DE1445059A1 - Process for the preparation of new pharmacologically valuable carbostyril derivatives - Google Patents

Description

procedure for the preparation of carbostyril derivatives The present invention relates to processes for the preparation Creation of new 57 carbostyrilders of the general formula I. where R1 is an ethyl radical or a phenyl radical optionally substituted by a methoxy radical, R2 is hydrogen or a methyl radical, R3 is hydrogen, a chlorine atom or the methyl radical, R4 is hydrogen or an alkyl group with at most 2 carbon atoms, and R5 is hydrogen or an alkyl group with at most 2 carbon atoms.

As has now been found, surprisingly, these compounds have and their salts with inorganic or organic acids are valuable pharmacological 3 properties, in particular analgesic, anti-inflammatory and anti-pyretic effectiveness. They are suitable e.g. for enamel relief and for the treatment of rheumatic diseases, they are administered orally or parenterally.

The anti-inflammatory and analgesic effects, as well as the The toxicity of the following compounds was investigated and compared: I 7-chloro-4- (4'-diethylamino-1'-methyl-butylamino) -quinoline (according to Canad.med.A.J. 77, 1957, 182-194) II l-methyl-4-dimethylamino-carbostyril III 1-Methyl-4-dimethylamino-7-chlorocarbostyril IV 1,6-Dimethyl-4-dimethylamino-carbosyril V 1-methyl-4-dimethylamino-6-chlorocarbostyril VI 1-phenyl-4-dimethylamino-carbosyril VII l-methyl-4-methylamino-carbostyril VIII l- (p-methoxyphenyl) -3-methyl-4-ethylamino-carbostyril IX 1-methyl-4-methylamino-7-chlorocarbostyril X 1-methyl-4-aminocarbostyril XI 1,3-Dimethyl-4-amino-carbostyril XII 1- (p-methoxyphenyl) -3-n-butyl-4-hydroxy-carbostyril (according to French patent specification 1,238,740).

1. Antiphlogistic Effect The antiphlogistic effect of the test compounds was determined from the influence on edema of rat paws which edema caused Formalin injection.

Each of the test substances to be examined was given to 20 rats of one Weight of 120-145 g, administered peror1. 5 min. after application 0.1 ccm of a 0.5% aqueous formalin solution is placed in one hind paw of a injected into each test animal, 2 hours, after this injection the animals were sacrificed, both hind paws amputated and the degree of swelling determined, by taking the weight of the paws treated with the formalin solution equal to the weight of the untreated paws. The one with each of the test substances to be tested The mean reduction in swelling achieved is expressed as a percentage and calculated from the mean swelling determined in each test series and from the in the blind tests after simply injecting the formalin solution Swelling.

II. Analgesic effect The analgesic effect was demonstrated on the mouse examined with the FRIEBEL apparatus. Each dose was 10 animals in weight of 18-25 g used. The reaction time (stimulus threshold) to one is measured Light-heat stimulus before and after the application of the substance to be examined. the Compound is administered orally at an amount of 200 mF / ke and 30, 45, 60, 90 and 120 minutes thereafter, the average change in the stimulus threshold was determined. the The following table shows the means from the first hour after application measured values (average numbers of 10 mice each).

III. Toxicity The test animals used were lice weighing 19-24 g, to which various doses of the substances to be investigated were administered. The test animals were observed for one week after the administration. The letalis 50 dose (DL 50) represents the amount of substance at which half of the treated animals die. It is determined by graphical interpolation from two doses used, one of which kills less and the other more than half of the treated animals. IV. Results 1. Verb. 2. herkuft 3. Tent Ia) 4. Test IIb) 5. Test IIIc) 6. Therapy index I see introduction +0.8 +5 2400 <6 XII see introduction +2.8 +3 5000 II Example 1 -35 +112 880 12.4 III 2 -30 +147 750 5.3 IV "2 -46 +26 2160 9.4 V "14-39 4430 VI 5 '5 -33 1350 VII "1-28 4430 VIII 1 -27 2400 IX "15-24 1750 X "3 -19 +48 1350 6.7 XI "6 +18 2680 10.5 a) Edema inhibition in% with administration of a dose of 250 mg / kg po b) Change in reaction time in%, mean of the 1st hour, dose 200 mg / kg po c) Dose letalis 50 in mg / kg po

