HU184253B - Process for producing 4-amino-3-quinoline carboxylic acids and esters - Google Patents

Abstract

Aminoquinolinecarboxylates I (R1=alkyl, Ph, o-alkyl, s-alkyl, halo, CF3, cyano, dialkylamino; R2=alkyl, Ph, phenylalkyl, o-alkyl, s-alkyl, halo, cyano, OH, carbamoyl, carboxy, acetyl, CF3, nitro; R3=H, alkyl, alkyldimethylamino, alkoxyalkyl, allyl; n=0-2) were prepd. Thus, 5.31g ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate in 40mL THF was reacted with 2.12g o-toluidine in 40mL THF at 60≰C for 18 hrs. to give 7.13g ethyl 8-methoxy-4-[(2-methylphenyl)amino -3-quinoline-carboxylate. HCl.

Description

The present invention relates to a process for the preparation of 4-amino-3-quinolinecarboxylic acids and esters. More particularly, the present invention relates to the preparation of 4-amino-3-quinolinecarboxylic acids and esters which reduce the excretion of gastric secretion by excitatory agents such as histamine, tetragastrin and food and are thus useful in the prevention or treatment of gastric ulcer in mammals.

Hanifin, J.W., U.S. Patent 3,470,186, and J. Med. Chem., 12 (6), 1969, pp. 1096-1097. In the literature there are described the diuretic and antidepressant effect of certain 4-anilino-3-quinolinecarboxylic acid esters and their 6-chloro derivatives.

Kermack et al., J. Chem. Soc., 1951, 1389-1392. The preparation of 4-anilino-3-quinolinecarboxylic acids and esters substituted at the 6-position from these compounds is described in the literature. Sen et al., J. Indiana Chem. Soc., 34, 906-908. (1957) describe the preparation of 7-substituted 4-amino-3-quinolinecarboxylic acid amides. Elslager et al., J. Med. Pharm. Chem., 5, 546-558. (1962) describe the preparation of 4-anilino-7-chloro-3-quinolinecarboxylic acid and its ethyl ester.

The secretory and anti-ulcer inhibitory activity of? 4-amino-3-quinolinecarboxylic acids and esters has not yet been described in the literature.

The 4-amino-3-quinolinecarboxylic acids and esters useful in the treatment of gastric ulcers in mammals of the present invention are those of formula I wherein R1 is lower alkyl, phenyl, O- (lower alkyl) -,

Denotes S- (lower alkyl), trifluoromethyl, cyano or dialkylamino or halogen,

R _{2 is} lower alkyl, phenyl, phenyl (lower alkyl), or phenyl substituted with 1 or 2 substituents wherein the substituents are lower alkyl, O- (lower alkyl), S (lower alkyl), cyano; , carbamoyl, carboxyl, acetyl, trifluoromethyl, hydroxy, nitro, or if they are logic,

R ₃ is hydrogen, lower alkyl, dimethylamino, lower alkyl, or lower alkoxy (lower alkyl).

Also included within the scope of the invention are pharmaceutically acceptable acid addition salts thereof.

The inhibitory effect on the decreased flow of weed juice and hydrochloric acid was demonstrated in rats with gastric gating needles, and animals were administered orally, subcutaneously, intraperitoneally, intraduodenally, and intravenously with 4-amino-3-quinolinecarboxylic acids. Decreased fecal formation was also demonstrated in rats bound with a stomach gate. The compounds of Formula I above have reduced the hormone secretion induced by, for example, histamine, tetragastrin and methacoline. Gastric acid production in food-stimulated Heidenhain gastric (deprived of the planetary nerve) dogs was also reduced.

The compounds of the present invention, as active ingredients of pharmaceutical compositions, control excess gastric acid in mammals and are useful in the treatment of gastric ulcer.

The present invention relates to a novel process for the preparation of 4-amino-3-quinolinecarboxylic acids and esters.

The term "lower alkyl" as used herein, includes such groups having up to 4 carbon atoms, linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

Representative of "phenyl-lower alkyl" groups are benzyl, (phenylmethyl), α-methylbenzyl, phenylethyl, phenylpropyl, phenylbutyl and the like.

The compounds can be prepared the corresponding 4-chloro-3-kinolinkarbonsavészterekből prepared according to the accompanying drawings A) under general reaction illustrated method, wherein, Ri and _R2 are as hereinbefore defined and R ₃ represents lower alkyl.

II. Compounds of Formula I were prepared by chlorination of the corresponding 4-hydroxy-3-quinolinecarboxylic acid esters with phosphorus oxychloride, generally according to Kermack and Storey, J. Chem. Soc., 1951, 1389-1392. in the literature. The reaction is represented by Reaction equation B in the attached drawing, wherein R 1 is as defined above and R _{3 is} lower alkyl.

Those are listed in Annex III. Compounds of Formula I wherein R _{3 is} ethyl are prepared by heating a mixture of appropriately substituted anilines and diethylethoxymethylene malonate, and the resulting anilino acrylate intermediate is obtained according to Price and Roberts, J. Amer. Chem. Soc., 68, 1204-1208. . The reaction is illustrated in Reaction C, shown in the accompanying drawings, in a high boiling point solvent, such as diphenyloxide.

The acids (R _{3 is} hydrogen) may be prepared from esters (R ₃ lower alkyl) by conventional methods such as hydrolysis, and other esters may be prepared by conventional transesterification.

In our experiments, we found that the effect of ethyl 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride on histamine-induced gastric juice secretion was 43% greater than that of ethyl- - methoxy 4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate at half dose.

Using the method described by Price and Roberts, diethyl ethoxymethoxymalononate and aniline or known aniline derivatives were prepared as described in Table III below. ethyl 4-hydroxy-3-quinolinecarboxylate of general formula:

ethyl 4-hydroxy-8-methoxy-3-quinolinecarboxylate from 2-methoxyaniline, m.p. 243-246 ° C;

ethyl 4-hydroxy-8-ethoxy-3-quinolinecarboxylate from 2-ethoxyaniline, m.p. 198-200 ° C;

ethyl 4-hydroxy-8-phenyl-3-quinolinecarboxylate from 2-aminobiphenyl, m.p. Mp: 250-252.5 ° C;

ethyl 4-hydroxy-8-methyl-3-quinolinecarboxylate from 2-methylaniline, m.p. 271-274 ° C;

ethyl 4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylate from 2-trifluoromethylaniline. mp 211-213.5 ° C; ethyl 4-hydroxy-8-methylthio-3-quinolinecarboxylate from 2-methylthioaniline, m.p. 201-204 ° C; ethyl 4-hydroxy-8-chloro-3-quinolinecarboxylate from 2-chloroaniline, m.p. 255-259 ° C;

ethyl 4-hydroxy-8-cyano-3-quinolinecarboxylate from 2-cyanoaniline, m.p. 234-236 ° C;

Preparation 1 below is prepared as described in Preparation II. illustrates the synthesis used for the preparation of 4-chloro compounds of formula I, which are the starting materials for the preparation of compounds of formula I.

