FI68827B - ANALOGIFICATION OF THE THERAPEUTIC ACQUISITION OF THERAPEUTIC NETWORK 2-PHENYL-ELLER-PYRIDYL-PYRAZOLO (4,3-C) QUINOLIN-3 (1 OCH5H) -ON-FOERENINGAR - Google Patents

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

m «« ANNOUNCEMENT sQonn B 11 UTLÄGG NIN G SSKRI FT 6 882 7 C (45) Γ "exam granted II il 1935 (51) Kv.lk.4 / lnt.CI.4 C ° 7 D 471/04 / / (C 07 D 471/04, C 07 D 231: 00, C 07 D 221: 00) FINLAND-FINLAND (21) Patent application - Patentansöknlng 8 0 1964 (22) Application date - Ansöknlngsdag 18.06.80 (23) Starting date - Giltighetsdag 18.06.80 (41) Made public - Bllvit offentlig 22 12 80

National Board of Patents and Registration ....... ...,. .., '/ 44I Date of opening and issue of the publication—,. .. oc

Patent and Registration Office in the United Kingdom of Great Britain and Northern Ireland 3 I .U / .Ö3 (32) (33) (31) Privilege claimed - Begärd priority 21 .06.79 USA (US) 50716 (71) Ciba-Geigy AG, Klybeckstrasse 141 , CH-4002 Basel, Switzerland-Switzerland (CH) (72) Naokata Yokoyama, Cliffside Park, New Jersey, USA {Jk) Oy Jalo Ant-Wuorinen Ab (5 * 0 Analogue method for new therapeutically active 2-phenyl- or -pyridyl-pyrazolo [1,3 ', 3-quinolin-3 (1 and 5H) -one compounds - Analogs for the preparation of 2-phenyl-pyrrolidin-1-pyrazolo [1,3-c] However, 2-unsubstituted 3-phenyl-pyrazolo (4,3-c) quinolin-3-ones or their 3-hydroxyautomers have been described in .7k-n (3 and 5H) -oneforen; In contrast, 2-phenyl-pyrazolo (3,4-c) isoquinolin-3-ones (or -3-ols) are disclosed in J. Chem. Soc. 1959, 599 and European Patent Application 5745 discloses a 3- phenylpyrazolo (3,4-c) isoquinolin-5-ones shown in anti-infl as amatorial, central nervous system-depressant and analgesic agents.

This invention relates to an analogous process for the preparation of novel therapeutically active 2-phenyl- or pyridyl-pyrazolo (4,3-c) -quinolin-3 (1 or 5H) -one compounds of general formulas I and II in the amount of 2 68827 κ ,. . *! - ¥ - ¥ - * R, IrlT1? *> W \ Wv \ I H I D3 I li li ·. *. „· · · ·

^ V V V V V

I 1 \ (1) (Π) in which hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, R represents phenyl which is unsubstituted or substituted by at most two identical or different substituents which are lower alkyl, lower alkoxy, lower alkyl , hydroxy, halogen, trifluoromethyl, nitro, amino, mono- or di-lower alkylamino, cyano, carbamoyl, lower alkylcarbamoylamino or carboxy; pyridyl, lower alkylpyridyl or halopyridyl, R 1 represents hydrogen, lower alkyl or (di-lower alkylamino or haloethyl) lower alkyl, and R 2 represents hydrogen or lower alkyl; wherein in each "lower" means a residue having 1 to 4 carbon atoms; for the preparation of their 3-hydroxyautomeric compounds or their salts.

The phenylene residue is unsubstituted or substituted by one substituent R-j which is lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl; lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy; hydroxy; halogen, e.g. fluorine, chlorine or bromine or trifluoromethyl.

The phenyl or pyridyl residue at the R 2 position is preferably said ortho-unsubstituted phenyl residue which, as defined above, is unsubstituted or contains at most two substituents, but R is also 3-, 4- or 2-pyridyl or one of said alkylated or halogenated pyridyl, preferably (4-methyl or 5-chloro) -2-pyridyl. Of the above-mentioned substituents, only one of the substituents listed starting from trifluoromethyl is preferably used in each case.

6 S ε 2 7

The symbol R 1, either in the 1- or more preferably 5-position, is preferably hydrogen, but also one of said alkyl groups or a dialem-alkylamino-lower alkyl group which separates adjacent heteroatoms by at least 2 carbon atoms. Such residues include 2- (dimethylamino or diethylamino) ethyl, 2- or 3- (dimethylamino) propyl.

The residue 1 * 2 in the 4-position is also preferably hydrogen or one of the abovementioned alkyl groups, in particular methyl.

Due to said 1- or 5-substituents, the compounds of this invention are in fact 3-ones or 3-oxy derivatives. However, when the symbol R 1 denotes hydrogen, the compounds can, depending on the medium and the substitution, form a small amount of tautomeric 3-hydroxy compounds. In general, however, they are weak bases or acids, the salts being obtained with either strong acids or bases. In fact, said (hydroxy or amino) -Ph derivatives form acyl derivatives. Said acyl derivatives are lower alkanoyl, carbamoyl, mono- or dialkylalkylcarbamoyl derivatives of the above-mentioned (hydroxy or amino) phenyl compounds or (hydroxy or amino) phenylene compounds. Such derivatives are, for example, acetyl, propionyl, pivaloyl, (methyl or ethyl) carbamoyl derivatives. The salts are preferably alkali metal salts, e.g. the sodium or potassium salts of 1- or 5-unsubstituted compounds (R 1 = H) and / or carboxy- (phenyl or phenylene) compounds, or the acid addition salts of all said compounds with acids, in particular below. with said acids.

The term "lower" defines the above or the following mentioned organic residues or compounds as containing up to 7, preferably up to 4, in particular 1 or 2 carbon atoms.

The compounds according to the invention have valuable pharmacological properties, namely psychoactive effects, in particular antidepressant or analgesic properties. These can be detected by in vitro or in vivo test methods, preferably mammals, e.g. mice, rats or monkeys are used as experimental animals. Said compounds may be administered to experimental animals enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. in the form of injectable capsules or in the form of suspensions or aqueous solutions or suspensions containing starches. The dose used may be about 0.01 to 100 mg / kg / day, preferably about 0.05 to 5 mg / kg / day, especially about 0.1 to 0.5 mg / kg / day.

Said antidepressant properties can be detected in the mouse by the "Behavioral Despair" test (Arch, Int.Pharmacodyn.Ther. 229 (2), 327-336, October 1977). In this test, the test animal is forced to swim in a cramped cylinder from which it cannot escape, resulting in a depressed state. After a short lively active period, the mouse adopts a typical, immobile body position that is easily identifiable. The occurrence of this immobility is reduced by the compounds of this invention, other tricyclic antidepressants, monoamine oxidase inhibitors, atypical antidepressants, and electroconvulsive shock.