D @ 50 d) calculated from (p.o. mouse) DE50 V. Conclusion From the The above results show that the products of the process are most experimental produced formalinoedem of the rat at a dosage of 250 mg / kg p.o., hence from at most 1/3 of the DL50, give a significant inhibitory effect, while the previously known Compounds 7-chloro- (4'-diethylamino-l'-methylbutylamino) -quinoline (compound I) and 1- (p-Methoxyphenyl) -3n-butyl-4-hydroxy-carbostyril (Compound XII) in the same Dosage are practically ineffective. It is also shown that the process products a clear analgesic component (as a very desirable additional effect) show that with the best preparations the same comparison products by more than a power of ten.

To prepare compounds of the general formula I, compounds of the general formula II are used, where Hal is chlorine or bromine and R1, R2 and R3 are as stated above, with ammonia or amines of the general formula III, wherein R4 and R5 have the meaning given above to.

The compounds of the general formula I obtainable by the process described above include, inter alia, compounds of the following three general ones Formulas Ia, Ib and Ic: R5 R3 - R2 R3 - R2 X (Ia) ß (Ib> I. Ru 3; C0 (1?) R1 These three types of compounds can be produced by reaction with a reactive ester of a compound of the general formula IV, R4 '- OH (IV) and / or by reaction with a reactive ester of a compound of the general formula V, R51 - OH (V), where R4' and R5 ', with the exception of hydrogen, have the meaning given for R4 and R5, can be subsequently converted into other compounds of the general formula I in the presence of an acid-binding agent. The types of compounds of the formulas Ia, Ib and Ic falling under the general formula 1 can also be obtained by reaction with lower oxoalkanes under reducing conditions convert into corresponding other compounds of general formula 1.

With the proviso that in the above process the substituent R2 not hydrogen but one. Represents a methyl radical, the first reaction stage takes place possibly so that when using dialkylamines of the general formula III a mixture of the primary unsubstituted and the secondary monoalkyl-substituted Amine because general formula I is formed. The primary and secondary ones thus obtained Amines of the general formula I can be used in the second reaction stage, after that described above Alkylation processes into secondary and tertiary amines, if necessary of the general formula I can be converted. If desired, the obtained Compounds of general formula 1 in their salts with inorganic or organic Acids transferred. Acids suitable for salt formation are e.g.

Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, Ethanedisulfonic acid, acetic acid, lactic acid, succinic acid, maleic acid, fum, arsvure, r. epPclic acid, tartaric acid, citric acid, benzoic acid, phthalic acid, salicylic acid and mandelic acid. Compounds of general formula II can be made accordingly substituted 4-hydroxycarbostyrils are obtained.

Various 4-hydroxy-carbosyril derivatives are known and numerous others can be produced in an analogous manner By treating with a Mineral acid chloride or bromide, e.g. POCI3, PBr3, PCI5, .SOCl2, can use these compounds were converted into the starting materials of the general formula II. The connection of the general formula II, especially those with a different from hydrogen The rest of R2 are valuable starting products not only in the reaction according to the invention, but also in the synthesis of other pharmacologically valuable substances. The implementations of compounds of the general formula II with amines of the general formula III are used at temperatures of approx.

80-250 ° C in the presence or absence of solvents and thinners such as ethanol or phenol and catalysts such as copper powder, sodium or Potassium iodide carried out.

Depending on the necessary reaction temperature and the boiling point of the The amine to be converted and the solvent, if any, are used to set the reaction components in a closed system. In the case of the above-mentioned modification of the procedure is made with organic solvents and in a pressure vessel at temperatures above 220 ° C worked. If necessary, serves to bind the released hydrohalic acid an excess of reacting amine is expedient.

