IE49993B1

IE49993B1 - Pyrazoloquinolines,process for their manufacture,pharmaceutical preparations containing these compounds and their therapeutic application

Info

Publication number: IE49993B1
Application number: IE1279/80A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1979-06-21
Filing date: 1980-06-20
Publication date: 1986-01-22
Also published as: NZ194102A; IL60357A; IE801279L; DD151754A5; CY1357A; KR840000421B1; DE3068673D1; MY8700556A; FI68827B; ZA803714B; ATE8629T1; EP0022078B1; NO153430C; AU538890B2; JPH039114B2; DK160762B; CA1148159A; PT71420A; NO801866L; JPS5618980A

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A compound of the general formulae I and II see diagramm : EP0022078,P19,F1 and see diagramm : EP0022078,P19,F2 wherein R3 is hydrogen or not more than 3 identical or different members selected from C1 -C7-alkyl, C1 -C7 -alkoxy, C1 -C7 -alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-C1 -C7 -alkylamino, cyano, carbamoyl and carboxyl ; R is phenyl or phenyl substituted by not more than 3 of the radicals as defined for R3 , pyridyl, C1 -C7 -alkylpyridyl, or halopyridyl ; R1 is hydrogen, C1 -C7 -alkyl or (hydroxy, di-C1 -C7 -alkyl-mino or R3 -phenyl)-C1 -C7 -alkyl, wherein the hydroxy or amino group is separated from the ring nitrogen atom by at least 2 carbon atoms, and R2 is hydrogen or C1 -C7 -alkyl ; their 3-hydroxy-tautomers ; C1 -C7 -alkanoyl, carbamoyl, mono- or di-C1 -C7 alkylcarbomoyl derivatives of said (hydroxy or amino)-(phenyl or phenylene) compounds ; or salts thereof. For the Contracting State AT 1. A process for the preparation of a 2-aryl-pyrazolo [4,3-c] quinolin-3-(1 or 5H)-one of the general formulae I and II see diagramm : EP0022078,P21,F1 and see diagramm : EP0022078,P21,F2 wherein R3 is hydrogen or not more than 3 identical or different members selected from C1 -C7 -alkyl, C1 -C7 -alkoxy, C1 -C7 -alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-C1 -C7 -alkylamino, cyano, carbamoyl and carboxy ; R is phenyl or phenyl substituted by not more than 3 of the radicals as defined for R3 , pyridyl, C1 -C7 -alkylpyridyl, or halopyridyl ; R1 is hydrogen, C1 -C7 -alkyl or (hydroxy, di-C1 -C7 -alkylamino or R3 -phenyl)-C1 -C7 -alkyl, wherein the hydroxy or amino group is separated from the ring nitrogen atom by at least 2 carbon atoms, and R2 is hydrogen or C1 -C7 -alkyl ; their 3-hydroxy-tautomers ; C1 -C7 -alkanoyl, carbamoyl, mono- or di-C1 -C7 -alkylcarbamoyl derivatives of said (hydroxy or amino)-(phenyl or phenylene) compounds ; or a salts thereof, which comprises a) cyclising a compound of the formula IV see diagramm : EP0022078,P21,F3 wherein X is -NH-NH-R and Y is hydroxy or C1 -C7 -alkoxy ; or X is halogen and Y is see diagramm : EP0022078,P21,F4 ; or X is C1 -C7 -alkoxyamino or azido, and Y is NH-R, and, if desired, reacting a resulting compound, or an alkali metal salt thereof, with a reactive ester of the alcohol R1 -OH, or b) condensing a compound of the formula V see diagramm : EP0022078,P21,F5 wherein W and R1 are both hydrogen, Z is see diagramm : EP0022078,P21,F6 and R1 ' is C1 -C7 -alkyl ; or W is see diagramm : EP0022078,P22,F7 and Z is hydrogen ; or W is see diagramm : EP0022078,P22,F8 and Z is R2 -CO, or see diagramm : EP0022078,P22,F9 together is isocyano ; and, if desired, converting a resulting compound into another compound of the invention, and/or, if desired, converting a resulting compound into a salt thereof, or a resulting salt into the corresponding free compound or into another salt, and/or, if desired, separating a mixture of isomers obtained into the individual isomers.

Description

2-Aryl-pyrazolo/4,3-<^quinolin-3-ones have not been described in the chanical literature yet. However, 2-unsubstituted 4-phenylpyrazolo/4,3-c7quinolin-3-ones, or 3-hydray-tautcmers thereof respectively, are described in Monatsh. 57, 52 (1931). In contrast, 2-phenyl5 pyrazolo /4,3-c7iscquinolin-3-cnes (or 3-ols) are described in J. Chem. Soc. 1959, 599; and European Patent Application 5,745 discloses antiinf lanmatory, CNS-depressant and anti-anxiety 3-phenyl-pyrazolo /3,4-c7-isoquinolin-5-ones.

The present invention relates to 2-aryl-pyrazolo/4,3-c7 quinolin-3-(l and 5H)-ones conpounds, in particular of the general Ebnnulae I and II Rj- N - N R, —ί— II I ^AnA *2 IjJ - N - R /'AAo (I) and R,—t H )1 W'R, I 7 (II), wherein R, is hydrogen or not more than 3 identical or different members selected fron C^-C^alkyl, C^-C^alkoxy, C^-C^alkylthio, hydroxy, halogen, trifluorcmethyl, nitro, amino, mono- or di-C^C.? alky lamino, cyano, carbamoyl and carboxy; R is phenyl or phenyl substituted by not more than 3 of the radicals as defined for R,, pyridyl, C^-G^alkylpyridyl, or halopyridyl; R^ is hydrogen, C,-Cy&lkyl or (hydroxy, di-C^-C^alkylamino or R,-phenyl)-C-^-C^alkyl, wherein the hydroxy or amino group is separated from the ring nitrogen atcm by at least 2 carbon atoms, and R, hydrogen or C-^-Cyalkyl; their 3-hydrcay-tautcmers; Cj-C? alkanoyl, carbamoyl, mono- or di-C^-Gyalkylcarbamoyl derivatives of said (hydroxy or amino)-(phenyl or phenylene) compounds; or salts. especially phannaoeufcically acceptable salts thereof; process for their manufacture, pharmaceutical preparations containing these psychoactive compounds and their therapeutic application. lhe 1,2-phenylene group is preferably unsubstituted, or substituted by one, two or three members selected from the following groups: lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl; lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy; lower alkylthio, e.g. methylthio or ethylthio; hydroxy; halogeno, e.g. fluoro, chloro or bromo; trifluoromethyl; nitro; amino; mono- or dilower alkylamino, e.g. mono- or di-(methyl, ethyl, n- or i-propyl)amino; cyano, carbamoyl or carboxy.

The phenyl or pyridyl radical R in 2-position is preferably an ortho-unsubstituted phenyl group as defined for the unsubstituted or up to trisubstituted 1,2-phenylene Ph above, but also 3-, 4- or preferably 2-pyridyl, or said alkylated or halogenated pyridyls, advantageously (4-methyl or 5-chloro)-2-pyridyl. Of said 1,2-phenylene and/or R-substituents, listed above and starting iron trifluoranethyl, preferably but cne thereof is present.

The radical R^, in either the 1- or preferably 5-position, is advantageously hydrogen, but also one of said alkyl groups, or a (hydroxy, di-lower alkylamino or H-Ph)-lower alkyl group, which preferably separates adjacent hetero-atoms by at least 2 carbon atoms, such as 2-(hydroxy, dimethylamino or diethylamino)-ethyl, 2- or 3(hydroxy or diraethylamino)-propyl; benzyl, 1- or 2-phenethyl.