The analgesic effects are routinely observed in the rat by the classical Metrazol antagonism test or by the Cook-Davidson conflict method using male Wistar rats. The body weight of these rats is reduced by diet, without limiting water intake, to 80% of normal body weight. They are trained to press a lever inside the air-conditioned chamber. The chamber also includes a dropper for the liquid, a light source, a loudspeaker and a lattice base. Both the lever and the cage are connected to an electric shock source. The chamber is located in a sound-insulated space where, during the test method, a white noise source blocks external sound. Each 47-minute trial period consists of two alternating programs. The first is a 30-second variable interval (VI) program that is repeated for 5 minutes. In this program, a sweetened dose of condensed milk is given to the rat 30 seconds after the first lever contact. The reduction in lever contact performance caused by the active substance is considered an indication of neutrological deficiency. Immediately after the (VI) program, a 1000 Hz sound and light signal is activated simultaneously, signaling the start of another so-called "Fixed Ratio" (FR) program lasting 2 minutes. During this time, a foot shock is immediately caused by the freezing of ten lever presses, at the same time as the milk dose, creating a conflict situation. The intensity of said shock is 2.0-3.6 mA. It varies with each experimental animal so that during this program, throughout the experimental period, the number of lever presses would be about 25-100. The increase in this performance provided by the active agent during the FR program is considered to be an indication of the analgesic effect that the compounds of this invention thus have.

The analgesic effects of the new compounds can also be evaluated by the "Diazepam Receptor-Binding" assay in vitro, e.g. as described in Nature 266, (1077) or Proc.Nat, Acad.

Sci. USA 74, 3805 (1975). Diazepam binds specifically and with high affinity to crude synaptosomal, rat forebrain membrane preparations. This binding is inhibited by other analgesic compounds, e.g. pharmacologically active benzodiazepines. When tritiated diazepam is used, the interaction of other active substances with said receptor can be easily assessed as follows: rat forebrain membranes are incubated at 0-5 ° with different concentrations of tritiated diazepam and test substances in physiological medium, pH 7.5. Membranes containing receptors, along with varying amounts of tritium-labeled diazepam, are filtered through a glass fiber filter. These are then shaken on a liquid scintillation counter. The concentration of the compounds of the invention required to inhibit the specific binding of 2 nM tritiated diazepam by 50%, i.e. the ICj-q (Inhibitory Concentration), can be calculated graphically. This concentration is less than about 0.6 nM. This concentration is on the order of magnitude lower than that of diazepam (5 nM) and almost four potencies lower than that of chloridiazepoxide (400 nM).

Thus, the compounds of the invention are valuable in the treatment of mental depression and in particular in the treatment of pain conditions similar to those treated with diazepam. In contrast to diazepam, the compounds of the invention clearly do not show any tendency to neurological deficiency at doses at which the analgesic effect already exists. In addition, the new compounds can be used as intermediates in the preparation of other valuable, in particular pharmacologically active, preparations.

6 68827

Preferred are compounds of formula (III): • · · · · ^ \ / \ / V. \ ^ R "—4— li II 0 '(III), ·. · ·

VV

wherein R "represents hydrogen, alkyl or alkoxy each having 4 carbon atoms, hydroxy, fluorine, chlorine, bromine or trifluoromethyl, R 'represents hydrogen, o- or m-fluorine or p-fluorine, when R" represents chlorine; or salts thereof, especially pharmaceutically acceptable alkali metal or acid addition salts, due to their superior antidepressant activity.

Compounds of formula (III) wherein R "is as defined above, R 'is alkyl or alkoxy each having 4 carbon atoms, hydroxy, chlorine, bromine, trifluoromethyl, nitro, amino, monoalkylamino or alkylcarbamoylamino, in each case has up to 4 carbon atoms, or cyano or p-fluorine when R "is other than chlorine, or salts thereof, especially pharmaceutically acceptable alkali metal or acid addition salts, are particularly preferred due to their superior analgesic activity.

Compounds of formula (III) wherein R "represents hydrogen or 8- (methyl, methoxy, fluorine or chlorine), R 'represents hydrogen or 4-fluorine when R" is 8-chloro; or salts, especially pharmaceutically acceptable alkali metal or acid addition salts, are preferred due to their superior antidepressant activity.

Compounds of formula (III) wherein R "represents hydrogen or 8- (methyl, methoxy, fluorine or chlorine) or R 'represents 4- (methyl, methoxy, chlorine, bromine, amino or cyano) or 4-fluoro when R" "is different from 8-chlorine; or salts, especially their pharmaceutically acceptable alkali metal or acid addition salts, are preferred due to their superior analgesic activity.

Further compounds of general formula (III) wherein R 'is hydrogen and R "is hydrogen, 8- (methoxy, fluorine or chlorine) or R' is 4-fluoro and R" is 8-chloro; or salts, especially their sodium salt, hydrochloride or methanesulfonate, are preferred because of their superior antidepressant activity.

Compounds of formula (III) in which R 'represents 4- (methyl, chlorine or amino) and R "represents hydrogen; or salts, in particular their sodium salt, hydrochloride or mesylate, are particularly preferred because of their superior analgesic activity.

The compounds according to the invention are prepared according to methods known per se, e.g. by la-ringing the compounds of formula (IV)

X

K3 \ * '! * YV “« V,.

V v wherein X represents a residue -NH-NH-R and Y represents hydroxy or alkoxy, or lb) ring-closing compounds of formula (IV) in which X represents halogen and Y represents H 2 N-NR, or lc) ring-closing compounds of formula (IV) wherein X is lower alkoxyamino and Y is NH-R.

The ring closure of said acids or amides of formula (IV) is carried out by heating to a temperature of about 80-180 ° C, preferably with inert solvents, e.g. aliphatic or aromatic hydrocarbons and / or ethers such as toluene, xylene, biphenyl and / or in the presence of diphenyl ether, distilling off the water or alkanol formed. Said hydrazides of formula (IV) are ring-closed in a similar manner, but preferably under neutral conditions, e.g. in the presence of aqueous alkali metal hydroxides, to neutralize the hydrohalic acids formed. The ring closure of said amides of formula (IV) is effected by heating to a temperature of about 120-30 ° C, preferably about 200-250 ° C, especially also in the presence of said inert solvents. .

Some of the starting materials of formula (IV) are novel, however, they can be readily prepared from known starting materials in which X represents hydroxy by condensation with the corresponding arylhydrazines. Such methods are described, for example, in the examples or in J.Med. Chem. 1_2, 1 096 (1 969) or C.R.Acad.Sc. Paris, Vol 280, C, 1385 (1975). Said hydrazides are obtained by condensing 4-chloroquinoline-3-carboxylic acid chlorides and β-acylated arylhydrazines, e.g. trifluoroacetates, which hydrolyze under ring closure conditions. Said amides are preferably prepared by condensing 4-halo-quinoline-3-carboxylic acid halides with R-amines followed by o-lower alkylhydroxylamines or alkali metal azides.

Another method for the preparation of the compounds according to the invention is based on 2a) condensing the compounds of formula (Va) vrr * o C \> (Va) 3> \ Il I Tl CR, • · / / \ / \ s • l \ h wherein both W and R 1 represent hydrogen and 'represents lower alkyl, or 2b) condensing compounds of formula (Vb) 68827

Ji ~ TF

% \ A * m,) • · i il i V \ C0K2 ΐ-Η * 1 or 2c) condensing compounds of formula (Vc)

V

3V \ / cfi i ή 2 (Vc)

Vy ™ 2 R 1 and, if desired, the compound obtained are converted into another compound of the invention, and / or, if desired, the compound obtained is converted into a salt thereof, or the salt obtained is converted into the free compound or another salt, and / or the mixture of isomers obtained is separated into individual isomers.