184,253

Preparation 1

Ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate

A mixture of 66.63 g (0.269 mol) of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate and 350 ml of phosphorus oxychloride was heated with stirring until the solid was completely dissolved and refluxed for two hours. The mixture was cooled to below 100 ° C and concentrated in a rotary evaporator. The oily residue was dissolved in acetone (100 mL) and poured into ice-water (800 mL). The mixture was then neutralized with 6N sodium hydroxide solution and the solid product was successively extracted with 450 ml, 250 ml and 100 ml portions of methylene chloride. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and evaporated to give 68.16 g of crude product. This crude product is dissolved in 500 mL of hot toluene and the solution is filtered to remove a small amount of insoluble material. The toluene solution is filtered through a bed of 250 g of fluorosil, then 2 L of toluene and 4 L of chloroform are passed through the bed. The purified solution was concentrated to give 64.17 g (89%) of an oil which crystallized on cooling as an off-white solid. Melting point 75-77 C. Analytical results for ₃ H ₂ NO ₃ Cl:

Calculated: C 58.77%, H4.55%, N5.27%;

Found: C, 58.58; H, 4.61; N, 5.33.

2-15. production

In the same manner as in Preparation 1 and using the appropriate procedure for Preparation III. The following ethyl 4-chloroquinoline-3-carboxylates were prepared using ethyl 4-hydroxy-3-quinolinecarboxylates of general formula:

(3) ethyl 4-chloro-8-ethoxy-3-quinolinecarboxylate, (6) ethyl 4-chloro-8-phenyl-3-quinolinecarboxylate, (7) ethyl 4-chloro-8-methyl-3-quinolinecarboxylate , (8) ethyl 4-chloro-8-trifluoromethyl-3-quinolinecarboxylate, (9) ethyl 4-chloro-8-methylthio-3-quinolinecarboxylate, (10) ethyl 4,8-dichloro-3- quinolinecarboxylate, (13) ethyl 4-chloro-8-cyano-3-quinolinecarboxylate, (15) ethyl 4-chloro-8- (dimethylamino) -3-quinolinecarboxylate,

Esters of formula I (R ₃ lower alkyl) are generally prepared by reacting a suitable 4-chloro-3-quinolinecarboxylic acid ester with a suitable amine in a polar, non-proton-free solvent such as tetrahydrofuran or dioxoxane. and adjusting the temperature and reaction time to complete the reaction. In some cases, the reactive amine may be used as a solvent. Different solvents may be used for recrystallization. The free base is prepared from the salt by dissolving the salt, adding a base such as sodium hydroxide and extracting the free base with a suitable organic solvent. The free base is mixed with an alcoholic solution of an acid such as phosphoric acid or sulfuric acid to form an addition salt.

A general description of the ester preparation is given above. Examples 1 and 2 below illustrate the preparation of esters; and 56-62. The esters of Examples 1 to 5 are also the corresponding amine and the corresponding esters of Examples 1-15. ethyl 4-chloro-3-quinolinecarboxylate. 63-66. Examples _{3 to 6} illustrate the preparation of esters wherein R _{3 is} lower alkyl, lower alkyl dimethylamino, lower alkyl lower alkoxy, then esters wherein R _{3 is} lower alkyl are esterified. The preparation of the acids of formula I and their salts (R _{3 is} hydrogen) is illustrated in Examples 54 and 55, wherein the ester is hydrolyzed to the acid. Metal salts of acids, such as alkali metal salts, may also be prepared in conventional manner by reaction with an alkali metal base and isolation of the salts. 67-70. EXAMPLE 1 illustrates the conversion of free bases of esters to acid addition salts. The physical constants of the products and the analytical results are shown in Figs

Table 2 contains. However, it is not intended to limit the scope of the invention to those set forth in the examples.

Example 1

Ethyl 8-methoxy-4 - [(2-methylphenylammonium] · 3-quinolinecarboxylate hydrochloride

Ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate (5.31 g, 19.9 mmol) was dissolved in tetrahydrofuran (40 mL) and o- (2.15 g, 20.06 mmol) dissolved in tetrahydrofuran (40 mL) was added. toluidine. The solution was stirred at 60 ° C for 18 hours, excluding moisture. The yellow precipitate was filtered off and washed with isopropyl ether. 7.13 g (95.7%) of product are obtained; it was recrystallized three times from a mixture of methylene chloride and ethyl acetate.

Melting point: 191-193.5 ° C.

Analysis calculated for C ₂ H _{3 0 2} C1N ₂ O ₃ calcd: C 64.43%, H 5.68%, N 7.51%;

Found: C, 64.36%, H5.65%, N7.62%. '

Example 2

Ethyl-4- (phenylamino) -8-methoxy-3-quinolinecarboxylate

Ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate (6.0 g, 22.5 mmol) was dissolved in tetrahydrofuran (80 mL) and aniline (2.3 g, 24.8 mmol) dissolved in tetrahydrofuran (60 mL) was added. The solution is heated briefly and after standing for 10 minutes, a yellow precipitate begins to form. The mixture was allowed to stand at room temperature for 18 hours. The solvent was then evaporated in a rotary evaporator. The residue was dissolved in methanol (200 mL) and the solution was made slightly basic (pH 8) with sodium bicarbonate. Water (700 mL) was added to form an oily solid which solidified and, upon standing, further solid crystallized. The solid was filtered and air-dried. 6.9 g (95%) of crude product are obtained. This is dissolved in 300 ml of hot isooctane, the aqueous solution is clarified with activated carbon and filtered. The filtrate was concentrated to 150 ml. Upon cooling, the product precipitates in the form of pale yellow needles; yield: 6.5 g (89%); mp 120-121 ° C.