The radical R2 in 4-position is preferably also hydrogen, or one of said alkyl groups, advantageously methyl.

On account of said 1- or 5-substituents R^ the compounds of this invention are correctly depicted as 3-ones, or 3-oxo-derivatives respectively. But in case R^ = H, they may also form a minor amount of 3-hydroxy-tautomers, depending on milieu and substitution. In general, however, they are weak bases or acids, forming acyl-derivatives only with said (hydroxy or amino)-Ph compounds, and salts with either strong acids or bases. Said acyl derivatives are the lower alkanoyl, carbamoyl, mono- or di-lower alkylcarbamoyl derivatives of the above (hydroxy or ainino)-(phenyl or phenylene) compounds, e.g. the acetyl, propionyl, pivaloyl; (methyl or ethyl)-carbamoyl derivatives; and the salts are preferably alkali metal, e.g. sodium or potassium salts of Ιθ the 1- or 5-unsubstituted compounds (R^ = H) and/or the carboxy(phenyl or phenylene) compounds; or addition salts of all of said compounds with acids, especially with the pharmaceutically acceptable acids listed below.

The term lower", referred to above or hereinafter in connec15 tion with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, and advantageously those with one or two carbon atoms.

The compounds of the invention exhibit valuable pharmacological properties, i.e. psychoactive effects, primarily antidepressant or 2q anxiolytic properties. They are demonstrable by in vitro and in vivo tests, using advantageously mammals, e.g. mice, rats, or monkeys, as test objects. Said compounds can be applied to them enterally or parenterally, advantageously orally or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules or in the form of starchy suspensions or aqueous solutions or suspensions respectively. The applied dosage may range between about 0.01 and 100 mg/kg/day, preferably between about 0.05 and 5 mg/kg/day, advantageously between about 0.1 and 0.5 mg/kg/day.

Said antidepressant properties can be shown in mice according ;0 to the Behavioral Despair test (Arch. Int. Pharmacodyn. Ther. 229 (2) : 327-336, Oct. 1977). It induces a depressed state therein by forcing them to swim in a narrow cylinder from which they cannot escape. After a brief period of vigorous activity the mice adopt a characteristic immobile posture, which is readily identifiable. Immobility is reduced by the compounds of this invention, other tricyclic antidepressants, monoamine oxidase inhibitors, atypical antidepressants and electroconvulsive shock.

Anxiolytic effects are routinely observed, for example, according to the classical metrazole antagonism test in rats, or according to the Cook-Davidson conflict procedure, using male Wistar rats which are maintained at 80 Z of normal body weight by dietary-, but not water-restriction. They are trained to press a lever within a conditioning chamber, also containing a liquid dipper, a house light, a speaker and a grid-floor. Both lever and grid are connected to an electrical shock source and the chamber is situated in a soundattenuated room in which a white noise-source is activated during testing, in order to mask any extraneous auditory cues. Each session of 47 minutes duration consists of two alternating schedules. The first is a Variable Interval (VI) schedule of 30 seconds, lasting for 5 minutes, during which a sweetened, condensed milk reinforcement is delivered following the first lever-press after the 30 seconds have elapsed, and a drug-induced decrement of this performance is taken as an indication of a neurological deficit. Immediately following the VIschedule both a 1000 Hz tone and a light-cue are activated, indicating the commencement of the second, Fixed Ration (FR) schedule, lasting for 2 minutes, wherein the milk reinforcement is delivered concomitant with an electric foot shock immediately following the tenth response, thereby establishing a conflict situation. The intensity of said shock ranges between 2.0 and 3.6 mA, varying with each animal, in order to adjust them to about 25-100 responses during this schedule over the entire session. A drug-induced enhancement of performance during the FR-schedule is taken as indication of antianxiety effects, as exhibited by said compounds of this invention. 4999 3 The anxiolytic effects of said new compounds can also be estimated by the Diazepam Receptor Binding Assay in vitro, e.g. as described in Nature 266, 732 (1977) or Proc. Nat. Acad. Sci. USA 74, 3805 (1977). Diazepam binds specifically and with high affinity to crude synaptosomal membrane preparations from rat fore-brain. This binding is inhibited by other anxiolytic compounds, e.g. other pharma· cologically more active benzo-diazepines. When tritiated diazepam is used, the interaction of other drugs with said receptor can be readily assessed thus: Membranes from rat fore-brain are incubated at 0-5° with tritiated diazepam and various concentrations of the test substances in a physiological medium at the pH = 7.5. The membranes, containing the receptors with various amounts of tritiated diazepam, are filtered onto glass fiber filters, which are then shaken in a liquid scintillation counter. The concentration of the compounds of this invention, required to inhibit the specific binding of 2 nM tritiated diazepam by 50 7., i.e. the Ιϋ^θ (Inhibitory Concentration) is determined graphically and ranges down to about 0.6 nM, what is an order of magnitude lower than the value for diazepam (5 nM) and almost four orders lower than the value for 2o chlordiazepoxide (400 nM).

Accordingly, the compounds of this invention are useful in the treatment of mental depression and preferably for combatting anxiety problems similar to those treated with diazepam. In contrast to diazepam, said compounds of the invention appear to be devoid of neurological deficit liability at doses where antianxiety effects are already established. Finally, the compounds of the invention are also valuable intermediates in the preparation of other useful products, especially of corresponding pharmaceutical compositions.

Particularly useful are compounds of Formulae I and II wherein is hydrogen or one or two matters selected fran C-^-Cyalkyl, C^-C^alkoxy, C^-C^alkylthio, hydroxy, halogen, trifluoranethyl, nitro, amino, mono- or di-C^-C^alkylamino, cyano, carbamoyl and carboxy; R is phenyl or phenyl substituted by one or two of the substituents as defined for Rg, pyridyl, Cj-Cyalkylpyridyl or halopyridyl; R^ is hydrogen, C^-C^ alkyl or (hydroxy, di-C^-Cyalkylamino or Rg-phenyl)-C^-C^alkyl, wherein the hydroxy or amino group is separated from the ring-nitrogen atom by at least 2 carbon atoms; and R2 is hydrogen or lower alkyl; or lower alkanoyl, carbamoyl, mono- or di-lower alkylcarbamoyl derivatives of said (hydroxy or amino)-(phenyl or phenylene) compounds; or salts, especially pharmaceutically acceptable alkali metal or acid addition salts thereof.

More preferred are those compounds of formula III H wherein R is hydrogen, alkyl or alkoxy, each containing 4 carbon atoms, hydroxy, fluorine, chlorine, bromine or trifluoro methyl; and R' is hydrogen, alkyl or alkoxy each containing carbon atoms, hydroxy, fluorine, chlorine, bromine, trifluoro methyl, nitro, amino, monoalkylamino or alkylcarbamoylamino, each containing 4 carbon atoms, or cyano; or salts, especially pharmaceutically acceptable alkali metal or acid addition salts thereof.

Particularly preferred compounds of the invention are those of formula III, wherein R is hydrogen, or 8-(methyl, methoxy, fluoro or chloro) and R' is hydrogen of 4-fluoro, if R is 8-chloro; or salts, particularly pharmaceutically acceptable alkali metal or acid addition salts thereof, for their predominant antidepressant activity.

Outstanding are the compounds of Formula III, wherein R is hydrogen or 8-(methyl, methoxy, fluoro or chloro), and R' is 4-(methyl, methoxy, chloro, bromo, amino or cyano); or it is 4-fluoro when R is different from 8-chloro; or salts, especially pharmaceutically acceptable alkali metal or acid addition salts thereof, for their predominant anxiolytic activity.