The ring closure condensation of the starting materials of formula (Va) is preferably carried out with strong, aprotic condensing agents, e.g. polyalkosphoric acid lower alkyl esters. When using the starting material of formula (V), the water formed in the ring closure is preferably removed azeotropically. Preferably, the above-mentioned hydrocarbons and / or ethers are used, if desired in the presence of customary molecular sieves and / or a catalytic amount of an acid, e.g. hydrochloric acid.

Finally, the compounds of formula (Vc) are ring-capped under neutral conditions, optionally in the presence of dehydrating agents, e.g. thionyl halides, phosphorus oxyhalides or polyphosphoric acid lower alkyl esters.

10 6 S 8 2 7

The starting materials of the formulas (V) are also novel, but can be prepared according to methods known per se, e.g. by condensing 1-aryl-pyrazolidine-3,5-diones with ortho-formic acid ethyl ester and aniline. Said second starting material of formula (Vb) can be obtained in the same manner as described in Khim.Geterotsikl. Soedin. Akad. Nauk. Latv. SSR. 1965, 587, however, using the corresponding compounds having an o-nitro group which is subsequently reduced with catalytically activated hydrogen. The last group of starting materials of formula (Vc) is prepared, respectively, starting from said conventional 1-R-3- (o-nitrophenyl) -5-pyrazolones, by reduction, N-acylation and, if desired, dehydration with a mixture of phosgene or dimethylformamidothionyl halide, whereby said isonitriles are obtained.

The compounds according to the invention obtained can be converted into one another in a manner known per se. Thus, for example, compounds in which R 1 represents hydrogen may be substituted in the 1-position by a reactive ester of R 4 -OH. These esters are derived, for example, from hydrohalic acids, aliphatic or aromatic sulfonic acids, and mean, for example, R 1 - (halides, sulphates, aliphatic or aromatic sulphonates), such as methyl iodide, dimethyl sulphonate, methyl esters, sulphonyl sulphonate or methanesulphonate. There are thus obtained compounds of formula (I) which are 1-substituted. Such compounds of formula (II) are similarly prepared from the corresponding alkali metal salts, in which, for example, R 1 represents sodium or potassium, the substitution being in the 5-position. Furthermore, the lower alkoxy compounds obtained can be hydrolyzed to the corresponding phenols with strong hydrohalic acids, e.g. hydrobromic acid. The resulting nitro compounds can be reduced to the corresponding amines with catalytically activated or generated hydrogen, e.g. hydrogen in the presence of noble metal catalysts, e.g. nickel, palladium or platinum catalyst, or hydrogen formed by the action of reactive metals with alcohols or acids, e.g. zinc and halogen. Said amines can be alkylated as described for compounds in which R 1 = H, or they can be alkylated by reductive alkylation or they can be acylated, e.g. with corresponding, reactive acid derivatives, e.g. anhydrides, halides or iso-

II

1 1 6 3 8 2 7 with cyanates. The resulting nitriles can be converted to the corresponding amides in a manner known per se, e.g. by treatment with aqueous alkali metal hydroxide solutions, e.g. aqueous sodium hydroxide solution, ethanol and hydrogen superoxide, or they can be converted into the corresponding acids by hydrolysis, e.g. with aqueous sodium hydroxide, e.g.

Finally, the resulting compound can be converted either to its alkali metal salts, preferably using alkali metal hydrides, hydroxides or lower alkoxides, or to its acid addition salts (especially in the case of amino-substituted compounds), preferably using inorganic or organic acids to give therapeutically useful salts. Such acids include, for example, strong, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid or sulfuric, phosphoric, nitric or perchloric acid; or aliphatic or aromatic carboxylic and sulfonic acids, e.g. non-monetary, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, lemon, maleic, hydroxymaleic, pyruvic, phenyl -acetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotine, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic , toluenesulfonic, naphthalenesulfonic, sulfanilic, cyclohexylsulfamic acid; or ascorbic acid. These or other salts, e.g. picrates, can also be used to purify amino bases. The bases are converted to their salts, the salts are separated and the free compounds are liberated from the salts. Since the novel compounds are very similar in free form and in the form of their salts, the above and the following free compounds and salts are to be understood simultaneously and expediently as meaning possibly also the corresponding salts or free compounds. Acid addition salts of compounds which do not contain any basic substituents, e.g. they do not contain any amino group, are generally hydrolyzed in a substantially neutral, aqueous medium.

The above reactions are carried out according to methods known per se, catalysts in the presence or absence of diluents, preferably those which are inert to and soluble in the reagents, and / or in an inert atmosphere, refrigeration, at room temperature or at elevated temperatures. preferably at the boiling point of the solvent used, at normal or elevated pressure.

The resulting mixtures of isomers can be separated into the individual isomers by methods known per se, e.g. by fractional distillation, crystallization and / or chromatography.

The invention also relates to variants of this process in which the intermediate obtained at any stage of the process is used as starting material and the missing process steps are carried out, or the process is stopped at any stage, or in which the starting material is prepared under reaction conditions, e.g. starting material of formula (IV) where X = NH- NH-R, is prepared starting from its precursors where X represents chlorine or where the starting material is used in the form of a salt.

The starting materials used in the process according to the invention are preferably those which give the compounds initially described as being particularly valuable, in particular the compounds of the formula (III).

The pharmacologically useful compounds of this invention can be used in the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with carriers suitable for enteral or parenteral administration. Tablets or gelatin capsules containing the active ingredient together with diluents, e.g. lactose, dextrose, crude sugar, mannitol, sorbitol, cellulose and / or glycine and lubricants, e.g. diatomaceous earth, talc, stearic acid or its salts, such as magnesium or calcium, are preferably used. and / or polyethylene glycol; the tablets also contain binders, e.g. magnesium aluminum silicate, starch pastes, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, disintegrants and e.g. disintegrants, e.g. starches, agar, or alginic acid; or adsorbents, colorants, flavors and sweeteners. Formulations for injection are preferably isotonic, aqueous solutions or suspensions, and suppositories are primarily fat emulsions or suspensions. The pharmaceutical preparations may be sterilized and / or may contain adjuvants, e.g. preservatives, stabilizers, wetting and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.

6 8 8 2 7 13 These pharmaceutical preparations, which may, if desired, contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. by customary mixing, granulating or granulating methods, and contain from about 0.1 to about 75%, in particular from about 1-50% of active ingredient.

The following examples illustrate the invention without limiting the scope thereof. Temperatures are given in degrees Celsius and parts given are parts by weight. Unless otherwise specified, the solvents are evaporated under reduced pressure, e.g. at about 0.1-15 mmHg.