Analysis for C ₉ H ₈ N _{2 3} G ₃ calcd: C 70.79%; H, 5.63% N8,69%;

Found: C, 70.91; H, 5.65; N, 8.77.

3-53. example

3. Ethyl 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate by neutralization according to Example 1.

-3184 253

4. Ethyl 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate sulfate (1: 1) from Example 3 and sulfuric acid.

5. Ethyl 8-methoxy-4 - {(2-methylphenyl) amino] -3-quinolinecarboxylate phosphate (1: 1) from Example 3 and phosphoric acid.

6. Ethyl 8-methoxy-4- (phenylamino) -3-quinolinecarboxylate hydrochloride from Preparation 1 and aniline.

7. Ethyl 8-methoxy-4 - [(2-methoxyphenyl) amino] -3-quinolinecarboxylate hydrochloride from Preparation 1 and o-anisidine.

8. Ethyl 8-methoxy-4 - [(2-methylthio-phenyl) -amino] -3-quinolinecarboxylate hydrochloride from Preparation 1 and 2-methylthio-aniline.

9. Ethyl 4 - [(2-chlorophenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and 2-chloroaniline.

10. Ethyl 4 - [(2-cyanophenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and 2-aminobenzonitrile.

11. Ethyl 4 - [(2-trifluoromethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and 2-trifluoromethylaniline.

12. Ethyl 4- [2- (aminocarbonyl) phenyl] amino] -8-methoxy-3-quinolinecarboxylate monohydrochloride ethanol (5: 2) from Preparation 1 and anthranilamide.

13. Ethyl 4 - [(2-fluorophenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and 2-fluoroaniline.

14. Ethyl 4 - [(2-acetylphenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and 2'-Aminoacetophenone.

15. Ethyl 4- (butylamino) -8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and n-butylamine.

16. Ethyl 8-methoxy-4 - [(3-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride monohydrate from Preparation 1 and m-toluidine.

17. Ethyl 8-methoxy-4 - [(4-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride monohydrate from Preparation 1 and p-toluidine.

18. Ethyl 8-methoxy-4 - [[(2-methoxyphenyl) methyl] amino] -3-quinolinecarboxylate from Preparation 1 and 2-methoxybenzylamine,

19. Ethyl 8-methoxy-4 - [(2,6-dimethylphenyl) amino] -3-quinolinecarboxylate from Preparation 1 and 2,6-dimethylaniline.

20. Ethyl 8-methoxy-4 - [(2,6-dimethylphenyl) amino] -3-quinolinecarboxylate hydrobromide from Example 18 and hydrogen bromide.

21. Ethyl 8-methoxy-4 - [(1-phenylethyl) amino] -3-quinolinecarboxylate monohydrate from Preparation 1 and α-methylbenzylamine.

22. Ethyl 4 - [(2-chloro-5-methoxyphenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrobromide from Preparation 1 and 2-chloro-5-methoxyaniline.

23. Ethyl 8-methoxy-4 - [(3-methylthio) phenyl] amino-3-quinolinecarboxylate from Preparation 1 and 3-methylmercaptoaniline.

24. Ethyl 4-benzylamino-8-methoxy-3-quinolinecarboxylate phosphate (1: 1) methanolate (1: 1) from Preparation 1 and benzylamine.

25. Ethyl 8-methoxy-4 - [(2,4-dimethoxyphenyl) amino] -3-quinolinecarboxylate from Preparation 1 and 2,4-dimethoxyaniline.

26. Ethyl 4 - [(2-ethoxyphenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and 2-ethoxyaniline.

27. Ethyl 8-methoxy-4 - [(4-methoxy-2-methyl-phenyl) -amino] -3-quinolinecarboxylate from Preparation 1 and 2-methyl-4-methoxy-aniline.

28. Ethyl 4 - [(2-ethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate from Preparation 1 and 2-ethylaniline.

29. Ethyl 4 - [(2-ethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate phosphate (1: 2) from Example 28 and anhydrous phosphoric acid.

30. Ethyl 4 - [(2-ethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate sulfate (1: 1) from Example 28 and alcoholic sulfuric acid.

31. Ethyl 4 - [(2,6-dichlorophenyl) amino] -8-methoxy-3-quinolinecarboxylate from Preparation 1 and 2,6-dichloroaniline.

32. Ethyl 8-methoxy-4 - [(2-methyl-5-nitrophenyl) amino] -3-quinolinecarboxylate from Preparation 1 and 2-methyl-5-nitroaniline.

33. Ethyl 8-methoxy-4 - [[(2-methylphenyl) methyl] amino] -3-quinolinecarboxylate hydrochloride ethanol (2: 1) from Preparation 1 and o-methylbenzylamine, ethanol and hydrochloric acid.

34. Ethyl 8-ethoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride from Preparation 3 and o-toluidine.

35. Ethyl 8-ethoxy-4- [2- (trifluoromethylphenyl) amino] -3-quinolinecarboxylate hydrobromide from Preparation 3 and o-trifluoromethylaniline.

36. Ethyl 8-ethoxy-4 - [(2-methoxyphenyl) amino] -3-quinolinecarboxylate hydrochloride from Preparation 3 and o-anisidine.

37. Ethyl 8-ethoxy-4- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate phosphate (1: 1) from Preparation 3 and methylthioanaline and alcoholic phosphoric acid.

38. Ethyl 4 - [(2-methylphenyl) amino] -8-trifluoromethyl-3-quinolinecarboxylate from Preparation 8 and o-toluidine.

39. Ethyl 4 - [(2-methylphenyl) amino] -8-methylthio-3-quinolinecarboxylate from Preparation 9 and o-toluidine.

40. Ethyl 4 - [(2-methoxyphenyl) amino] -8-methylthio-3-quinolinecarboxylate hydrochloride from Preparation 9 and o-toluidine.

41. Ethyl 8-methylthio-4 - [(2-methylthiophenyl) amino] -3-quinolinecarboxylate from Preparation 9 and 2-methylthioaniline.

42. Ethyl 8-methyl-4- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate hydrochloride from Preparation 7 and 2-methylthioaniline.

43. Ethyl 4 - [(2-methoxyphenyl) amino] -8-methyl-3-quinolinecarboxylate hydrochloride from Preparation 7 and o-anisidine.