Special attention deserve the compounds of Formula III with R' being hydrogen; and R being hydrogen, 8-(methoxy, fluoro or chloro), or R' being 4-fluoro and R being 8-chloro, or salts, especially the sodium salt, hydrochloride or mesylate thereof, for their predominant antidepressant activity; as well as the compounds of Formula III with R' being 4-(methyl, chloro or amino); and R being hydrogen; or salts, especially the sodium salt, hydrochloride or mesylate thereof, for their predominant anxiolytic activity.

The compounds of the invention are prepared according to conventional methods, for example by 1) ring closing compounds of Formula IV R. '3 '•-COY '2 wherein X is -NH-NH-R and Y is hydroxy or lower alkoxy; or X is t halogen and Y is H2N-R; or X is lower alkoxy-amino or azido, and Y is NH-R; and, if desired, reacting a resulting compound, or an alkali metal salt thereof, with a reactive ester of the alcohol Rj-OH.

The ring-closure of said acids or esters IV occurs by heating then fo temperatures between about 30 and ISO’, advantageously ir. the presence of inert solvents, such as aliphatic or aromatic hydrocarbons and/or ethers, e.g. toluene, xylenes, biphenyls and/or diphenyl ethers, while distilling off the water or alkanols generated. Said hydrazides IV are similarly ring-closed, but advantageously under basic conditions, in order to neutralize the generated hydrohalic acids, for example in the presence of aqueous alkali metal hydroxides. The ring-closure of said amides IV occurs by heating them to temperatures between about 120 and 3009, preferably between 200 and 250°, advantageously also in the presence of said inert solvents .

Some of the starting material of Formula IV is new, but can easily be prepared from the known precursors with X · OH, e.g. as illustrated by the examples herein or described in J. Med. Chem. 12, 1096 (1969) or C.R. Acad. Sc. Paris, t. 280, C, 1385 (1975), by condensation with corresponding aryl-hydrazines. Said hydrazides are prepared by condensing 4-chloroquinolin-3-carboxylic acid chlorides and β-acylated aryl-hydrazines, e.g. the trifluoroacetates, which 48993 hydrolyze under ring-closing conditions. Said amides are preferably obtained by condensing 4-haloquinolin-3-carboxylic acid halides with R-amines, and subsequently with 0-lower alkylhydroxylamines or alkali metal azides.

Another process for preparing the compounds of the invention consists in 2) condensing compounds of formula V Ί-Ζ (V) Ί £0N-Ri wherein both W and R are hydrogen, Z is R_-C=<1 N.Cand R' is lower alkyl; or W is CH-COR, and Z is R-ά-ώ . T c\ * hydrogen; or W is CH, and Z is R.-CO, or R -N-Z R-N-CD L 1 together is isocyano; and, if desired, converting any resulting compound into another compound of the invention, and/or, if desired, converting a resulting compound into a salt thereof, or any resulting salt into the corresponding free compound or into another salt, and/or, if desired, resolving a mixture of isomers obtained into the single isomers.

Said ring-closing condensation of the W = H compounds is preferably carried out with strong aprotic condensation agents, such as polyphosphoric acid lower alkyl esters. In case the compounds with Z = H are ring-closed, the water generated is advantageously removed azeotropically, preferably in said hydrocarbons and/or ethers, if desired, in the presence of conventional molecular sieves, and/or a catalytic amount of acid, e.g. hydrochloric acid.

Lastly, compounds V with carbon containing H and Z are ringclosed under neutral conditions, optionally in the presence of de49993 hydrating agents, such as thionyl halides, phosphorus oxyhalides or lower alkyl polyphosphate esters.

The starting material of Formula V is also new, but can be prepared according to known methods, e.g. by condensing an 1-aryl pyrazolidin-3,5-dione with ethyl orthoformate and an aniline. Said second starting material V can be prepared analogous to the process described in Izv. Akad. Nauk. Latv. S.S.R. 1965, 587, but chosing analogs with an o-nitro group, which is subsequently reduced with catalytically activated hydrogen. Said final starting material V is similarly prepared from said common l-R-3-(o-nitrophenyl)-5-pyrazolones, by reducing, N-acylating and, if desired, dehydrating them to said isonitriles with phosgen or dimethyl formamide/thionyl halide mixtures.

The resulting compounds of the invention can be converted into each other according to conventional methods. For example, compounds with = H can be 1-substituted with reactive esters of R^-OH, e.g. such of hydrohalic, aliphatic or aromatic sulfonic acids, such as R^-(halides, sulfates, aliphatic or aromatic sulfonates), e.g. methyl iodide, dimethyl sulfate, benzyl chloride or methyl mesylate or tosylate, in order to yield the 1-substituted compounds of Formula X. Those of Formula II are similarly obtained from the corresponding alkali metal salts, e.g. with R^ being sodium or potassium, whereby -substitution occurs. Furthermore, resulting lower alkoxy compounds may be hydrolyzed to the corresponding phenols withstrong hydrohalic acids, e.g. hydrobromic acid. Resulting nitro compounds may be hydrogenated to the corresponding amines with catalytically activated or nascent hydrogen, e.g. hydrogen in the presence of noble metal catalysts, such as nickel, palladium or platinum; or generated by the action of reactive metals on alcohols or acids, such as zinc on hydrohalic acids. Said amines may be alkylated as shown for the compounds with = H, or by reductive alkylation; or acylated, for example, with the use of corresponding reactive acid derivatives, e.g. anhydrides, halides or isocyanates. Resultant nitriles can be converted into the corresponding amides in a manner known per se, e.g. by treatment with aqueous alkali metal hydroxides, e.g. aqueous sodium hydroxide, ethanol and hydrogen peroxide, or into the corre5 sponding acids by hydrolysis, e.g. with aqueous alkali metal hydroxides, such as sodium hydroxide.

Finally, a resulting compound can either be converted into its alkali metal salts, advantageously with the use of alkali metal hydrides, hydroxides or lower alkoxides; or into its acid addition salts (especially if amino-substituted compounds are involved), preferably with the use of pharmaceutically acceptable inorganic or organic acids, such as strong inorganic acids, for example, hydrohaLic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sul15 fonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic tartaric, citric, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethane-sulfonic, hydroxyethanesulfonic, ethylenesulfonic; halogeno20 benzene sulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or ascorbic acid. These or other salts, for example the picrates, can also be used for purification of the amino-bases obtained; these are converted into salts, the salts are separated and the free compounds liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances. Acid addition salts of compounds devoid of basic substituents, e.g. an amino group, usually hydrolyse in about neutral aqueous media.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably at the hoiling point of the solvents used, at atmospheric or superatmospheric pressure.

Resulting mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography.

The invention further includes any variant of the above processes in which an intermediate product, obtainable at any stage thereof is used as starting material, and any remaining steps are carried out, or said process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, e.g. those of Formula IV with X = NH-NH-R, from their precursors with X = Cl, or in which the reaction components are used in the form of their salts.

Mainly those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being especially valuable, e.g. those of Formula III.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunctionor admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine, and lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for cablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, e.g. starches, agar, alginic acid or its salts, enzymes of the binders or effervescent mixtures and/or adsorbents, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional_mixing, granulating or coating methods respectively and contain about 0.1 to 75 7,, preferably about 1 to 50 % of the active ingredient.

The following examples, illustrating the invention, are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, all parts wherever given are parts by weight and, if not otherwise stated, all evaporations are carried out under reduced pressure, e.g. between about 0.1 and 15 mmHg.