The compounds mentioned in the following examples with too high a melting point are described by their IR or NMP spectra. Example 1:

A mixture of 1681 g of 4-chloroquinoline-3-carboxylic acid ethyl ester, 1017 g of p-chlorophenylhydrazine and 25,000 ml of xylene is heated under nitrogen at 105 ° for 24 hours with stirring. The resulting suspension is cooled to 20 °, 14,000 ml of 2N aqueous sodium hydroxide solution are added, stirred for 15 minutes and diluted with 30,000 ml of water. Stirring is continued for 1 hour, the aqueous phase is separated, washed five times with 8000 ml of diethyl ether each time, filtered and the filtrate is treated with a solution of 1600 g of ammonium chloride in 8000 ml of water while stirring under a nitrogen atmosphere. The resulting suspension is stirred at room temperature overnight, filtered and the residue is washed five times with 12,000 ml of hot water. The residue is dried at 5 mmHg and 90 ° and 1665 g of it are dissolved in 8400 ml of dimethylformamide at 130 °. The solution is filtered and allowed to cool to room temperature while stirring. The suspension obtained is filtered, washed twice, each time with 500 ml of cold dimethylformamide and then washed four times with 1000 ml of diethyl ether and the residue is dried at 0.1 mmHg and 100 °. 2- (p-Chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one of the formula • - · 4 · (N-N - ') - Cl

Il I \ =.

/ \ / ‘V Ϊ II II 0 • · · vy 68827 1 4 and which melts at 324-327 ° while decomposing.

The starting material is prepared as follows (according to a commonly used method): 2953 g of ethoxymethylene-malonic acid diethyl ester are added to 1272 g of aniline over 20 minutes, while stirring, and stirring is continued for 135 minutes at 90-92 °. The ethanol formed is distilled off for 4 hours at 10 mmHg and 80 °. The residual oil is allowed to crystallize on the plates. The crystals are ground and dried at 5 mmHg and room temperature. Phenylaminomethylene malonic acid diethyl ester is obtained, melting at 45-46 °.

1085 g of the latter compound are added over 45 minutes to 10,850 ml of a eutectic mixture of diphenyl ether-biphenyl (73.5: 26.5 parts by weight) under a nitrogen atmosphere, while stirring, at 215-220 °. After the addition is complete, the temperature rises to 238 ° and the resulting mixture of ethanol and diphenyl ether is collected in a separator (about 390 ml) for 4 hours. The reaction mixture is allowed to cool to room temperature while stirring. The resulting suspension is filtered, the residue is washed twice, each time with 500 ml of diethyl ether and dried at 0.1 mmHg and 85 °. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester is obtained, melting at 276-280 °.

1630 g of the latter compound are added to 2463 ml of phosphorus oxychloride over 30 minutes under a nitrogen atmosphere with stirring. The mixture is stirred for 15 minutes at 70 ° and for 2 hours at 95 ° and then the liquid is distilled off at 11 mmHg and 60 °.

The residue is dissolved in 8000 ml of methylene chloride, the solution is cooled to 0 ° and treated with 5000 g of broken ice. The mixture is stirred, treated below 3000 with 3000 ml of 50% aqueous sodium hydroxide solution, and when pH 12 is reached, the organic layer is separated. This is washed twice with water, each time with 2000 ml of water and then washed once with 2000 ml of saturated aqueous sodium chloride solution, dried and evaporated. The residual oil is allowed to crystallize on plates. The crystals are ground and dried at 0.1 mmHg at room temperature. 4-Chloroquinoline-3-carboxylic acid ethyl ester is obtained, melting at 44-46 °.

To a solution of 1445 g of p-chloroaniline in 3375 ml of 38% hydrochloric acid and 5650 ml of water is added at -5 to -8 ° under 68827 for 15 hours under a nitrogen atmosphere, while stirring a solution of 793 g of sodium nitrite in 3300 ml: in water. After 15 minutes, 7617 g of stannous chloride in 9000 ml of 38% hydrochloric acid are added, over a period of 30 minutes and at a temperature below 25 °. The resulting suspension is stirred for one hour in an ice bath and filtered. The residue is suspended in 30,000 ml of water and added under a nitrogen atmosphere, while stirring 5,000 g of solid sodium hydroxide over one hour at 0-25 °. The mixture is extracted twice with 8000 ml of diethyl ether, the combined extracts are washed twice with 4000 ml of water and once with saturated aqueous sodium chloride solution, dried, filtered and evaporated. The residue is dried at 5 mmHg and room temperature. P-Chlorophenylhydrazine is obtained, melting at 82-87 °.

Example 2:

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

Example 3:

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

Example 4:

A mixture of 3 g of 2- (p-chlorophenyl) -pyrazolo (4,3-c) quinolin-3 (5H) -one and 100 ml of dimethyl sulphate is stirred at 110-130 ° for 2 hours and evaporated. The residue is dissolved in 1N aqueous sodium hydroxide solution, the solution is extracted with methylene chloride and the extract is evaporated. The residue is recrystallized from diethyl ether. 1-Methyl-2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3-one is obtained, melting at 158-161 °.

Example 5:

A mixture of 5 g of 2- (p-chlorophenyl) -pyrazolo (4,3-c) -quinolin-3 (5H) -one, 0.81 g of 50% sodium hydride in mineral oil 16,682827 and 100 ml of anhydrous tetrahydrofuran, reflux for 2 hours. The mixture is cooled to room temperature, 3 g of methyl iodide are added with stirring and after 1 hour, another 1 g of methyl iodide is added with stirring. The mixture is stirred overnight at room temperature, filtered and the residue is recrystallized from tetrahydrofuran-heptane. 5-Methyl-2- (p-chlorophenyl) -pyrazolo (4,3-c) Quinolin-3-one is obtained, melting at 322-323 °.

Example 6:

A mixture of 10 g of 2- (p-chlorophenyl) -pyrazolo (3,4-c) quinolin-3 (5H) -one, 1.8 g of 50% sodium hydride in mineral oil and 250 ml of 1,2- dimethoxyethane, stir at 100 ° until dissolution occurs. The mixture 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 is decanted and the residue is treated with said solution. 5- (3-Dimethylaminopropyl) -2- (p-chlorophenyl) -pyrazolo (4,3-c) quinolin-3-one is obtained, melting at 189-1910.

In a similar manner, 5- (2-dimethylaminoethyl) -2- (p-chlorophenyl) -pyrazolo [4,3-c] quinolin-3-one is obtained, melting at 184-186 °.

Example 7:

A 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, stir at 100 ° until dissolution occurs. The mixture is cooled to room temperature, 3.9 g of o-fluorobenzyl chloride in 2 ml of 1,2-dimethoxyethane are added and the mixture is refluxed for 4 hours. The mixture is cooled to room temperature, filtered, the residue is washed with diethyl ether, slurried in 10 ml of 1N aqueous sodium hydroxide solution, filtered again, washed with water and dried. 5- (o-Fluorobenzyl) -2- (p-chlorophenyl) -pyrazolo (3,4-c) quinolin-3-one is obtained, melting at 338-339 °.