44. Ethyl 8-methyl-4 - [(2-methylphenyl) methyl] amino-3-quinolinecarboxylate hydrobromide from Preparation 7 and 2-methylbenzylamine.

45. Ethyl 8-chloro-4 - [(2-methoxyphenyl) amino] -3-quinolinecarboxylate hydrochloride from Preparation 10 and o-anisidine.

46. Ethyl 8-cyano-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride from Preparation 13 and aniline.

47. Ethyl 4- (phenylamino) -8-phenyl-3-quinolinecarboxylate from Preparation 6 and aniline.

48. Ethyl 4 - [(2-carboxyphenyl) amino] -8-phenyl-3-quinolinecarboxylate hydrochloride hemihydrate from Preparation 6 and 2-amino o-benzoic acid.

49. Ethyl 4-benzylamino-8-phenyl-3-quinolinecarboxylate from Preparation 6 and benzylamine.

50. Ethyl 8- (dimethylamino) -4- (phenylamino) -3-quinohydrocarboxylate hydrochloride from Preparation 15 and aniline.

51. Ethyl 8- (dimethylamino) -4 - [(2-methylphenyl) alanine] -3-quinolinecarboxylate from Preparation 15 and o-toluidine.

52. Ethyl 8-cyano-4- (phenylamino) -3-quinolinecarboxylate from Preparation 13 and aniline.

53. Ethyl [(2-hydroxyphenyl) amino] -8-methoxy-3-quinolinecarboxylate from Preparation 1 and o-hydroxyaniline.

Example 54

8-Methoxy-4 - [(2-methyl-phenylamino} -3-kmoliri-carboxylic acid

A mixture of ethyl 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate (15.00 g, 0.0445 mol) in 3N sodium hydroxide (100ml) and ethanol (100ml) was stirred for 16 hours.

184,253 is stirred at room temperature. The mixture was then diluted with 300 ml of whisk and acidified to pH 6.8 with 6N hydrochloric acid. The precipitate was collected by filtration, washed successively with water and acetone and then air-dried for about one and a half hours. 13.41 g (98%) of solid product are obtained; mp; 272 ° C (dec.).

Analysis for C Hi _{lg 6} N ₂ O ₃ Calcd: C 70.12%, H 5.23%, N 9.09%;

Found: C, 70.10; H, 5.27; N9.09.

Example 55

8-Methoxy-4 - [(2-methylphenyl-famino) -3-quinoline anchoric acid hydrochloride

4.35 g of 8-methoxy-4 - [(2-methyl] phenyl) amino] -3-quinolinecarboxylic acid of Example 54 is triturated with 100 ml of hot absolute ethanol. After cooling, the solid was collected by filtration and air-dried. 3.87 g are obtained. This is suspended in 25 ml of absolute ethanol and an excess of ethereal hydrochloric acid is added. A clear solution is obtained. The addition of isopropyl ether gave a yellow precipitate which was collected and recrystallized from absolute ethanol / isopropyl ether. 3.14 g of product are obtained, m.p. 257 ° C (dec.).

Analysis for C _Jg E A. O ₃ Cl ₂ Calcd: C 62.70%, H 4.97%, N8,12%;

Found: C, 62.53; H, 4.93; N, 8.18.

56-62. example

56. Ethyl 8-methyl-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate monohydrochloride from Preparation 7 and o-toluidine.

57. Ethyl 8-methoxy-4 - [[2- (1-methylethyl) phenyl] amino] -3-quinolinecarboxylate from Preparation 1 and o -isopropylaniline.

58. Ethyl 8-chloro-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate from Preparation 10 and o-toluidine.

59. Ethyl 4 - [(2-chloro-6-methylphenyl) amino] -8-methoxy-3-quinolinecarboxylate monohydrochloride from Preparation 1 and

2-chloro-6-methylaniline.

60. Ethyl 8-methoxy-4 - [(2,3-dimethylphenyl) anrino] -3-quinolinecarboxylate monosulfate from Preparation 1 and 2,3-dimethylaniline.

61. Ethyl 8-methoxy-4 - [(2-nitrophenyl) amino] -3-quinolinecarboxylate from Preparation 1 and 2-nitroaniline.

62. Ethyl 8-methoxy-4 - [(2-nitrophenyl) amino] -3-quinolinecarboxylate, ethylsulfate (1: 1), ethanol (1: 1) from Example 61 and concentrated sulfuric acid in absolute ethanol .

Example 63

-Methylethyl-8-methoxy-4 - [(2-methylphenylphamino) -3-quinolinecarboxylate, monohydrochloride, monohydrate

Two sodium pellets were added to 150 ml of dry 2-propanol followed by 5.38 g (15.99 mmol) of 50 ml of dry

Ethyl 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate dissolved in 2-propanol. The solution is heated to reflux for 6 hours, with the exclusion of moisture, while refluxing with 120 ml of distillate in a Dean-Starke trap. The solvent was evaporated and the residue was dissolved in 50 ml of 2.9 mol / l hydrochloric acid and water (100 ml) was added. The solution was adjusted to pH 8 with 1M aqueous sodium bicarbonate solution and the resulting oily substance was extracted three times with 100 ml of methylene chloride. The combined extracts were dried over magnesium sulfate and the solvent was evaporated. Yield: 4.60 g (82%) of the free base, m.p. 120-122 ° C after recrystallization from acetone / hexane.

The free base is dissolved in isopropyl ether and a solution of hydrochloric acid in ether is added. The solvent was evaporated and the residue was recrystallized from methylene chloride / acetone. The title compound is thus obtained in the form of a yellow crystalline solid, m.p. 140-143 ° C.

Example 64

2- (methoxyethyl) -8-methoxy-4 - [(2-methylphenyl) -3-quinolinecarboxylate -anúno}

Example 3 was transesterified with 2-methoxyethanol as in Example 81 to give the title compound.

Example 65

3- (dimethylamino) ethyl-8-methoxy-4 - [(2-methylphenyl) amino} ·

-3-quinolinecarboxylate

The compound of Example 3 was transesterified with 2-dimethylaminoethanol as described in Example 81 using sodium ethylate as catalyst and toluene as solvent. This gives the title compound.

