrylic acid ethyl ester and 2 g of j -toluenesulphonic acid were dissolved in 300 ml of ethanol and 27.1 g of o-fluorobenzylhydrazine were added under nitrogen. After stirring for two hours the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 146°. Yield 11 g (2796).
Example 41 3-Amino~1-(2-fluoro-5-chlorobenzyl)-pyrazol-5-one 21.6 g of 2-fluoro-5-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 19.8 g of β-amino-β-ethox acrylic acid ethyl ester and 0.5 g of j-toluene-sulphonic acid in 100 ml of ethanol, in the course of which addition the temperature rose from 20° to 30°. After stirring for two hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 160°. Yield: 17 g (57 ).
Example 42 3-Amino-1 -( .4-dibromobenzyl)-p.yrazol-5-one 12.2 g of p-amino-p-ethoxyacrylic acid ethyl ester and I g of p_-toluenesulphonic acid were dissolved in 200 ml of ethanol. A solution of 21.6 g of 3, 4-dibromobenzylh.ydrazine in 50 ml of ethanol was added dropwise thereto, under nitrogen. After stirring overnight, the solvent was concentrated in vacuo and the compound identified above, which had separated out as a precipitate , was filtered off and re-crystallised from ethanol. Melting point: 182°. Yield: II g (41%).
Example 43 3-Amino-1-(3-methyl-4-chlorobenzyl)-pyrazol-5-one 20.5 g of 3-methyl-4-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 19.1 g of β-amino-p-ethoxyaerylie acid ethyl ester and 1.5 g of p_-toluenesulphonic acid in 200 ml of ethanol. The reaction solution was stirred overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 131°. Yield: 10 g (3 %).
Example 44 5-Amino-1 -( 4-tert-butylbenzyl)-pyrazol-5-one 24.6 g of p-tert .-butylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 22 g of p-amino- -ethoxyacr lic acid ethyl ester and 1 g of p_-toluenesulphonic acid in 100 ml of ethanol, in the course of which the temperature rose from 24° to 30°C. After stirring overnight, the solvent was distilled off in vacuo and the oily residue consolidated after addition of 50 ml of petroleum ether. The compound identified above was filtered off and recrystallised from ethanol. Melting point: 126°. Yield: 8 g (24 ). 42562/2

Claims (20)

1. A pharmaceutical composition containing as an a active ingredient/3-amino-pyrazol-5-one compound of the following general formula or salts thereof, in which R is a naphthyl radical optionally substituted by halogen or a phenyl radical which carries either no substituents or the following substituents: (a) 1 , 2 or 3 identical or different substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy and phenyl; or (b) one trifluoromethoxy , nitro or cyano; or (c) an annellated branched or unbranched 5, 6 or 7- membered ring built by an alkylene group of 3 to 5 carbon atoms or a methylenedioxy group; in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent.
2. A composition according to Claim 1 in which the active ingredient is a compound as defined in Claim 1 in which R is a phenyl, naphthyl or halonaphthyl radical, the phenyl radical carrying as substituent(s) : 42562/2 (a) 1 , 2 or 3 straight or branched-chain alkyl radicals- with up to 8 carbon atoms each; or 1 , 2 or 3 straight or branched-chain alkoxy radicals with up to 6 carbon atoms; • or 1 , 2 or 3 halogen atoms; or 1 or 2 trifluorometh l radicals; or (b) one tri luoromethoxy, nitro or cyano radical; or a group (c) as defined in Claim 1 .
3. A composition according to claim 1 in which the said active ingredient is 3-amino-1 - ( 4-chlorobenzyl)-pyrazol-5-one or a salt thereof .
4. The "composition of claim 1 in which the said active ingredient is 3-amino-1- (4-bromobenzyl)-pyrazol-5-one or a salt thereof.
5. A composition according to claim 1 in which the said ■inactive ingredient is 3-amino-1-(3,4-dimethylbenzyl)-pyrazol-5-one or a salt thereof.
6. A composition according to claim 1 in which the active ingredient is any compound as defined in claim 1 which is hereinbefore specifically mentioned other than those mentioned in claims 3, 4 and 5·
7. A pharmaceutical composition according to any of claims 1 to 6 in which the said active ingredient is a water-soluble salt.
8. A composition according to claim 7 in which the said active ingredient is a sodium, potassium, ethanolamine, diethanolamine, triethanolamine , amino-tris-hydroxymeth 1-methane, glucosamine or N-methyl-glucosamine salt.
9. A pharmaceutical composition containing as active ingredient a compound as defined in any of claims 1 to 8 in the form of a sterile or isotonic aqueous solution.
10. A composition according to any of claims 1 to 9 containing from 0.5 to 90 percent of the active ingredient by weight.
11. A pharmaceutical composition according to any preceding claim, substantially as hereinbefore described.
12. A medicament in dosage unit form comprising a compound as defined in any of claims 1 to 8 either alone or in admixture with a diluent.
13. A medicament in the form of tablets, pills, dragees, capsules, ampoules or suppositories comprising a compound as defined in any of claims 1 to 8 either alone or in admixture with a diluent.
14. 1 . A medicament in dosage unit form according to claim 12 or 13, substantially as hereinbefore described.
15. A method of combating circulatory disturbances and 42562/2 disturbances of salt metabolism in non-human animals which comprises administering to the animals a compound as defined in any of claims 1 to 8 either alone or in admixture with a diluent or in the form of a medicament according to claim 12, 13 or 14·
16. A method according to claim 15 in which the compound is administered perorally.
17. A method according to claim 16 in which the compound is administered in an amount of 0.1 to 10 mg/kg body weight per day.
18. A method according to claim 15 in which the active com-pound is administered orally.
19. A method according to claim 18 in which the compound is administered in an amount of 0.5 to 100 mg/kg of body weight per day.
20. A method of combating circulatory disturbances and disturbances of salt metabolism according to any of claims 15 to 19, substantially as hereinbefore described. Le A 14 199-R F - 47 -
IL42562A 1972-06-23 1973-06-20 Pharmaceutical compositions containing 3-amino-pyrazol-5-ones IL42562A (en)

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USRE30420E (en) * 1973-04-17 1980-10-21 Bayer Aktiengesellschaft Pyrazol-5-ones
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