Example 8:

A mixture of 3.5 g of 4- (2,4-dichloro-phenyl-hydrazino) -quinoline-3-carboxylic acid ethyl ester and 40 ml of eutectic diphenyl ether-biphenyl is heated at 175 ° for 4 hours, cooled to room temperature. and diluted with diethyl ether. The resulting suspension is filtered, the residue is washed with diethyl ether and dissolved in 1N aqueous sodium hydroxide solution. The solution is washed with diethyl ether, the pH is adjusted to anunonium chloride

II

68827 17 8.5 and the precipitate obtained is separated. The precipitate is washed successively with water, methanol and diethyl ether. 2- (2,4-Dichlorophenyl) -pyrazolo (4,3-c) quinolin-3 (5H) -one with bands 890, 867, 845, 832, 816, 796, 775, 767 in the IR spectrum is obtained. 756, 732 and 701 cm -1.

The starting material is prepared as follows: A mixture of 2.8 g of 4-chloroquinoline-3-carboxylic acid ethyl ester, 2.1 g of 2,4-dichlorophenylhydrazine and 40 ml of eutectic diphenyl ether-biphenyl is heated at 80-90 ° overnight, while stirring. The mixture is cooled to room temperature, diluted with diethyl ether and the precipitate is separated. This is dissolved in 1N aqueous sodium hydroxide solution, the solution is extracted with diethyl ether, the extract is washed with water, dried, filtered, concentrated and the precipitate is separated. 4- (2,4-Dichloro-phenylhydrazino) -quinoline-3-carboxylic acid ethyl ester is obtained, melting at 151-153 °.

Example 9:

A mixture of 3.6 g of 4-chloro-2-methyl-quinoline-3-carboxylic acid ethyl ester, 1.8 g of phenylhydrazine and 40 g 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 solution, the solution is washed with diethyl ether and the pH is adjusted to 8.5 with ammonium chloride. The precipitate obtained is separated and washed successively with hot water, methanol and diethyl ether. 4-Methyl-2-phenyl-pyrazolo (4,3-c) quinolin-3 (5H) -one with bands 874, 867, 858, 850, 822, 780, 765, 756, 750, 740 and 722 cm -1.

In a similar manner there is also prepared 4-methyl-2- (p-chlorophenyl) pyrazolo (4,3-c) quinolin-3 (5H) -one, m.p. 349-350 °.

Example 10:

A mixture of 2.7 g of 4-chloro-6-methoxy-quinoline-3-carboxylic acid ethyl ester, 1.4 g of p-fluorophenylhydrazine and 20 ml of eutectic diphenyl ether-biphenyl is heated for 4 hours at 160-165 °, then cooled to room temperature and diluted with diethyl ether. The crystalline product obtained as a precipitate is separated off, washed thoroughly with diethyl ether and dried. 2- (p-Fluorophenyl) -8-methoxy-pyrazolo [4,3-c] quinolin-3 (5H) -one hydrochloride is obtained, melting at 322-324 °.

68827 18

Example 11:

A mixture of 4 g of 4-chloroquinoline-3-carboxylic acid ethyl ester, 2.04 g of 2-hydrazino-pyridine and 50 ml of eutectic diphenyl ether-biphenyl is stirred under a nitrogen atmosphere at 110-130 ° for 3 hours. The mixture is cooled to room temperature, diluted with diethyl ether, filtered, the solid washed with diethyl ether and dissolved in 100 ml of aqueous sodium hydroxide solution.

The solution is washed with diethyl ether and the pH is adjusted to 8.5 with ammonium chloride. The resulting precipitate is separated and washed successively with water, methanol and diethyl ether. 2- (2-Pyridyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one with bands 887, 865, 853, 788, 780, 765, 756, 737 and 726 cm-1 is obtained in the IR spectrum. 1.

In a similar manner, 8-fluoro-2- (2-pyridyl) -pyrazolo (4,3-clquinolin-3 (5H) -one with bands 895, 868, 826, 792, 776, 758 and 725 in the IR spectrum is also prepared. cm-1.

The starting material for the latter compound is prepared as follows: A mixture of 28.9 g of 6-fluoro-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (jACS 69, 371 (1947)) and 240 ml of phosphorus oxychloride is boiled under a nitrogen atmosphere. 3 hours at reflux. Cool to room temperature, evaporate the solution and treat the residue with ice water and chloroform. The organic layer is dried and evaporated. The residue is dissolved in aqueous sodium hydrogen carbonate solution and diethyl ether, the ether layer is dried and evaporated. 4-Chloro-6-fluoro-quinoline-3-carboxylic acid ethyl ester is obtained, melting at 55-57 °.

Example 12:

A 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 one hour and concentrated to about 50 ml. . The concentrate is cooled to room temperature, the precipitate is separated, washed with methanol and diethyl ether and dissolved in dilute aqueous sodium hydroxide solution. The solution is washed with diethyl ether, then adjusted to pH 8.5 with ammonium chloride. The precipitate obtained is separated, washed with methanol, then with diethyl ether and dried. 2- (p-Hydroxyphenyl) -pyrazolo (4,3-c) -quinolin-3 (5H) -one is obtained, melting at 294-296 °.

19 68827

Example 13;

A solution of 1.9 g of 2- (p-nitrophenyl) -pyrazolo (4,3-c) -quinolin-3 (5H) -one in a mixture of 18.6 ml of 2N aqueous sodium hydroxide solution and 75 ml of ethanol, hydrogenate with 0.2 g of platinum oxide in 2.7 atmospheres for 6 hours. The mixture is filtered, the filtrate is evaporated, the residue is dissolved in water and the solution is washed with diethyl ether. Its pH is adjusted to 8.5 with ammonium chloride, the precipitate is separated and washed successively with methanol and diethyl ether and dried. 2- (p-Aminophenyl) -pyrazolo {4,3-c) -quinolin-3 (5H) -one with bands 896, 885, 865, 840, 820, 815, 782, 776, 761 in the IR spectrum is obtained. , 740, 736 and 720 cm-1.

Example 14;

To a mixture of 1.4 g of 2- (p-aminophenyl) -pyrazolo (4,3-c) -quinolin-3 (5H) -one, 4.1 ml of 37% aqueous formaldehyde, 1 g of sodium cyanoborohydride and 20 g of ml of acetonitrile, is added while stirring 0.6 g of glacial acetic acid. The mixture is further stirred at room temperature overnight and then diluted with water. The precipitate obtained is dissolved in dilute sodium hydroxide solution, the aqueous solution is washed with diethyl ether and adjusted to pH 8.5 with ammonium chloride solution. The precipitate obtained is separated off, washed first with methanol and then with diethyl ether and dried. 2- (p-Methylaminophenyl) -pyrazolo (4,3-c) quinolin-3 (5H) -one is obtained, melting at 302-304 °.

Example 15;

A mixture of 0.7 g of 2- (p-aminophenyl) -pyrazolo (4,3-c) quinolin-3 (5H) -one, 1.4 g of methyl isocyanate and 25 ml of methanol is boiled for 7 hours. at reflux, and left to stand at room temperature overnight. The mixture is evaporated, the residue is taken up in dilute aqueous sodium hydroxide solution and diethyl ether, the aqueous solution is separated, washed with diethyl ether and adjusted to pH 8.5 with ammonium chloride. The precipitate obtained is separated off, washed first with methanol and then with diethyl ether and dried. 2- (p-Methylcarbamoylaminophenyl) -pyrazolo (4,3-c) -quinolin-3 (5H) -one with bands 895, 869, 850, 825, 816, 812, 785 in the IR spectrum is obtained , 780, 767 and 738 cm-1.