Example 66

3- (Dimethylamino) propyl-8-methoxy-4 - [(2-methylphenyl) amino} -3-quinolinecarboxylate

The compound of Example 3 was transesterified with 3-dimethylamino-1-propanol as described in Example 63 using toluene as solvent. The title compound is thus obtained.

Example 67

2- (Dimethylamino) ethyl-8-methoxy-4 - [(2-methylphenyl) amino} · -3-quinolinecarboxylate fumarate (1: 1.5)

The title compound is prepared from the compound of Example 65 and fumaric acid.

Example 68

3- (Dimethylamino) -propyl-8-methoxy-4 - [(2-methyl-phenyl} · -emino} -3-quinolinecarboxylate dihydrochloride monohydrate

The title compound is prepared from the compound of Example 66 and ethereal hydrochloric acid.

Example 69

Ethyl 8-methoxy-4 - [(2-methylphenylamino) -3-quinolinecarboxylate ethanesulfonate (1: 1) (salt)

The title compound is prepared from the compound of Example 3 and ethanesulfonic acid in absolute ethanol.

184,253

Example 70

Ethyl 8-methoxy-4 - [(2-methylphenyl} amino] -3-quinolinecarboxylate-2-hydroxyethane sulfonate (1: 1) (salt)

The title compound is prepared from the compound of Example 3 and 2-hydroxyethanesulfonic acid in absolute ethanol.

Example 71

Allyl-8-methoxy-4 - \ (2-triisopropylsilanyloxy-phenyl) amino} -3-kmolmkarboxilát

The title compound was prepared as described in Example 63 using allyl alcohol instead of 2-propanol.

Table 1

Compounds of formula I

Example Ltd. R r. Salt melting point number CC) First 8 CHjO- 2-CH ₃ C ₄ H ₄ - C ₃ H _s - HC1 191-1933 Second 8-CH _a O- c "h ₅ - c, h ₃ - - 120-121 Third 8-CH 3 O- 2-CH ₃ -C ₄ H ₄ - c, h ₃ - - 1383-140 4th 8-CH 3 O- 2-CH ₃ -C ₄ H ₄ - c, h ₃ - h ₃ so ₄ 192-194 5th 8-CH 3 O- 2-CH _a -C ₄ H ₄ - C, H ₃ - h, after ₄ 99-102 6th 8-CH 3 O- C _e H, - C ₃ H ₅ - HC1 1653-168 7th 8 CHjO- 2 — CH ₃ OC ₄ H ₄ - CjHj- HC1 204-207 8th 8-CH 3 O- 2-CH _a SC ₄ H „- Cj H _s - HC1 275-278 9th 8-CH 3 O- 2-Cl-C ₄ H ₄ - c, h ₃ - HC1 193-194 10th 8-CH 3 O- 2-CN-C ₄ H ₄ - c ₃ h ₅ - HC1 204-2063 11th 8-CH 3 O- 2-CF ₃ -C ₄ H ₄ - c, h ₃ - HC1 199-201 12th 8-CH, O- 2-NH, OC-C _a H ₄ - C ₃ H _s - 1HC1.O.4C H ₃ OH 251-254 13th 8-CH 3 O- 2-FC ₄ H ₄ - c, h ₃ - HC1 204-206 14th 8-CH _a O- 2-CH 3 CO - C ₆ H ₄ - C, H ₃ - HC1 203-204 15th 8-CH 3 O- CH ₃ (-CH,) ₃ - c, h ₃ - HC1 171-172 16th 8-CH 3 O- 3-CH ₃ C ₄ H ₄ - C, H _s - HCl.H ₃ 0 156-158 17th 8-CH 3 O- 4-CH ₃ C ₄ H ₄ - C, H _S - HClH, O 155-156 18th 8 CHjO- 2-CH ₃ OC ₄ H ₄ CH _{3 -} c, h ₅ - - 132-137 19th 8-CH 3 O- 2.6- (CH ₃ ), C ₄ H ₃ - c, h ₃ - - 160-163 20th 8-CH 3 O- 2.6 (CH 2), C ₄ H ₃ - C, H _s - HBr 182-184 21st 8-CH 3 O- C ₆ H ₅ (CH _a ) CH- C, H _s - HJO 97-99 22nd 8-CH _a 2-Cl-5-CH ₃ OC ₄ Η, - c, h ₃ - HBr 160-162 23rd 8-CH 3 O- 3-CH ₃ SC ₄ H - c, h ₃ - - 123-1243 24th 8-CH 3 O- c ₄ h ₃ ch, - c, h ₃ - H ₃ PO „.CH ₃ OH 221-223 25th 8-CH 3 O- 2.4 (CH ₃ O) - C ₄ H ₃ - C, H _s - - 128-131 26th 8-CH 3 O- 2-C, H ₃ OC ₄ H ₄ - c, h ₃ - HC1 208D 27th 8-CH 3 O- 2-CH _a -4-CH ₃ OC ₆ H _a - C, H _s - - 175-176 28th 8-CH 3 O- 2-C, H _s -C ₄ H ₄ - C, H _s - - 152-153 29th 8-CH 3 O- 2-C, H _s -C ₄ H '- C, H, - 2H ₃ PO ₄ 140-142 30th 8-CH 3 O- 2-C, H, -C ₄ H ₄ - c, h ₃ - HjSO ₄ 177-1783 31st 8-CH 3 O- 2,6-Cl-C ₄ H ₃ - C, H _s - - 178-180 32nd 8-CH 3 O- 2-CH ₃ -5-NO, -C ₄ H _a - c, h ₃ - - 2513-253 33rd 8-CH 3 O- 2-CH _a -C ₄ H ₄ CH ₃ - c, h ₃ - HC1.1 / 2C H ₃ 0H 1973-198 34th 8-C ₃ H 10 - 2-CH _a -C ₄ H ₄ - c ₃ h ₅ - HC1 208-209 35th 8-C, H _and O 2-CF _a -C ₄ H ₄ - C, H ₃ - HBr 185-191 36th 8-C, H _and O 2-CH _a OC ₄ H ₄ - C, H _S - HC1 205-2063 37th 8-C, H _and 0 2-CH _a SC ₄ H „- C ₃ H _s - H ₃ PO ₄ 185-190 38th 8-CF3 2-CH _a -C ₄ H ₄ - c, h ₃ - - 147-148 39th 8-CH 3 S- 2-CH _s -C ₄ H ₄ - c, h, - - 168-170 40th 8-CH ₅ S- 2-CH _a OC ₄ H ₄ - c, h _s - HC1 169-172 41st 8-CH 3 S- 2-CH ₃ SC ₄ H ₄ - C, H _s - - 1403-142 42nd 8-CH3 2-CH ₃ SC ₄ H ₄ - C ₃ H _s - HC1 172-174 43rd 8-CH3 2-CH _a OC ₄ H ₄ - c, h ₃ - HC1 186-188 44th 8-CH3 2-CH "-C ₄ H ₄ CH, - c, h ₃ - HBr 182-183 45th 8-Cl 2-CH ₃ OC ₄ H ₄ - c, h ₃ - HC1 203-205 46th 8-CN 2-CH ₃ -C ₄ H ₄ - c, h ₃ - HC1 215-219 47th 8 CjHj- C ₄ H _s - C, H ₃ - - 123-125 48th 8-C ₆ H _s - 2-COOH-C ₄ H ₄ - C, H, - HC1.1 / 2H, O 213-2Í4 49th 8-C ₄ H _s - C ₄ H ₃ CH, - c ₃ h ₅ - 130-131 50th 8- (CH ₃ ), N- C _e H _s - c, h _s - HC1 179-181 51st 8- (CH ₃ ), N- 2-CH 3 -C ₆ H ₄ - c ₃ h ₃ - 110-114 52nd 8-CN C ₄ H _s - C, H, - - 194-196 53rd 8-CH ₃ O- 2-OH-C ₄ H ₄ - C ₂ H ₃ - - 229-231 54th 8-CH 3 O- 2-CH _a -C ₄ H ₄ - H 272d 55th 8-CH 3 O- 2-CH ₃ -C ₄ H ₄ - H HC1 257 56th 8-CH3 2-CH ₃ -C ₄ H ₄ - C, H, - HC1 162-164 57th 8-CH 3 O- 2- (CH ₃ ), CH-C ₄ H ₄ - c, h, - - 136-138 58th 8-C1 2-CH 3 -C ₄ H ₄ - c, h ₃ - 189-191 59th 8-CH 3 O- 2-CH ₃ -C ₄ H ₄ - c ₃ h ₃ - HC1 207-209 60th 8-CH _a 0- 2,3- (CH ₃ ) -C ₄ H _} - C ₃ H _s - H ₃ SO ₄ 177-181 61st 8-CH 3 O- 2-NO, -C ₄ H „- c ₃ h ₃ - - 180-182 62nd 8-CH 3 O- 2-NO, -C ₄ H ₄ - C "H ~ c ₃ h ₃ oh 85-90