The compounds named in the following examples having too high a melting point, are characterized by their IR or NMR spectral data.

Example 1; The mixture of 1681 g of ethyl 4-chloro-quinoline-3carboxylate, 1017 g of p-chlorophenylhydrazine and 25000 ml of xylene is heated to 105° for 24 hours while stirring under nitrogen. The resulting suspension is cooled to 20°, combined with 1400 ml of 2N aqueous sodium hydroxide, stirred for 15 minutes and diluted with 30000 ml of water. Stirring is continued for 1 hour, the aqueous phase separated, washed five times with 8000 ml of diethyl ether each, filtered and the filtrate treated with the solution of 1600 g of ammonium chloride in 800 ml of water while stirring under nitrogen. The resulting suspension is stirred overnight at room temperature, filtered and the residue washed 5 times with 12000 ml of hot water. This residue is dried at 5 mmHg and 90° and 1665 g thereof are dissolved in 8400 ml of dimethylformamide at 130°. The solution is filtered and allowed to cool to room temperature while stirring. The resulting suspension is filtered, washed twice with 500 ml of cold dimethylformamide each, four times with 1000 ml of diethyl ether and the residue is dried at 0.1 mmHg and 100°, to yield the 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one of the formula rr I II II ·. · · VY melting at 324 - 327 with decomposition.

The starting material is prepared according to the following (generally applicable) method: To 1272 g of aniline 2953 g of diethyl ethoxymethylenemalonate are added during 20 minutes while stirring, and stirring is continued for 135 minutes at 90 - 92°. Thereafter the generated ethanol is distilled off during 4 hours at 10 mmHg and 80°. The residual oil is allowed to crystallize on trays, it is pulverized and dried at 5 mmHg and room temperature to yield the diethyl phenylaminomethylenemalonate melting at 45 - 46°. 1085 g thereof are added during 45 minutes to 10850 ml of the eutectic diphenyl ether-biphenyl mixture (73.5 : 26.5 parts by weight) at 215-220°, while stirring under nitrogen. After completed addition the temperature is raised to 238° and the generated mixture of ethanol and diphenyl ether is collected in a trap during 4 hours (about 390 ml). The mixture is allowed to cool to room temperature while stirring, the resulting suspension is filtered, the residue washed twice with 500 ml of diethyl ether each and dried at 0.1 mmHg and 85°, to yield the ethyl 4-hydroxyquinolin-3-carboxylate melting at 276-280°. 1630 g thereof are added to 2463 ml of phosphorus oxychloride during 30 minutes while stirring under nitrogen. The mixture is stirred for 15 minutes at 70° and for 2 hours at 95°, whereupon the liquid is distilled off at 11 mm Hg and 60°. The residue is dissolved in 8000 ml of methylene chloride, the solution is cooled to 0° and treated with 5000 g of crushed ice. The mixture is stirred, combined with 3000 ml of 50 % aqueous sodium hydroxide below 15° , and when the pH = 12 is reached the organic layer is separated. It is washed twice with 2000 ml of water each, once with 2000 ml of saturated aqueous sodium chloride, dried and evaporated. The residual oil is allowed to crystallize on trays, it is pulverized and dried at 0.1 mmHg and room temperature, to yield the ethyl 4-chloro-quinolin3-carboxylate melting at 44-46°.

To the solution of 1445 g of p-chloroaniline in 3375 ml of 38 2 hydrochlorid acid and 5650 ml of water the solution of 793 g of sodium nitrite in 3300 ml of water is added during 1 hour at -5 to -8° while stirring under nitrogen. After 15 minutes 7617 g of stannous chloride in 9000 ml of 38 2 hydrochloric acid are added during 30 minutes below 25°. The resulting suspension is stirred in an ice bath for one hour, filtered, the residue suspended in 30000 ml of water, and 5000 g of solid sodium hydroxide are added during 1 hour at Q - 25°, while stirring under nitrogen. The mixture is extracted twice with 8000 ml of diethyl ether, the combined extracts washed twice with 4000 ml of water and once with saturated aqueous sodium chloride, dried, filtered, evaporated and the residue dried at 5 mmHg and room temperature, to yield the p-chlorophenylhydrazine melting at 82 - 87°.

Example 2: The mixture of 1 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one and 3.38 ml of N aqueous sodium hydroxide is stirred under nitrogen at room temperature overnight. The resulting solution is filtered, evaporated and the residue dried under reduced pressure, to yield the corresponding sodium salt melting at 280 - 284°.

Example 3; The mixture of 1 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one, 20 ml of trifluoroacetic acid and 0.325 g of methanesulfonic acid is stirred at room temperature for 1 hour and evaporated. The residue is triturated with diethyl ether and filtered off, to yield the corresponding mesylate melting at 250 - 255°.

Example 4: The mixture of 3 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one and 100 ml of dimethyl sulfate is stirred at 110 130° for 2 hours and evaporated. The residue is dissolved in N aqueous sodium hydroxide, the solution extracted with methylene chloride and the extract evaporated. The residue is recrystallized from diethyl ether, to yield the l-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 158 - 161°.

Example 5: The mixture of 5 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one, 0.81 g of 50 Z sodium hydride in mineral oil and 100 ml of anhydrous tetrahydrofuran is refluxed for 2 hours. It is cooled to room temperature, combined with 3 g of methyl iodide while stirring and another 1 g thereof is added after one hour. The mixture is stirred overnight at room temperature, filtered and the residue 993 recrystallized from tetrahydrofuran-heptane, to yield the 5-methyI-2(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 322 - 323°.

Example 6: The mixture of 10 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]quino1in-3(5H)-one, 1.8 g of 50 Z sodium hydride in mineral oil and 250 ml of 1,2-dimethoxyethane is stirred at 100° until dissolution.

It is cooled to room temperature and 15 g of 3-dimethylaminopropyl chloride in 10 ml of 1,2-dimethoxyethane are added. The mixture is stirred at 150° overnight, cooled, the supernatant solution decanted off and the residue treated with said solvent, to yield the 5-(3-dimethylaminopropyl)-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 189 - 191°.

Similarly the 5-(2-dimethylaminoethyl)-2-(p-chlorophenyl)pyrazolo[4,3-c]quinolin-3-one is obtained, m.p. 184 - 186°.

Example 7: The mixture of 2 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]~ quinolin-3(5H)-one, 0.33 g of 50 % sodium hydride in mineral oil and 50 ml of 1,2-dimethoxyethane is stirred at 100° until dissolution.

It is cooled to room temperature, combined with 3.9 g of o-fluorobenzyl chloride in 2 ml of 1,2-dimethoxyethane and the mixture refluxed for 4 hours. It is cooled to room temperature, filtered, the residue washed with diethyl ether, slurried in 10 ml of N aqueous sodium hydroxide, filtered again, washed with water and dried, to yield the 5-(o-fluorobenzyl)-2-(p-chlorqphenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 338 - 339°.

Example 8: The mixture of 3.5 g of ethyl 4-(2,4-dichloropheny1hydrazino)-quinolin-3-carboxylate and 40 ml of eutectic diphenyl ether-biphenyl is heated to 175° for 4 hours, cooled to room temperature and diluted with diethyl ether. The resulting suspension is filtered, the residue washed with diethyl ether and dissolved in N aqueous sodium hydroxide. The solution is washed with diethyl ether, its pH adjusted to 8.5 with ammonium chloride and the precipitate 49983 formed collected. It is washed successively with hot water, methanol and diethyl ether, to yield the 2-(2,4-dichlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing peaks in the IR-spectrum at 890, 867, 845, 832, 816, 796, 775, 767, 756, 730 and 701 cm1.