Example 16:

After stirring for 3 hours at 115-120 °, a mixture of 38.5 ml of a 0.17 molar solution of 4-chloro-quinoline-3-carboxylic acid ethyl ester in xylene and 0.96 g of p-cyanide is heated. phenylhydrazine in 30 ml of xylene. The mixture is cooled to room temperature and stirred with 20 ml of 1N aqueous sodium hydroxide solution and the amount of water required to dissolve the solid. The aqueous layer is separated, washed twice with diethyl ether and then treated with an aqueous solution of 1.07 g of ammonium chloride. The precipitate obtained is separated off, washed with water and dried. 2- (p-Cyanophenyl) -pyrazolo- (4,3-c) quinolin-3 (5H) -one with bands 885, 830, 780, 755 and 730 cm-1 in the IR spectrum is obtained.

Example 17;

One gram of 2- (p-cyanophenyl) -pyrazolo (4,3-c) quinolin-3 (5H) -one, 3.50 ml of 1N aqueous sodium hydroxide solution and 10 ml of ethanol are mixed and the mixture is stirred at room temperature until the solid dissolves. The solution is then treated with 1.4 ml of 30% hydrogen peroxide, at the same time separating the precipitate. The mixture is stirred for 2 hours at room temperature, filtered and the solid is recrystallized from dimethylformamide. 2- (p-Carbamoylphenyl) -pyrazolo (4,3-c) quinolin-3 (5H) -one with bands 885, 853, 830, 785, 775, 752 and 732 cm-1 in the IR spectrum is obtained.

Example 18:

One gram of 2- (p-cyanophenyl) -pyrazolo [4,3-c] quinol 3 (5H) -one and 50 ml of 2N aqueous sodium hydroxide solution are stirred and the mixture is refluxed for 3 hours. The solution is acidified with 50 ml of hydrochloric acid, filtered and the separated precipitate is dried. This is dissolved in 25 ml of 1N aqueous sodium hydroxide solution and the pH of the solution is adjusted to 6-7 with 1N hydrochloric acid. The solid obtained is filtered off with suction, triturated with water and dried. 2- (p-Carboxyphenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one 3/2 hydrate with bands 886, 858, 820, 780, 770, 760 and 730 cm-1 is obtained 1.

Example 19:

To a solution of 1 g of 4-chloro-quinoline-3- (N-phenyl-N-trifluoroacetamido) carboxamide in as little as possible of 50% aqueous tetrahydrofuran, the pH is adjusted to 10. 63827 by adjusting lithium hydroxide. The mixture is stirred for 48 hours at room temperature, concentrated to remove most of the tetrahydrofuran, washed with dichloromethane and the pH is adjusted to 3 with dilute hydrochloric acid. The precipitate obtained is filtered off with suction and purified by preparative thin layer chromatography on silica gel. Elute for toluene: ethanol: conc. ammonium hydroxide (70: 30: 3). 2-Phenyl-pyrazolo (4,3-c] quinolin-3 (5H) -one is obtained, melting at 326-328 °.

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

A mixture of 1.5 g of the latter compound, 100 ml of tetrahydrofuran and 0.06 g of lithium hydride is stirred to obtain a solution at room temperature for 5 hours, while being protected from moisture. Separately, 1.9 g of 4-chloro-3-chlorocarbonyl-quinoline hydrochloride in 100 ml of tetrahydrofuran are stirred together with 0.06 g of lithium hydride at 10 ° for one minute while being protected from moisture, and this solution is added to 10 ml of in portions to the above solution. The reaction mixture is stirred at room temperature for 18 hours, then refluxed for 8 hours and concentrated under reduced pressure. 4-Chloro-quinoline-3- (N-phenyl-N-trifluoroacetamido) -carboxamide is obtained, which is used without further purification.

Example 20:

A mixture of 0.211 g of 4- (O-methylhydroxylamino) quinoline-3- (N-p-chlorophenyl) carboxamide and 15 ml of eutectic diphenyl ether biphenyl is heated under nitrogen for 2 hours at 240 °. The mixture is cooled to room temperature, diluted with 150 ml of petroleum ether and the precipitate obtained is separated. This is washed with petroleum ether, stirred for 1 hour with 15 ml of diethyl ether and 3 ml of 2N aqueous sodium hydroxide solution, the solid is filtered off with suction and the phases of the filtrate are separated.

22 6 8 8 2 7

The aqueous phase is treated with 0.32 g of ammonium chloride. A yellow precipitate is obtained which is separated and recrystallized from ethanol. 2- (p-Chlorophenyl) -pyrazolo (4,3-c) quinolin-3 (5H) -one is obtained, melting at 327 °. The product is identical to the product of Example 1.

The starting material is prepared as follows: A mixture of 11.62 g of 4-hydroxyquinoline-3-carboxylic acid (M. Hamana et al., Chem. Pharm. Bull. 26, 38 56 (1978)), 7.84 g of p- chloroaniline, 17.95 g of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and 150 ml of dimethylformamide are heated to give a clear solution at 60-70 ° for 2 hours. The solution is cooled, filtered and evaporated on a rotary evaporator. The residue is triturated with diethyl ether, filtered and the precipitate is washed with diethyl ether. A mixture is obtained which contains the residue of the acid used as starting material. The mixture is stirred for 1.5 hours with 100 ml of 2N aqueous sodium hydroxide solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3- (N-p-chlorophenyl) carboxamide having bands 3450, 3260 and 3210 cm-1 in the IR spectrum is obtained.

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

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

Example 21:

A solution of 308 mg of 1- (p-chlorophenyl) -4-hydroxymethylene-3- (o-nitrophenyl) -4,5-dihydropyrazol-5-one in 80 ml of tetrahydro-68827 23 rofuran is hydrogenated. 50 mg of 5% platinum-carbon katalysaatto-buffer at room temperature and 3 atmospheres pressure for half an hour. The mixture is filtered, the filtrate is evaporated and the residue is dissolved in 150 ml of toluene. To the solution is added 0.1 ml of conc. hydrochloric acid and the mixture are refluxed for 18 hours while using a water separator. The mixture is cooled, the resulting precipitate is filtered and purified by preparative thin layer chromatography on silica gel. Acetic acid ethyl ester: ethanol: conc. ammonium hydroxide mixture (17: 3: 3). 2- (p-Chloro-phenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one is obtained, melting at 327 °. The product is identical to the product of Example 1.

The starting material is prepared as follows: A solution of 39.6 g of malonic acid monoethyl ester, 50 mg of 2,2-bipyridyl (indicator) and 650 ml of tetrahydrofuran is cooled to -70 ° and then slowly added under a nitrogen atmosphere with stirring, 305 ml of 1 , 97 molar n-butyllithium in hexane. The temperature is allowed towards the end of the addition, after the red color of the indicator Rosa is constant, rise to about -5 °. The mixture is re-cooled to -65 ° and a solution of 31.7 g of o-nitrobenzoyl chloride in 50 ml of tetrahydrofuran is added dropwise over 10 minutes. The resulting mixture is stirred at room temperature for 1 hour and then poured into a mixture of 650 ml of 1N hydrochloric acid and 1100 ml of diethyl ether. The organic layer is separated, washed successively with 350 ml of saturated aqueous sodium hydrogen carbonate solution, 400 ml of water and 200 ml of saturated aqueous sodium chloride solution, dried and evaporated. 2- (o-Nitrobenzoyl) -acetic acid ethyl ester is obtained as a colorless oil.