According to a further process, the compound of the general formula I is obtained by adding compounds of the general formula VI, or their, tautomeric form VI a, R N l R5 (VIa) R3- L in which R2, R3, R4 and R have the meaning given above, in the presence of an acid-binding agent or after conversion into salts of metals with reactive esters of compounds of the general formula VII., R11 - OH (VII) in which R11 is a radical ontsprcchond of the above for R1 is the definition given with the exception of aromatic radicals, or reacts with diazomethane. To carry out the reactions, the compounds of the general formula VI are dissolved, for example, in methanolic or ethanolic potassium hydroxide solution or sodium hydroxide solution, fWot gradually the required reactive ester, such as methyl iodide, ethyl iodide, Add dimethyl sulfate or diethyl sulfate and warm the Ge. mixed, e.g. for boiling under reflux or at higher @ temperatures in a closed system. some starting materials of the general formula VI are known and others can be prepared in a manner known per se, for example by heating optionally substituted 2,4-dioxyquinoline with suitable monoamines or diamines.

The following 3 examples are intended to carry out the inventive Explain the method in more detail, but in no way limit the invention. Parts mean therein parts by weight. These are related to parts of volume as g to cm3. The temperatures are given in degrees Celsius.

Example 1 370 parts of 1-methyl-4-chlorocarbostyril are heated with titanium 620 parts of 50% anhydrous ethanolic dirnethylain in 15 hours in a pressure vessel to 1500. After cooling and evaporation of the solvent extracted from the residue with ether, filtered the extract and sucks that which crystallizes out of the filtrate on cooling l-methyl-4-dimethylamino-carbostyril, which ran as needles with a melting point of 50-55 ° receives. After recrystallization from ether, white crystals with a melting point are obtained 580. The hydrochloride melts at 172 °. In analogue quiet, ran gets related Ethanolic methyl amine solution, the l-methyl-4-methylamino-carbostyril of m.p. 230-232 °.

Using the appropriate starting materials, mm after the Procedure described in the above example 1- (p-Kethoxyphenyl-3-methyl-4-dimethylaminocarbostyril before, m.p. 146-148 ° (from ethyl acetate), 1-p-methoxyphenyl-3-methyl-4-ethylamino-carbostyril 1 with a melting point of 151-154 ° (from methanol) and 1-p-methoxyphenyl-4-ethylaminocarbostyril of m.p. 257-259 ° (from methanol).

Example 2 40 parts of 1-methyl-4,7-dichlorocarbostyril are mixed with 300 Divide 5iFe of anhydrous ethanolic dimethylamine in a pressure vessel for 15 hours Heated to 220 °. ac the work-up described in Example 1 is obtained from 1-Methyl-4-dimethylamino-7-chloro-carbostyril melting at 102 °.

Using the appropriate starting materials, one obtains according to the in the above example described process 1-methyl-4-dimethylamino-6-methyl-carbostyril of melting point 70-72 ° (from ether) Example 3 100 parts of 1-methyl-4-chlorocarbostyril heated together with 800 parts of liquid ammonia and 75 parts of triethylamine Addition of some copper powder in a pressure vessel to 1200 for 48 hours. After cooling and evaporating the ammonia, the residue is treated with water, whereby the 1-methyl-4-aminocarbostyril separates in crystalline form.

It is filtered off and recrystallized from methanol-ether, white crystals with a melting point of 1960 are obtained.

In an analogous manner, starting from 120 parts of 1-methyl-4,7-dichloro-carbostyril, one obtains the 14 / ethyl-4-amino-7-chlorocarbostyril.

Example 4 15 parts of 1-> ethyl-4-chlorocarbostyril are heated together with 60 parts of 50% alcohol-safe diethylamine in a pressure vessel for 15 hours to 1500. After cooling, the solvent is distilled off and the residue with ether extracted. The ethereal solution becomes r: it l-n.

Hydrochloric acid extracted and the reaction product from the acidic aqueous solution irit 2-n. Sodium hydroxide solution precipitated and separated by extraction with ether. To Evaporation of the ether extract leaves the 1-methyl-4-ethylarino-carbostyril as Gel obtained by distillation at 1400 and 0.001 torr. For conversion into the hydrochloride, the base is dry in the ethereal solution Hydrochloric acid gas initiated. The precipitated hydrochloride is made from methanol ether recrystallized. Melting point 1100.