The starting material is prepared as follows.' The mixture of 2.8 g of ethyl 4-chloroquinolin-3-carboxylate, 2.1 g of 2,4-dichlorophenylhydrazine and 40 ml of eutectic diphenyl ether-biphenyl is heated to 80 - 90’ overnight while stirring. It is cooled to room temperature, diluted with diethyl ether and the precipitate collected. It is taken up in N aqueous sodium hydroxide, the solution extracted with diethyl ether, the extract washed with water, dried, filtered, concentrated and the precipitate collected, to yield the ethyl 4-(2,4dichlorophenyl hydrazino)-quinolin-3-carboxylate, melting at 151 - 153°.

Example 9: The mixture of 3,6 g of ethyl 4-chloro-2-methyl-quinolin-3carboxylate, 1.8 g of phenylhydrazine and 40 ml of xylene is refluxed for 4 hours, cooled to room temperature, diluted with diethyl ether and filtered. The residue is dissolved in 50 ml of 2N aqueous sodium hydroxide, the solution washed with diethyl ether and its pH adjusted to 8.5 with ammonium chloride. The precipitate formed is collected, washed successively with hot water, methanol and diethyl ether, to yield the 4-methyl-2-phenyl-pyrazolo[4,3-c]quinolin-3(5H)-one, snowing in the -IR-spectrum peaks at 874, 867, 858, 850, 822, 780, 765, 756, 750, 740 and 722 cm1.

Analogously the 4-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one is prepared, melting at 349 - 350°.

Example 10: The mixture of 2.7 g of ethyl 4-chloro-6-methoxy-quinolin3-carboxylate, 1,4 g of p-fluorophenylhydrazine and 20 ml of eutectic diphenyl ether-biphenyl is heated to 160 - 165° for 4 hours, then 9 9 9 a cooled to room temperature and diluted with diethyl ether. The precipitated crystalline product is collected, washed thoroughly with aiethyl ether and dried, to yield the 2-(p-fluorophenyl)-8-methoxypyrazolo[4,3-c]quinolin-3(5H)-one hydrochloride melting at 322 - 324°.

Example 11: The mixture of 4 g of ethyl 4-chloroquinolin-3-carboxylate 2.04 g of 2-hydrazinopyridine and 50 ml of eutectic diphenyl etherbiphenyl is stirred at 110 - 130° for 3 hours under nitrogen. After cooling to room temperature it is diluted with diethyl ether, filtered the solids washed with diethyl ether and dissolved in 100 ml of Ιθ aqueous sodium hydroxide. The solution is washed with diethyl ether and the pH thereof adjusted to 8.5 hy addition of ammonium chloride. The precipitate formed is collected, washed successively with water, methanol and diethyl ether, to yield the 2-(2-pyridyl)-pyrazolo[4,3-c]quinolin-3(5H)-one showing in the IR-spectrum peaks at 887, 15 865, 853, 788, 780, 765, 756, 737 and 726 cm-1.

Analogously the 8-fluoro-2-(2-pyridyl)-pyrazolo-[4,3-c]quinolin 3(5H)-one is prepared,showing IR-peaks at 895, 868, 826, 792, 776, 758 and 725 cm"1.

The starting material for the latter is prepared as follows: 2q The mixture of 28.9 g of ethyl 6-fluoro-4-hydroxy-quinolin-3-carboxylate [J.A.C.S., 69, 371 (1947)] and 240 ml of phosphorus'oxychloride is refluxed under nitrogen for 3 hours. After cooling to room temperature, the solution is evaporated and the residue treated with icewater and chloroform. The organic layer is dried and evaporated. The residue is taken up in aqueous sodium bicarbonate and diethyl ether, the ethereal layer is dried and evaporated, to yield the ethyl 4chloro-6-fluoro-quinolin-3-carboxylate melting at 55 - 57°.

Example 12: The mixture of 3 g of 2-(p-methoxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one and 260 ml of 48 % hydrobromic acid is refluxed for 1 hour and concentrated to about 50 ml. The concentrate is cooled to room temperature, the precipitate collected, washed with methanol and diethyl ether, and dissolved in diluted aqueous sodium hydroxide.

The solution is washed with diethyl ether, then its pH adjusted to 8.5 by addition of ammonium chloride, precipipating a solid which is collected, washed with methanol, then with diethyl ether and dried, to yield to 2-(p-hydroxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one melting at 294 - 296°.

Example 13: The solution of 1.9 g of 2-(p-nitrophenyl)pyrazolo[4,3-c]~ quinolin-3(5H)-one in the mixture of 18.6 ml of 2N aqueous sodium jq hydroxide and 75 ml of ethanol is hydrogenated over 0.2 g of platinum oxide at 2.7 atm. for 6 hours. The mixture is filtered, the filtrate evaporated, the residue taken up in water and the solution washed with diethyl ether. The pH thereof is adjusted to about 8.5 by addition of aqueous ammonium chloride, the precipitate collected, washed successively with methanol and diethyl ether and dried, to yield the 2-(p-aminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)one, showing IR-peaks at 896, 885, 865, 840, 820, 815, 782, 776, 761, 740, 736 and 720 cm-1.

Example 14: To the mixture of 1.4 g of 2-(p-aminophenyl)-pyrazolo2o [4,3-c]quinolin-3(5H)-one, 4.1 ml of 37 2 aqueous formaldehyde, 1 g of sodium cyanoborohydride and 20 ml of acetonitrile, 0.6 g of glacial acetic acid are added while stirring. Stirring is continued overnight at room temperature and the mixture diluted with water.

The precipitate formed is dissolved in diluted sodium hydroxyde, the aqueous solution washed with diethyl ether and its pH adjusted to 8.5 by addition of aqueous ammonium chloride. The precipitate formed is collected, washed with methanol, then with diethyl ether and dried to yield the 2-(p-methylaminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)one melting at 302 - 304°. 9993 Example 15: The mixture of 0.7 g of 2-(p-aminophenyl)-pyrazolo[4,3-c] quinolin-3(5H)-one, 1.4 g of methylisocyanate and 25 ml of methanol is refluxed for 7 hours and allowed to stand at room temperature overnight. It is evaporated, the residue treated with diluted aqueous sodium hydroxide and diethyl ether, the aqueous solution separated, washed with diethyl ether and its pH adjusted to 8.5 with ammonium chloride. The precipitate formed is collected, washed with methanol, then with diethyl ether and dried, to yield the 2-(p-methylcarbamoylaminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing IR-peaks of 895, 869, 850, 816, 812, 785, 780, 767 and 738 cm1.