A solution of 3.55 g of the latter compound and 1.7 g of p-chlorophenylhydrazine in 65 ml of toluene is refluxed for 3 hours while using a water separator. The mixture is evaporated and the residue is chromatographed on silica gel and heated with 15% ethyl acetate in toluene. 1- (p-chlorophenyl) -3- (o-nitrophenyl) -4,5-dihydropyrazol-5-one is obtained, melting at 138-141 °.

0.7 g of the latter compound in 10 ml of dimethylformamide dimethyl acetal are stirred at room temperature for 18 hours. The dark reaction mixture is poured into ice water, the precipitate is filtered off with suction, dissolved in ethyl acetate, washed with water, dried and evaporated. 1- (p-Chlorophenyl) -4-dimethylaminomethylene-3-24 6 8 8 2 7 o-nitrophenyl-4,5-dihydropyrazol-5-one is obtained, melting at 208-210 ° with decomposition.

2.5 g of the latter compound are stirred in a mixture of 20 ml of tetrahydrofuran and 20 ml of 20% aqueous hydrochloric acid, first at 60 ° for 3 hours and then at room temperature for 18 hours. The mixture is diluted with saturated aqueous sodium chloride solution, the precipitate is separated and washed with ethyl acetate. 1- (p-chlorophenyl) -4-hydroxymethylene-3- (o-nitrophenyl) -4,5-dihydropyrazol-5-one is obtained, melting at 155-157 °. Example 22:

A mixture of 650 mg of 1- (p-chlorophenyl) -2-methyl-4-alinomethylidene-pyrazolidine-3,5-dione, 2 g of polyphosphoric acid ethyl ester and 10 ml of 1,1,2,2-tetrachloroethane, boil for 24 hours under reflux. The solution is poured into 10 ml of 2N aqueous sodium hydroxide solution and the organic layer is chromatographed on a silica gel plate and eluted with toluene: ethanol: conc. with ammonium hydroxide (80: 20: 1). 1-Methyl-2- (p-chlorophenyl) -pyrazolo (4,3-c) quinolin-3-one is obtained. with an Rf value of 0.48. Using dichloromethane: methanol (19: 1) as eluent gives an Rf value of 0.33 for said compound. The product is identical to the product of Example 4.

The starting material is prepared as follows: 20 mg of malonic acid diethyl ester are added to 5.8 g of sodium metal dissolved in 100 ml of absolute ethanol. The mixture is stirred for 15 minutes, 17.8 g of p-chlorophenylhydrazine are added and then the excess ethanol is filtered off with suction. The residue is heated at 110-120 ° for 4.5 hours, then quenched with 500 ml of ice water. The resulting mixture was washed twice with diethyl ether and the pH of the aqueous layer was adjusted to conc. with hydrochloric acid to 2. The solid obtained is recrystallized from toluene. 1- (p-Chlorophenyl) -pyrazolidine-3,5-dione is obtained, melting at 189-193 °.

A mixture of 2 g of the latter compound, 2.81 g of ortho-formic acid triethyl ester, 0.97 g of aniline and 30 ml of ethanol is refluxed for 16 hours. The reaction mixture is cooled, filtered and the precipitate is washed with water. 1- (p-Chlorophenyl) -4-anilinomethylidene-pyrazolidine-3,5-dione is obtained, melting at 288-290 °.

Il 25 6 8 8 2 7

A mixture of 500 mg of the latter compound, 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 dissolved in water and dichloromethane, the organic phase is separated, dried and evaporated. 1- (p-Chlorophenyl) -2-methyl-4-anilino-methylidene-pyrazolidine-3,5-dione with NMR bands 3.14, 7.47, 8.42, 10.92 and 10.98 ppm.

Example 23:

A solution of 50 mg of 1- (p-chlorophenyl) -3- (o-formylamino-phenyl) -4,5-dihydropyrazol-5-one in 10 ml of dichloromethane is evaporated, leaving a thin film on the inner wall of the flask. This is heated for 30 minutes at 190-200 °, in a slow stream of nitrogen. The reaction product is chromatographed on a silica gel plate and eluted with acetic acid ethyl ester: ethanol: conc. with ammonium hydroxide (17: 3: 3). 2- (p-Chlorophenyl) -pyrazolo [4,3-c] quinolin-3 (5H) -one with an Rf value of 0.16 is obtained. Using 5% methanol in dichloromethane as eluent gives an Rf of 0.07. Eluting with toluene-ethanol: conc. the ammonium hydroxide mixture (70: 30: 3) has an Rf value of 0.32.

The starting material is prepared as follows: In 100 ml of ethanol 200 g of 5% platinum-carbon catalyst are hydrogenated with 2 g of 1- (p-chlorophenyl) -3- (o-nitrophenyl) -4,5-dihydropyrazole-5 at room temperature and 3 atmospheres. Since the product crystallizes from the mixture at the same time as it forms, the reaction mixture is diluted with dichloromethane to dissolve the crystalline product. The mixture is filtered, the filtrate is evaporated and the dried residue is recrystallized from ethanol. 3- (o-Aminophenyl) -1- (p-chlorophenyl) -4,5-dihydropyrazol-5-one is obtained, melting at 199-201 °.

Under a nitrogen atmosphere, while cooling with ice and stirring, 0.3 g of the latter compound is added to 10 ml of 97% formic acid to give a colorless solution. To this is added 1 ml of acetic anhydride, stirred overnight at room temperature and then poured into 300 ml of saturated aqueous sodium chloride solution. The colorless precipitate is separated, dissolved in 200 ml of diethyl ether, dried and evaporated. 1- (p-Chlorophenyl) -3- (o-formylaminophenyl) -4,5-dihydropyrazol-5-one is obtained, melting at 170-172 °.

Example 24:

The following compounds of formula (II) wherein = R 2 = H are also prepared according to the methods described in the above examples, in particular Examples 1 and 8-11.