-6184 253

Continuation of Table 1

Example száina R Ri Ri Salt melting point fc) 63rd 8-CH ₃ O— 2-CH ₃ -C ₈ H ₄ - (CH ₃ ) ₃ HC- HCl HJO 140-143 64th 8 CHjO- 2-CH ₃ -C, H ₄ - CH, O- (CH ₃ ) _a r- HC1 184-187 65th 8-CH ₃ O- 2-CH _s -C ₄ H ₄ - (CH ₈ ) ₃ N (CH _a ) _a - - 100-103 66th 8-CH ₃ O- 2-CH ₃ -C ₈ H ₄ - (CHjljNiCHj) - 95 to 97.5 67th 8 — CH ₃ O— 2-CH, -C ₈ H ₄ - (CHj) _a N (CH _a ) _a - fumarate 186-189 68th 8-CH ₃ O- 2-CH ₃ -C ₈ H ₄ - (CH ₃ ) _a N (CH ₃ ) ₃ - , H _is 02HCl 177-180 69th 8-CH ₃ O- 2-CH ₃ -C ₈ H ₄ - C _a H, - CHjCHjSOjOH 113-116 70th 8 CHjO- 2-CH ₃ -C ₈ H ₄ - c ₃ h ₃ - HO-CH ₃ CH ₃ SO ₃ OH 142-145

(a) is as described in J. Pharm. Chem. Soc., 1389 (1951), with a melting point of 99-100 ° C.

Table 2

1-88. The results of the analysis of the product of Example

Example Experience Calculated Number of Found Formula C% ^ H% N% C% H% N%

Example Experience Calculated Number of Found Formula C% H% N% C% H% N%

First

Second

Third

4th

5th

6th

7th

8. 9.

10th

11th

12th

13th

14th

15th 15th

17th

18th

19th

20. 21. 22.

23rd

24th

25th

26th

27th

28th

29th

30th

31st

32nd

33rd

34th

35th

36th

37th

38th

39th

40th

41st

42nd

43rd

44th

45th

46th

47th

48th

49th

50th

51st

52nd

53rd

54th

55th

56th

C _a0 H ₃₁ ClN ₃ O ₃ C ₁₉ H ₁₈ N _a O ₃ C ₂ „H _{a 0} N _a O ₃

64.63

70.79

71.41

55.29

55.30 63.60 61.78

C ₃₀ H ₃₃ N ₃ O ₇ PC _a , H _a , ClN _a O _s C ₃₀ H _3l ClN _a O ₄ C _a0 H _ai ClN _a O ₃ S 59.33 C, ₃ Hj, Cl ₃ N _a O ₃ 58 , 03 C _a0 H ₁₈ ClN ₃ O ₃ 62.59 C _a0 H ₁₈ N _a O ₃ F ₃ Cl 56.28 C, » ₄ H ₁₁₃ Cl ₃ N _u O _la 59.44 Cj, Hj, NjOjFCl 60.56 C _al H ₃₁ N ₃ O ₄ Cl ₁ C, 62.92, H ₃ N ₃ O C 1 _j C _jo H ₃₃ N ₃ 0 ₄ C1 UioH ₁₃ Cl ₄ N _{0 j} C H _O N _aa, C _al H ₃₃ N _a O ₃ C _al H _a3 BrN _a O ₃ C _ai H _a4 N _a O ₄

60.26

61.46

61.46 68.84 71.98 58.48

68.46

C _J0 H _a0 NjO ₄ ClBr 51.35

C _ao H _ao N _a O _a S

65.20

54.08

65.96

62.61

68.84

71.98

C ₃₁ H ₃₇ N ₃ O ₈ PC _a , H _aa N _a O _s C ₃₁ H ₃₃ N _a O ₄ Cl C _a j H _{a 3} N _a O ₄ C ₃₁ H ₃₃ N _a O ₃