Example 5 50 parts of 1-phenyl-4-chlorocarbostyril are together with 300 parts of 15% anhydrous ethanolic dimethylamine for 15 hours in Pressure vessel heated to 150 °. After concentration of the solution # crystallized in vacuo the 1-pentyl-4-dimethylamino-carbostyril on cooling off.

After recrystallization from methanol-ether, the base melts at 1160.

Example 6 30 parts of 1,3-dimethyl-4-chlorocarbostyril are combined with 350 parts of 15% anhydrous ethanolic dimethylamine for 48 hours warmed to 2200 cw in the pressure vessel. The solvent is evaporated and the back pressure is removed dissolved in ether. The essential solution is added twice with 2-n. Hydrochloric acid extracted, the acidic extract was made alkaline at 50 and the precipitated oil was dissolved in ether. The ether solution is separated off, dried and concentrated. Crystallizes on cooling the 1,3-dimethyl-4-methylamino-carbostyril from. After recrystallization from ether the compound melts at 1250. The ethereal solution previously extracted with hydrochloric acid is concentrated in vacuo, the 1,3-dimethyl-4-amino -carbostyril crystallized out. After recrystallization from ether, its melting point is 178-181 °.

Example 7 86 parts l ebhyl-4-amino - earth dissolved in 1000 parts of 41/2% ethanolic potassium hydroxide solution. Then 260 parts of methyl iodide are added with stirring and the mixture is refluxed for 3 hours. The solvent is then freed and the residue is chromatographed on a column of neutral aluminum oxide. The fractions eluted with chloroform contain 1-methyl-4-dimethylamino-carbostyril. From ether it crystallizes in needles with a melting point of 56-58 °.

Example 8 A mixture of 10 parts of 1-methyl-4-monomethylaminocarbostyril in lOC) parts of dimethylformamide are added -2.5 parts of NaH mineral oil (1: 1) Heated to 800 for 1 hour.

It is cooled and 8 parts of ethyl iodide are added. The mix will stirred for one hour at room temperature and one hour at 500. On that if the solvent is evaporated in vacuo, the residue is taken up in ether and washed the extract in the water, dry and evaporate to dryness.

The residue is chromatographed on neutral aluminum oxide.

The fractions eluted with ether-petroleum ether 1: 1 result from ether recrystallized, pure 1-methyl-4-dimethylaminocarbostyril with a melting point of 580.

Example 9 A solution of 0.95 parts of 2-hydroxy-4-dimethylaminoquinoline in 40 Vozum. share dioxane is at 150 with an excess essential diazomethane solution offset. The mixture is left to stand at room temperature for 42 hours and then freed in vacuo from the solvent. The residue is chromium on neutral aluminum oxide. atographed. The fractions eluted with chloroform-ether (1: 8) contain 1-methyl-4-dimethylaminocarbostyril. It crystallizes from ether with a melting point of 580.

Example 10 To a stirred mixture of 1.3 parts of 2-hydroxy-4 -dimethylamir.o-quinoline and 1.06 parts, soda in 40 volumes divide dimethylformamide add 1.5 parts of methyl iodide dropwise. The suspension is at 3 hours Stirred for 250 and 2 hours at 45 ° and then to 200 parts by volume of ice water poured. >: it sucks in from. precipitated unchanged 2-hydroxy-4-dimethylamino-quinoline and the filtrate concentrated to dryness in a vacuum. The residue, a yellow gel, is chromatographed on neutral aluminum oxide.

The fractions eluted with chloroform-ether (1: 8) contain the 1-methyl-4-dimethylamino-carbostyril. It crystallizes from ether with the melting point from. 58 °.

Example 4 7.8 parts of 1-methyl-4,6-dichlorocarbostyril are used in 350 Parts of absolute ethanol dissolved and after the addition of 24 parts of its own ethanol Dimethylamine solution heated in a pressure vessel for 15 hours at 130 °. Then it will be the solvent is distilled off in vacuo and the residue is dissolved in 200 parts of chloroform and 20 parts of water dissolved. The chloroform solution is washed twice with water, dried and evaporated. The residue crystallizes from ether in prisms. The 1-methyl-4-dimethylamino-6-chlorocarbostyril melts at 9130.