Example 16: 38.5 ml of a 0.17 M solution of ethyl 4-chloro-quinoline3-carboxylate in xylene, and 0,96 g of p-cyanophenylhydrazine in 30 ml of xylene are mixed and heated at 115 to 120° for 3 hours. The mixture is then cooled to room temperature, and stirred with 20 ml of IN aqueous sodium hydroxide and sufficient water to dissolve all solids. The aqueous layer is separated, washed twice with diethyl ether, then treated with an aqueous solution of 1.07 g ammonium chloride, and the resulting precipitate is collected, washed with water and dried to yield the 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing peaks in the IR-spectrum at 885, 830, 780, 755 and 730 cm \ Example 17: One gram of 2-(p-cyanophenyl)-pyrazolo[4,3-cjquinolin-3(5H)-one, 3,50 ml of IN aqueous sodium hydroxide and 10 ml of ethanol are mixed and stirred at room temperature until the solid has dissolved. The solution is then treated with 1.4 ml of 30 % hydrogen peroxide, giving an immediate precipitate. After stirring for 2 hours at room temperature, the mixture is filtered, and the solid is crystallized from dimethylformamide, to yield the 2-(p-carbamoylphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing peaks in the IRspectrum at 885, 853, 830, 785, 775, 752 and 732 cm \ Example 18: One gram of 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one and 50 ml of 2N aqueous sodium hydroxide are mixed and refluxed for 3 hours. The solution is acidified with 50 ml of hydrochloric acid, filtered, and the collected precipitate dried. It is taken up in 25 ml of IN aqueous sodium hydroxide, and the solution neutralized to pH=6-7 with IN hydrochlorid acid. The resulting solid is filtered off, triturated with water and dried, to give the 2-(pcarboxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one 3/2 hydrate, showing IR-peaks at 886, 858, 820, 780, 770, 760 and 730 cm \ j^q Example 19: The pH of the solution of 1 g of 4-chloro-quinoline-3(N-phenyl-N-trifluoroacetamido)-carboxamide in the minimum amount of 50 X aqueous tetrahydrofuran is adjusted to 10 by the addition of lithium hydroxide. The mixture is stirred at room temperature for 48 hours, concentrated to remove most of the tetrahydrofuran, washed with dichloromethane, and acidified to pH=3 by addition of diluted hydrochloric acid. The precipitate formed is collected by suction filtration, and purified by preparative thin layer chromatography using toluene: ethanol: cone, ammonium hydroxide (70:30:3) as developing solvent on silica gel, to obtain the 2-phenyl-pyrazolo[4,3-c]2o quinolin-3(5H)-one melting at 326° - 328°.

The starting material is prepared as follows: To the ice-cooled solution of 10.8 g of phenylhydrazine in 120 ml of diethyl ether, 10.5 g of trifluoroacetic anhydride in 25 ml of diethyl ether are added dropwise over the period of 15 minutes. The mixture is stirred at 0-5° for 15 minutes, then at room temperature for 2 hours, whereupon it is filtered. The filtrate is washed with water, dried, evaporated and the residue crystallized from diethyl ether: n-heptane, to yield the β-trifluoroacetylphenylhydrazine melting at 119-121°.

The mixture of 1.5 g thereof in 100 ml of tetrahydrofuran and 0,06 g of lithium hydride is stirred under moisture exclusion for 49903 hours at room temperature, to form a solution. Separately, 1,9 g of 4-chloro-3-chlorocarbonylquinoline hydrochloride are stirred in 100 ml of tetrahydrofuran with 0.06 g of lithium hydride under moisture exclusion for one minute at 10°, and the solution is added to the former in 10 ml portions. The mixture is stirred at room temperature for 18 hours, then refluxed for 8 hours and concentrated under reduced pressure, obtaining the 4-chloroquinoline-3-(N-phenyl-N-trifluoroacetamido)-carboxamide, which is used without further purification.

Example 20: The mixture of 0.211 g of 4-(0-methylhydroxylamino)quinoline-3-(N-p-chlorophenyl)-carboxamide, and 15 ml of eutectic diphenyl ether-biphenyl is heated to 240° for 2 hours under nitrogen. It is cooled to room temperature, diluted with 150 ml of petroleum ether, and the resultant precipitate is collected. It is washed with petroleum ether, stirred with 15 ml of diethyl ether and 3 ml of 2N aqueous sodium hydroxide for 1 hour, filtered to remove insoluble material, and the layers of the filtrate are separated. The aqueous phase is treated with 0.32 g of ammonium chloride, to give a yellow precipitate, which is collected and recrystallized from ethanol, to yield the 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one melting 2q at 327°; it is identical with that of Example 1.

The starting material is prepared as follows: The mixture of 11,62 g of 4-hydroxyquinoline-3-carboxylic acid [H. Hamana et al., Chem. Pharm. Bull., 26, 3856 (1978)], 7.84 g of p-chloroaniline, 17.59 g of l-ethoxycarbonyl-2-ethoxy-l,2-dihydro25 quinoline, and 150 ml of dimethylformamide is heated at 60-70° for 2 hours, to obtain a clear solution. It is cooled, filtered and evaporated in a rotary evaporator. The residue is triturated with diethyl ether, filtered, and the collected solid is washed with diethyl ether, to yield a mixture containing starting acid. It is stirred in 100 ml of 2N aqueous sodium hydroxide for 1.5 hour, filtered, washed with water, and dried to obtain the 4-hydroxy49993 quinoline-3-(N-p-chlorophenyl)-carboxamide, showing IR-peaks at 3450, 3260 and 3210 cm1.

The mixture of 1 g thereof and 25 ml of phosphorus oxychloride is heated at 80° for 3 hours to obtain a clear solution. It is evaporated, the residue treated with 400 ml of a 1:1 mixture of ice and 2N aqueous sodium hydroxide, stirred with 200 ml of dichloromethane, filtered and the layers separated. The organic phase is dried and evaporated, to yield the 4-chloroquinoline-3-(N-p-chlorophenyl)carboxamide, melting at 229-234°. (It may also be prepared by treating said acid with phosphorus oxychloride first, and the resulting dichloride with said aniline second).

The mixture of 0.5 g thereof, 1 g of 0-methylhydroxylamine hydrochloride and 1.65 g of diisopropylethylamine is heated to 100° in a small pressure vessel for 18 hours. The cooled mixture is then triturated with water, dissolved in tetrahydrofuran, dried, evaporated and the residue recrystallized from methanol, to yield the 4-(0methylhydroxylamino)-quinoline-3-(N-p-chlorophenyl)-carboxamide melting at 210-212°.

Example 21: The solution of 308 mg of 1-(p-chlorophenyl)-4-hydroxymethylene-3-(o-nitrophenyl)-4,5-dihydropyrazol-5-one in 80 ml of tetrahydrofuran is hydrogenated over 50 mg of 5 Z platinum on charcoal at room temperature and 3 atmospheres for 0.5 hour. The mixture is filtered, the filtrate evaporated and the residue taken up in 150 ml of toluene. To the solution, 0.1 ml of cone, hydrochloric acid is added, and the mixture refluxed at a water separator for 18 hours.

It is cooled, the precipitate formed filtered off and purified by preparative thin layer chromatography, using ethyl acetate: ethanol: cone, ammonium hydroxide (17:3:3) as developing solvent on silica gel, to yield the 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one melting at 327°, it is identical with that of Example 1. 49983 The starting material is prepared as follows: The solution of 39.6 g of monoethyl malonate, 50 mg of 2,2-bipyridyl (indicator) and 650 ml of tetrahydrofuran is cooled to -70°, whereupon 305 ml of 1.97 M n-butyl lithium in hexane are added slowly under nitrogen while stirring. The temperature is allowed to rise to about -5° near the end of addition, after the pink color of the indicator persists. The mixture is recooled to -65°, and the solution of 31.7 g of o-nitrobenzoyl chloride in 50 ml of tetrahydrofuran is added dropwise within 10 minutes. The resultant mixture is stirred at room temperature for 1 hour and then poured onto a mixture of 650 ml of IN hydrochloric acid and 1100 ml of diethyl ether. The organic layer is separated, washed successively with 350 ml of saturated aqueous sodium bicarbonate, 400 ml of water and 200 ml of saturated aqueous sodium chloride solution, dried and evaporated, to yield the ethyl 2-(o-nitrobenzoyl)-acetate, as a colorless oil.