_C, H, N, _a8, O ,, 46.16 _P C _{i H} is _"N, O, S 56.24 Ο Η ,, ^ Ν, Ο, Ο, 58.33

_J0 C, H ,, NO, 62.99 C ₄₄ H _8a N ₄ O ₇ Cl ₃ C 64.46 _3I H ₃₃ N ₃ O ₃ C1 65.20 C _Al H N _{a0 to a3} OjFjBr 51.97 C _i H N _a O ₄ Cl 62.61 C _ai H _a , N _a O, SP 52.50 C j # H ₃ , F ₃ N ₃ O ₃ 64.17 C _ao H _{a ()} N _a O _a S 68.16 C _{30 al} CLN H _{O 8} S C, 59.33 H _{o o} N _{O S} C, 62.47 _the "H N _{al O} C 61.77 _{SCL ai a0} H CLN _{3 O ai} C 64.73 H _A3 BrN _{O to} 60.73 C, Ti, N ₃ O ₃ C1 _{8 3} 58.03

C ₃₀ H ₁₇ N ₃ O ₃ 72.49

C ₃₄ H ₃₀ N ₃ O ₃ 78.24

C _S0 H ₄₄ a _a N ₄ O ₉ 65.57 C _{3 S} H ₃₃ N _a O ₃ 78.32 C _ao H ₃₃ N ₃ O _a Cl 64.60 C _al H ₃₃ N ₃ O _a 72.18 C ,, H ₁₅ N ₃ O _a 71.91 C ,, H ₁₈ N _a O ₄ 67.45 C, »H ₁₈ N ₃ O ₃ 70.12 σ ,, Η ,, Ν, Ο ^ 62.70

C 11 H _a , C ₃ O ₃ 67.32

5.68

5.63 5.99 5.10 5.34 5.34 5.44 5.23 4.61 4.73 4.25 5.37 4.81 5.28

6.84 5.93 5.93 6.05 6.33 5.37

6.57 4.31 5.47

5.84 5.80 5.75 6.05 6.33 5.17

5.39 4.12 5.02

6.39 5.99 4.15 5.75

5.75

4.58 5.72

5:23

5.24 5.44 5.68

5.58 4.61 5.17 5.47

4.84 6.05

5.96

6.63

4.76 5.36 5.23

4.97 5.93

7.51 64.36 5.65 7.62 20

8.69 70.91 5.65 8.77

8.33 71.52 5.94 8.35

6.45 55.68 5.02 6.42

6.45 54.92 5.37 6.53

7.81 63.25 5.33 7.69

7.20 61.55 5.57 7.07 25

6.92 59.04 5.38 6.87

7.12 57.89 4.69 7.13

10.95 62.23 4.95 10.73

6.56 56.33 4.34 6.60

10.00 59.25 5.21 10.03

7.43 60.28 4.87 7.32 30

6.99 62.56 5.48 6.76

8.26 59.3 9 6.80 8.20

7.17 61.40 5.92 7.21

7.17 61.73 5.76 7.33

7.65 68.61 6.04 7.51

7.99 72.16 6.33 8.01 35

6.49 58.48 5.41 6.52

7.60 68.47 6.51 7.59

5.99 51.27 4.30 6.04

7.60 65.18 5.48 7.66

6.01 54.32 5.58 6.23

7.33 66.06 5.75 7.28 40

6.95 62.61 5.84 6.94

7.65 68.94 6.06 7.68

7.99 72.02 6.29 8.03

5.13 46.07 5.22 5.12

6.25 56.09 5.43 6.24

7.16 58.52 4.13 7.21 ₄₅

11.02 63.02 5.08 11.03

6.83 64.09 6.22 6.96

7.24 65.25 6.01 7.26

5.77 52.22 4.14 5.89

6.95 62.67 5.76 7.05

5.83 52.08 5.35 5.77 cn

7.48 64.16 4.62 7.49

7.95 68.19 5.76 8.14

6.92 59.55 5.32 6.86

7.29 62.16 5.16 7.12

7.20 61.84 5.41 7.31

7.51 64.47 5.61 7.50 «

6.93 60.76 5.60 6.82 ⁰³

7.12 57.97 4.65 7.11

12.68 72.16 5.26 12.54

7.60 78.22 5.47 7.50

6.11 66.04 5.00 6.09

7.31 78.52 5.90 7.30

11.30 64.60 5.96 11.39

12.03 72.24 6.57 12.09

13.24 71.95 4.86 13.26

8.78 67.49 5.38 8.50

9.09 70.10 5.27 9.09

8.12 62.53 4.93 8.18

7.85 67.22 5.92 7.83 ^Bb

57. C ₁₃ H _a4 N _a O ₈ 72.51 6.64

58. C ₁ , H ,, N _a O _a a 66.90 5.03

59. C ₃₀ H ₃₀ N ₃ O ₃ Cl _a 58.98 4.95

60. C ₃₁ H _s4 N _a O ₇ S 56.24 5.39

61. Ci, H ₁₇ N ₃ O ₅ 62.12 4.66

62. C ₃₃ H a ₉ N ₃ O _le S 51.20 5.42

63. C ₃₁ H _as ClN _a O ₄ 62.30 6.22

64. C ₃₁ H a ₃ ClN _a O ₄ 62.61 5.75

65. C _aa H _{a 3} Ν _} 0 ₃ 69.64 6.64

66. C ₃₃ H ₃₇ N ₆ O _s 70,216.92

67. C ₃₈ H ₃₁ N, O, 60.75 5.64

68. C _{a 3} H ₃₁ CI ₃ NjO ₄ 57.03 6.45

69. Ο, ₃ Η ₃₈ Ν ₃ 0 ₈ S 59.18 5.87

70. C _{3 J} H _a8 N ₃ O, S 57.13 5.67

7.69 72.56 6.55 7.67

8.22 66.60 5.14 8.20

6.88 58.90 4.94 6.90

6.25 56.37 5.42 6.28

11.44 6 2.05 4.66 11.54 7.79 51.20 5.36 8.01

6.92 62.49 6.23 6.94

6.95 62.72 5.76 7.04

11.07 69.73 6.64 11.07 10.68 70.42 6.95 10.67 7.59 60.89 5.69 7.53

8.67 57.05 6.31 8.79

6.27 59.16 5.93 6.25

6.06 57.08 5.71 6.10

The effect of the 4-amino-3-quinolinecarboxylic acids and their esters on the weed secretion of the present invention was investigated in rats and dogs. Inhibition of secretion was measured and expressed as a percentage of gastric acid production. An anti-ulcer effect in rats was also studied. The results obtained with a representative representative of the compounds of the invention are shown in Table 3 below. Other compounds of the invention exhibit qualitatively identical activity in one or more of these experiments.