No. · Ph R sul.p. ° C or IR streaks cm 1 1 8-CH 3 O-C 6 H 3 2-pyridyl * 319 to 323 2 7-CF 3 -C 6 H 3 2-Pyridyl 348 to 350 3 4-CH 3 -2-pyridyl] 342 to 344 4 C 6 H 4 5-Cl- 2-pyridyl 886,835,828,797,778,756 δ C6H4 2,5-Cl2-phenyl 337-338 6 CtH. 3,4-Clo-phenyl 890,878,867,823,818,795 o 4 c 7 3,5 * -Cl 2 “phenyl 890,871,847,830,806,788

The following compounds of formula (III) are also prepared according to the methods described in the examples above: -------------------------

Well. R "R 'm.p. C or IR bands an 8 H o -CH- 349 - 350 J (HCl salt) 9 H P-CH3 338 - 340 10 H p-OCH3 268 - 270 11 p-SCH3 307 - 309 12 H pF 342 - 346 13 H mF 335 - 338 14 H oF 338 - 340 15 H o-Cl 336 - 339 16 H m-Cl 336 - 337 17 H p-Br 328 - 330 li 27 68827

Mo> R '* R' m.p. ° C or IF-bands an-1! 18 H p-CF 3 315 - 320 19 H p-NO 2 885,053,818,780,758,749 20 7-Cl H 872,851,830,818,798,770 23 7-Cl p-Cl 865,852,823,795,768,752 22 7-Cl pF 890,858,835,804,770,731 23 7-Cl m-Cl 333 - 335 245 25 8-CH3 P “CH3 340 - 342 26 8-CH3 p-Cl 335 - 337 27 8-OCH3 H 321 - 325 28 8-OCH3 p-OCH3 313 - 315 29 8-OCH3 oF 344 - 347 30 8-OCH3 m-Cl 324 - 327 31 8-OCH3 p-Cl 347 - 349 32 8-FH 327 - 328 33 8-F p-OCH3 289 - 292 34 8-F pF 884,868,827,767,715,708 35 8-F mF 900,881,865,839,827,774 36 8-F oF 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-Cl H 894,871,845,812,707,770 40 8-Cl OF 895,875,858,820,814,782 41 8-Cl mF 892,884,867,860,815,771 42 Cl 896,885,080,848,823,789 44 8-Cl p-Cl 890,842,820,006,782,768 6 8 8 2 7 28

Well. R "R1 m.p. ° C or IR bands cnf 45 8-C1 m-Cl 890,865,815,790,777,740 46 8-Cl p -NO 895,832,849,034,800,784 47 8-F p -NO 2 896.804,809,860,828,821 48 8-OCH 3 p -NO 338 - 340 49 6 -Cl p -Cl 825, 306, 762, 736, 720 50 7-CF3 H 324 - 327 51 7-CF3 pF 331 - 334 52 7 "CF3 m-Cl 317 - 320 53 7-CF3 p-Cl 890,854,826,800,770,756 _____J_______

Claims (3)

1. 1. (i) (II) joissa tarkoittaa vetyä, alempialkyyliä, alempialkoxia, hydrocilia, halogenia tai trifluorimethyliä, R tarkoittaa phenyylia, hydroxy, halogeni, trifluoroimethyl, nitro, amino, monotai di-alempialkyylamino, cyanoi, carbamoylyl, alempialkyylikarbamoyyliamino tai carboxy; pyridyyliä, alempialkyylipyridyyliä tai halogenipyridyyli, R R tarkoittaa vetyä, alempialkyyliä tai (di-alempialkyyliamino tai halogeniphenylylyl) -alempialkyyliä, yes R2 tarkoittaa vetyä joissa kaikissa "alempi" tarkoittaa tähdettä, jossa on 1-4 hiiliatomia; niiden 3-hydroxytomaerist yhdisteiden tai niiden suolojen valmistamiseksi, tunnettu siitä, etä la) renegassuljetaan yhdisteet, joiden kaava IV on X 3 · * V Ycoy (IV), · · · VV jossa X tarkoittaa tähdettä -NH-NH-NH hydroxia tai alkoksia, tai lb) purge gasuletaan kaavan IV mukaiset yhdisteet, jossa kaavassa X tarkoittaa halogeenia ja Y tarkoittaa I ^ NN-Riää, tai lc) purge gasuletaan kaavan IV mukaiset yhdisteet, jossa kaavassa X tarkoittaa ää, 68827 30 tai 2a) condensoid yhdisteet, joiden kaava Va on Ri'TTR 0 * ν '% (Va) 3Υ \ / Il I n CR »W Ri jossa sekä W että tarkoittaa vetyä ja R ^ 1 tarkoittaa alempialkyy-liä, tai 2b) condensoid yhdisteet, joiden kaava Vb on RX ~%> <vb) 3Y \ / scfi • · IHI cor2 Ri tai 1 2c) condensoid yhdisteet, joiden kaava Vc on v. M '„,; (a) only halutane yhdiste, jossa 1-ash mass on muu kuin vety, saatetaan saatu yhdiste, jossa R ^ on vety, reagoiman alcohol in R jossa R ^ on yllämääritelty tähde, ja b) only halutane yhdiste, jossa R ^ 5-asmassa on muu kuin vety, saatetaan saadun yhdisteen alkali metal metal, jossa R ^ on vety, reagoimaan alcohol in R ^ -OH reactin yllä määritelty tähde, ja c) kun halutaan yhdiste, jossa phenyyliryhmä R on substituoitu hydroxilla, hydrolysoidaan phenyyliryhmän R alempialkoksis substituent-ti, ja d) kun halutaan yhdiste, jossa phenyyliryhmä R , jossa phenyyliryhmä R on substituent monotai di-alempialkyyliaminolla, alkyloidaan phenyyliryhmän R aminosubstituentti; iryhmän R amino-substituentti mainitulla asyyliryhmällä, ja g) kun halutaan yhdiste, jossa phenyyliryhmä R on substituoitu karbamoyyIillä, muunnetaan fenyylhaymuhähtahayhayhaanhayhaanhayaan / tai i) haluttaessa, saatu yhdiste muutetaan suolaksi tai saatu suola muutetaan vapaaksi yhdisteeksi tai toiseksi suolaksi, ja / tai j) haluttaessa, saatu isomerizeos erotetaan yksittäisiksi isomerereiksi. 32 68827 Analogous Process for the Preparation of New Therapeutically 2-Phenyl or Pyridyl-Pyrazolo (4,3-c) Quinolin-3 (1 or 5H) -one Compounds of General Formulas I and II ° 'h ΪΥΥ' * VYv VY \ R 1 represents hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, R represents phenyl which is unsubstituted or substituted by up to 2 equal or different substituents which are lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, trifluorimethyl, nitro, amino, mono- or di-lower alkylamino, cyano, carbamoyl, lower alkylcarbamoylamino or carboxy; pyridyl, lower alkylpyridyl, or halogenpyridyl, represents hydrogen, lower alkyl or (di-lower alkylamino or halophenyl) lower alkyl, and R 2 represents hydrogen or lower alkyl; wherein all "position" designated residues have from 1 to 4 carbon atoms; their 3-hydroxy tautomer compounds or their salts, characterized in that 1a) compounds of formula IV X'Y2 - COY (IV), which X represents the residue -NH-NH-R 1a Y represents hydroxy or alkoxy, cyclops, or lb) compounds of formula IV, wherein X represents halogen and Y represents H2N-NR cycloids, or lc) compounds of formula IV, i which X represents lower alkoxy amino and Y represents NH-R, cyclones, 6,882,7 or 2a) compounds of the formula Va Rr-T-¥ -R 0. X0 (Va) 3> \ ./ w II ΐ II C-R_ W Ri in which both W and denote hydrogen and 'denotes lower alkyl are condensed, or 2b) compounds of the formula Vb R Js ~ J ° (Vb) V · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - - - - - - - - - - - - - - - - In condensing condensed compounds of formula Vc V XT> VCÄ2