The solution of 3.55 g thereof and 1.7 g of p-chlorophenylhydrazine in 65 ml of toluene is refluxed for 3 hours at a water separator. The mixture is evaporated, the residue chromatographed on silica gel with 15 % ethyl acetate in toluene as eluent, to yield the 1-(p-chlorophenyl)-3-(o-nitropheny1)-4,5-dihydropyrazol-5-one, melting at 138-141°. 0.7 g thereof is stirred in 10 ml of dimethylfonnamide dimethylacetal at room temperature for 18 hours. The dark reaction mixture is poured onto ice-water, the precipitate is collected by suction filtration, taken up in ethyl acetate, washed with water, dried and evaporated to leave the 1-(p-chlorophenyl)-4-dimethylaminomethylene3-o-nitrophenyl-4,5-dihydropyrazol-5-one, melting at 208-210° (decomposition). 2.5 g thereof are stirred in the mixture of 20 ml of tetrahydrofuran and 20 ml of 20 2 aqueous hydrochloric acid, at 60° for hours, then at room temperature for 18 hours. It is diluted with saturated aqueous sodium chloride solution, the precipitate collected and washed with ethyl acetate, leaving the l-(p-chlorophenyl)-4-hydroxymethylene-3-(o-nitropheny1)-4,5-dihydropyrazol-5-one, melting at 155-157°.

Example 22: The mixture of 550 mg of 1-(p-chlorophenyl)-2-methy1-4anilinomethylidene-pyrazolidin-3,5-dione, 2 g of ethyl polyphosphate and 10 ml of 1,1,2,2-tetrachloroethane is refluxed for 24 hours. The solution is poured onto 10 ml of 2N aqueous sodium hydroxide and the organic layer chromatographed on silica gel plates, using toluene: ethanol:conc. ammonium hydroxide (80:20:1) as eluent, to yield the 1methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one with an Rf= 0.48. When using dichloromethane:methanol (19:1) as eluent, said compound has the Rf « 0.33. The compound is identical with that of example 4.

The starting material is prepared as follows: g of diethyl malonate are added to 5.8 g of sodium metal dissolved in 100 ml of absolute ethanol. After stirring for 15 minutes, 17.8 g of p-chlorophenylhydrazine are added, and the resulting mixture is stripped to remove excess ethanol. The residue is heated at 110 to 120° for 4.5 hours, then quenched with 500 ml of ice-water. The resulting mixture is washed twice with diethyl ether and the aqueous layer is acidified with cone, hydrochlorid acid to a pH below 2. The resulting solid is recrystallized from toluene, to give the l-(pchlorophenyl)-pyrazolidin-3,5-dione melting at 189-193°.

The mixture of 2 g thereof, 2.81 g of triethyl orthoformate, 0.97 g of aniline and 30 ml of ethanol is refluxed for 16 hours. It is cooled, filtered and the residue washed with water, to yield the 1-(p-chlorophenyI)-4-anilinomethylidene-pyrazolidin-3,5-dione, melting at 288-290°. 4999 3 The mixture of 500 mg thereof, 15 mg of lithium hydride and 2 ml of dimethylformamide is heated at 70° for 3 hours. The solution is then cooled to 5°, and 700 mg of methyl iodide are added. The mixture is stirred for 16 hours at room temperature and evaporated.

The residue is taken up in water and dichloromethane, the organic phase separated, dried and evaporated, to yield the l-(p-chlorophenyl)2-methyl-4-anilinomethylidene-pyrazolidin-3,5-dione, showing NMR-peaks at 3,14, 7,47, 8,42, 10,92 and 10,98 ppm.

Example 23: The solution of 50 mg of 1-(p-chlorophenyl)-3-(o-formy1aminophenyl)-4,5-dihydropyrazol-5-one in 10 ml of dichloromethane is evaporated, leaving a thin film on the flask wall. This is heated at 190-200° for 30 minutes under a gentle stream of nitrogen. The reaction product is chromatographed on silica gel plates, using ethyl acetate:ethanol:conc. ammonium hydroxide (17:3:3) as eluent, to yield the 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one with an Rf = 0.16. When using 5 % methanol in dichloromethane, said compound has the Rf = 0.07, and with toluene:ethanol:cone, ammonium hydroxide (70:30:3), the Rf = 0.32.

The starting material is prepared thus: 2 g of l-(p-chlorophenyl)-3-(o-nitropheny1)-4,5-dihydropyrazol-5-one are catalytically hydrogenated in 100 ml of ethanol over 200 mg of 5 % platinum on carbon at room temperature and 3 atmospheres. Since the product crystallizes from the mixture as it is formed, the mixture is diluted with dichloromethane to dissolve said crystalline product. It is filtered, the filtrate evaporated, and the dried residue recrystallized from ethanol, affording the 3-(o-aminophenyl)-l-(p-chlorophenyl)-4,5dihydropyrazol-5-one melting at 199-201°. 0.3 g thereof are added to 10 ml of 97 % formic acid under ice cooling while stirring under nitrogen, to give a colorless solution. ml of acetic anhydride is added and the mixture stirred overnight at room temperature, then poured into 300 ml of saturated aqueous sodium chloride solution. The white precipitate is collected, dissolved in 200 ml of diethyl ether, dried and evaporated, leaving the l-(pchiorophenyl)-3-(o-formylaminophenyl)-4,5-dihydropyrazol-5-one, melting at 170-172°.

Example 24: According to the methods illustrated by the previous examples, advantageously Examples 1 and 8-11, the following compounds of Formula II are prepared: R^·· R^ « H. Ph refers to the 1,2phenylene portion of the quinoline moiety. o "1 No. Ph R m.p. C or IP-peaks cm 1 8-CH,0-C6H, 2-pyridyl 319 - 323 2 2-pyridyl 348 - 350 3C6»4 4-CHg-2-pyridyl 342 - 344 4C6H4 5-Cl-2-pyridyl 886, 835, 828, 797, 778, 756 5C6H4 2,5-Cl2~pIienyl 337 - 338 6C6H4 3,4-Cl2~phenyl 890, 878, 867, 823, 818, 795 7C6H4 3,5-C ^-phenyl 890, 871, 847, 830, 806, 788 As well as compounds of formula III: No. R R' m.p. °C or IR-peaks cm 8 H o-CH3 349 - 350 (HCl-salt) 9 Hp-ch3 338 - 340 10 H p-och3 268 - 270 11 H p-sch3 307 - 309 12 H p-F 342 - 346 13 H m-F 335 - 338 14 H o-F 338 - 340 15 H o-Cl 336 - 339 16 H rn-Cl 336 - 337 17 H p-Br 328 - 330 18 H p-cf3 315 - 320 Example 24: (Continued) „ -1 No. R R' m.p. C or IR-peaks cm 19 H p-no2 886, 853, 818, 780, 758, 749 20 7-C1 H 872, 851, 830, 818, 798, 770 21 7-C1 p-Cl 865, 852, 823, 795, 768, 752 22 7-C1 p-F 890, 858, 835, 804, 770, 731 23 7-C1 m-Cl 333 - 335 24 8-CH3 H 860, 810, 785, 770, 750, 730 25 8-CH3p-ch3 340 - 342 26 8-CH3 p-Cl 335 - 337 27 8-0CH3 H 321 - 325 28 8-0CH3 p-OCHj 313 - 315 29 8-0CH3 o-F 344 - 347 30 8-och3 m-Cl 324 - 327 31 8-OCH3 p-Cl 347 - 349 32 8-F a 327 - 328 33 8-F p-OCH^ 289 - 292 34 8-F p-F 884, 868, 827, 767, 715, 708 35 8-F m-F 900, 881, 865, 839, 827, 774 36 8-F o-F 868, 850, 815, 782, 750, 724 37 8-F p-Cl 342 - 345 38 8-F m-Cl 870, 810, 800, 775, 760, 714 39 8-C1 H 894, 871, 845, 812, 787, 770 40 8-C1 o-F 895, 875, 858, 820, 814, 782 41 8-C1 m-F 892, 884, 867, 860, 815, 771 42 8-C1 p-F 898, 890, 870, 855, 832, 820 43 8-C1 o-Cl 896, 885, 880, 848, 823, 789 44 8-C1 p-Cl 890, 842, 820, 806, 782, 768 45 8-C1 m-Cl 890, 865, 815, 790, 777, 740 46 8-C1 p-no2 895, 882, 849, 834, 308, 784 47 8-F p-no2 896, 884, 869, 860, 828, 821 48 8-0CH3 p-no2 338 - 340 Example 24; (Continued) No. R R' mp. °C or IR-peaks cm 1 49 6-C1 p-Cl 825, 806, 762, 736, 720 50 7-CF, H 324 - 327 51 7-CF, p-F 331 - 334 52 7-CF, m-Cl 317 - 320 53 7-CF3 p-Cl 890, 854, 826, 800, 770, 756 Example 25: Tablets each containing 5 mg of the active ingredient: 5 Formula (for 10 000 tablets) 2- 50 g Lactose Π57 g Corn Starch 75 g Polyethylene glycol 6,000 75 g Talcum powder 75 g 10 Magnesium stearate 18 g Purified water q.s.