Example 12 A solution of 30 parts of 1-methyl-4,7-dichloro-carbostyril and 36 parts of absolute methylamine in 50 parts of absolute ethanol is during Heated for 15 hours at 1500 in a pressure vessel. This is followed by a vacuum at 500 to dryness evaporated and the remaining oil recrystallized from 95% ethanol. That 1-Methyl-4-methylamino-7-chlorocarbostyril melts at 272-275 °.

The following compounds were also prepared in a manner analogous to these examples manufactured: 1-methyl-4-dimethylamino-earbostyril-sulfate, Samp. 161-162 ° C; 1 -Mon ethyl-4-methylamino-carbostyril hydrochloride, m.p. 220 ° C% 1 (decomp.) 1-methyl-4-methylamio-6-chlorocarbostyril, M.p. 284-236;

Claims (1)

Claims 1. The carbostyril compounds of the general formula I, wherein R1 is an alkyl radical having a maximum of 4 carbon atoms or a phenyl optionally substituted by halogen or lower alkoxy radicals. or benzyl radical, R2 is hydrogen or an alkyl radical with a maximum of 4 carbon atoms. a phenyl or a benzyl radical, R3 hydrogen. a halogen atom, an alkyl or alkoxy group with a maximum of 4 carbon atoms each, the nitro group or the trifluoromethyl group R4 is hydrogen or an alkyl group with a maximum of 4 carbon atoms and R, hydrogen, an alkyl group with a maximum of 4 carbon atoms, or, if R4 is hydrogen, also a dialkylaminoalkylene group each with a maximum of 4 carbon atoms per alkyl or alkylene radical means and their salts with organic and inorganic acids. 2. 1-methyl-4-dimethylamino-carbostyril, -3. 1-methyl-4-dimethylamino-7-chloro-carbostyril. 4. 1,6-Dimethyl-4-dimethylamino-carbostyril. 5. 1-Methyl-4-dimethylamino-6-chloro-carbostyril. 6. 1-Phenyl-4-dimethylamino-carbostyril. 7. 1-Methyl-4-methylamino-carbostyril. 8. 1- (p-Methoxyphenyl-3-methyl-4-ethylamino-carbostyril 9. 1-Methyl-4-aminocarbostyril. 10. 1,3-Dimethyl-4-aminocarbostyril. Claim 11.) Process for the preparation of carbostyril derivatives of the general formula I, wherein R1 is a methyl radical or a given. if phenyl radical substituted by a methoxy radical, R2 is hydrogen or a methyl radical, R3 is hydrogen, a chlorine atom or the methyl radical, R4 is hydrogen or an alkyl group with at most 2 carbon atoms and R5 is hydrogen or an alkyl group with at most 2 carbon atoms, characterized in that im known manner either a) a compound of general he. II, where Hal is chlorine or bromine, with ammonia or an amine of the general formula III, converts and optionally resulting compounds of the general formula I of type Ia, Ib or Ic, with help of a. reactive ester of a compound of the general formula IV R4t - OH (IV) and / or, with the aid of a reactive ester of a compound of the general formula V, R5 '- OH (V) where R4' and R51 are the , e sr, have a given meaning, in Ge0 "'ewart , ft1 'mu <lfh * lfU "Y" - "~~ wczcr hs-pCu. £ given oaa <': 1 ' an acid-binding problem converted into other compounds of general formula 1 and these latter finally, if desired, converted into salts with an 'inorganic or organic acid; or b) a compound of the general formula VI, or its tautonic form VIa, where R2, R3, R4 and R5 have the meaning given above, in the presence of an acid-binding agent or after conversion into a salt of a metal with a reactive ester of a compound of the general formula R1 '- OH (VII) where R1' is a radical corresponding to given definition for R1 with the exception of one, optionally substituted Phenyl radical means converts to a compound of the general formula 1.