All the powders are passed through a screen with openings of 0.6 am. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 25°, broken on a screen with 1.2 mm openings and 2o compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected. 499S3 Example 26: Capsules each containing 10 mg of the active ingredient: Formula (for 10 000 capsules) 2-ρΗβηγ1"ργϊΉΖθ1ο[4,3-c] quinolin-3(5H)—one 100 s Lactose 1800 g Talcum powder 100 g All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous No. 3 capsules are filled with 200 mg each, using a capsule filling machine.

Analogously tablets or capsules are prepared from the remaining compounds of the invention, e.g. those illustrated by the previous examples.

Claims

CLAIMS;

1. A Compound of the general formulae I and II RN-N-R r 3H- || II » L | 3 + II I ' (II) R.

2. A compound according to claim 1 of the formulae I and II, wherein R 3 is hydrogen or not more than 3 identical or 20 different members selected from C 1 -C 7 ~alkyl, C^-C 7 -alkoxy, C^-C 7 -alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino or mono- or di-C^-C 7 -alkylamino; and the other symbols have the meanings given in claim 1. ‘2 wherein R 3 is hydrogen or not more than 3 identical or

3. A compound according to claim 1 of the general formulae X and II, wherein R, is hydrogen or one or two members selected from C^-C^-alkyl, C^-C^-alkoxy, C 1 ~C 7 -alkyIthio, hydroxy, halogen, trifluoromethyl, nitro,

4. A compound according to claim 1 of the formulae I and II, wherein R, is hydrogen or one or two members 15 selected from lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-lower alkylamino; and the other symbols have the meanings given in claim 3. 5. 1, 3, 5, 8 or 9 for the manufacture of pharmaceutical preparations. 16. Use of a compound according to any one of claims 2,4,6,7 or 10 for the manufacture of pharmaceutical preparations.

5. A compound according to claim 1 of the formula III N H (III) wherein R” is hydrogen, alkyl or alkoxy, each containing 4 carbon atoms, hydroxy, fluorine, chlorine, bromine or trifluoromethyl; and R' is hydrogen, alkyl or alkoxy each containing 4 carbon atoms, hydroxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, amino, monoalkylamino or alkylcarbamoylaroino, each containing 4 carbon atoms, or cyano; or a salt thereof. 5 amino, mono- or di-C^-C^-alkylamino, cyano, carbamoyl and carboxy; R is phenyl or phenyl substituted by one or two of the substituents as defined for R,, pyridyl, C^-C^-alkylpyridyl or halopyridyl; R^ is hydrogen, C^-C^-alkyl or (hydroxy, di-Cj-C 7 -alkylamino or R,-phenyl)-C^-C^-alkyl, 5 different members selected from C^-Cyalkyl, C^-C^-alkoxy, C^-C^alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-C^-C^-alkylamino, cyano, carbamoyl and carboxy; R is phenyl or phenyl substituted by not more than 3 of the radicals as defined for R 3 , pyridyl, Cj-Cyalkylpyridyl,

6. A compound according to claim 1 of the formula Ill as indicated in claim 5, wherein R is hydrogen, alkyl or alkoxy, each containing 4 carbon atoms, hydroxy, fluorine, chlorine, bromine or trifluoromethyl, R' is hydrogen, o- or -m-fluorine, or a salt thereof.

7. 2-(p-Chlorophenyl)-pyrazolo /4.3-c7 quinolin-3(5H)-one or a salt thereof.

8. 2-Phenyl-pyrazolo /3.4-c7 quinolin-3(5H)-one or a salt thereof.

9. A compound according to claim 1 for use as psychoactive drug. 10. Of the invention, and/or, if desired, converting a resulting compound into a salt thereof, or a resulting salt into the corresponding free compound or into another salt, and/or, if desired, separating a mixture of isomers obtained Into the individual isomers. 10 17. A process for the manufacture of a 2-aryl-pyrazolo /4,3-c7 quinolin-3-(1 or 5H)-one as defined in claim 1, which comprises a) cyclising a compound of the formula IV ’Η - 'vV’\ (IV) 15 wherein X is —NH—NH—R and Y is hydroxy OT C. -C.,-alkoxy; I 1 ' or X is halogen and Y is H 2 N—R; or X is C^-Cy-alkoxyamino or azido, and Y is NH—R, and, if desired, reacting a resulting compound, or an alkali metal salt thereof, with a reactive ester of the alcohol R^—OH, or b) condensing a compound of the formula V r 3 —I - I \ Z ‘ X N-Z (V) wherein W and are both hydrogen, Z is and R-jJ is C^-C^-alkyl; or W is N=CCH-CORR-N-CO and Z is hydrogen; or W is R-N-CO I and Z is R 2 —CO, or R^—N—Z together is isocyano; and, if desired, converting a resulting compound into another compound

10. A compound according to claim 2 for use as psychoactive drug. 10 wherein the hydroxy or amino group is separated from the ring-nitrogen atom by at least 2 carbon atoms; and R, is hydrogen or C^^-Cy-alkyl. 10 or halopyridyl; R^ is hydrogen, C^-C^-alkyl or (hydroxy, di-C 1 -C 7 -alkylamino or R 3 -phenyl)-C^-C 7 -alkyl, wherein the hydroxy or amino group is separated from the ring nitrogen atom by at least 2 carbon atoms, and R 2 is hydrogen or Cj-Cy-alkyl; their 3-hydroxy-tautomers; C^-C 7 -alkanoyl, 15 carbamoyl, mono- or di-C 3 -C 7 ~alkylcarbamoy1 derivatives of said (hydroxy or amino) - (phenyl or phenylene) compounds; or salts thereof.

11. A pharmaceutical preparation containing a compound according to any one of claims 1,3,5,8 and 9, or a therapeutically acceptable salt thereof.

12. A pharmaceutical preparation containing a compound according to any of claims 2,4,6,7 and 10, or a therapeutically acceptable salt thereof.

13. A compound of any one of claims 1,3,5,8 and 9 for use as a psychoactive drug for treating the human or animal body.

14. A compound of any one of claims 2,4,6,7 and 10 for use as a psychoactive drug for treating the human or animal body. 15. Use of a compound according to any one of claims

15. 18. A compound obtainable according to the process of claim 17.