Table 3

AZL. The effect of the compound of Example 1b on stimulated weed secretion

species Dose (Gmol / kg) Dosage way stimulant Inhibition ¹ (%) Rat' 0.3 to 8.1 ARC. histamine '43 -96 Rat' 0,3-10-7 i.d. histamine 40-70 Rat' 0.3 to 8.1 TV. tetragastrin 27-85 Rat' 0.9 to 8.1 TV. methacholine 25-76 Dog' 2.7 and 8.1 TV. food 50 and 83 Dog' 32.4 po food 56

¹ inhibition was measured as the amount of stomach acid produced;

Rats were tested according to a modified version of the method of Ghosh and Shield (Brit. J. Pharmacol. 13, 54-61, 1958);

'Heidenhain stomach dogs were used for the experiment.

The compound of Example 1 was administered to rats whose gastric gates were tethered and whose gastric secretion was not artificially stimulated. The doses used were between 33 and 134 μιηοΐ / kg; inhibition of acid production was 38-55%

The gastric ulcer inhibitory activity of the compound of Example 1 was investigated in rats by Shay et al.

184,253 times (Gastroenterology, 5, 43-61, 1945). 4 to 90% protection against ulcer formation was provided at doses of 12 to 198 pmol / kg.

Pharmaceutical compositions containing the compounds of the present invention can be used to control histamine-stimulated acid release, to prevent or cure gastric ulcer. For example, the compositions may be administered orally in the form of solutions, emulsions, suspensions, pills, tablets, chewable tablets, pellets, capsules and the like, or they may be administered parenterally in the form of sterile solutions or mixtures.

For example, the compositions of the compounds of the present invention may be formulated with both carrier and liquid carriers. Examples of solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, peanut oil, water and any parenterally acceptable liquid.

Although very small amounts of the active ingredient are effective in treating mild gastric irritation or when the subject to whom the composition is administered is low, the dosage unit will generally contain a quantity of the active ingredient such that

Give 2-6 mg of active ingredient. Thus, the dosage unit may contain from 100 to 500 mg of active ingredient, preferably 200 to 500 mg for adults. Preferably, the active ingredient is administered in equal doses 1 to 4 times daily. The daily dose is about 100 mg to about 1200 mg, preferably about 300 to 900 mg per day. It is necessary to administer an effective dose of the active ingredient, i.e., an effective dose corresponding to the dosage unit used. The exact individual doses and daily doses will, of course, be determined according to the usual principles and under the guidance of a physician.

The preparation of formulations containing the compounds of the present invention is illustrated by the following examples.

1. Capsules

Parts Quantity (mg) Active ingredient (for example ethyl-8-methoxy-4- (2-methylphenyl) - amino-3-quinolinecarboxylate hydrochloride) 200 saccharose 100 Starch 30 talc 5 stearic 3 The ingredients are mixed 338 and gelatin

filled into capsules.

2. Pills

Ingredients Quantity (mg / tablet)

Active ingredient (e.g., ethyl 8-methoxy-4- (2-methylphenyl) amino-3-quinolinecarboxylate hydrochloride) 350.0

Alginic acid 20.0

Calcium and ammonium alginate 40.0

Starch 54.0

Lactose 75.0

Magnesium Stearate 2.2

721.2

The ingredients, other than magnesium stearate and half the amount of calcium ammonium alginate, were mixed and granulated with ethanol, passed through a 8 mesh screen and dried at 60 ° C for 16 hours. The dried granular material is then thoroughly mixed with the residual calcium ammonium alginate and magnesium stearate and tabletted.

3. Intravenous injection

Ingredients Quantity (mg)

Active ingredient (e.g. ethyl 8-methoxy-4- (2-methylphenyl) amino-3-quinolinecarboxylate hydrochloride 200)

Water ~ 2

Preservative (eg chlorobutanol)

Claims (13)

Patent claims A process for the preparation of 4-amino-3-quinolinecarboxylic acids and esters of the formula I and their pharmaceutically acceptable addition salts, wherein: Ri is lower alkyl, phenyl, O- (lower alkyl) -, Denotes S- (lower alkyl), trifluoromethyl, cyano or dialkylamino or halogen, R _{2 is} lower alkyl, phenyl, phenyl (lower alkyl), or phenyl substituted with 1 or 2 substituents wherein the substituents are lower alkyl, O- (lower alkyl), S (lower alkyl), cyano. , carbamoyl, carboxyl, acetyl, trifluoromethyl, hydroxy, nitro, or halogen, R 1 is hydrogen, lower alkyl, dimethylamino (lower alkyl), or (lower) alkoxy (lower) alkyl, characterized in that it is a TI. A 4-chloro-3-quinolinecarboxylic acid ester of the general formula (III), optionally chlorinated with 4-hydroxy-3-quinolinecarboxylic acid ester, is prepared from a compound of formula VII. with an amine of formula I wherein R ₁ and R _{2 are} as defined above and R _{3 is} lower alkyl and the resulting compound of formula I wherein R ₃ is lower alkyl is optionally reacted with hydrolysis or a suitable alcohol to form a compound of formula I wherein R ₃ is hydrogen, dimethylamino (lower alkyl), (lower alkoxy) (lower alkyl), and if desired, converting a compound of formula I into a pharmaceutically acceptable salt. (Priority: March 4, 1980) 2. A process for the preparation of 4-amino-3-quinolinecarboxylic acids and esters of formula I and pharmaceutically acceptable addition salts thereof, wherein: 184,253 R1 represents lower alkyl, phenyl, O- (lower alkyl), N- (lower alkyl), trifluoromethyl, cyano or dialkylamino or halogen, R _{2 represents} phenyl, phenyl-lower alkyl, or phenyl substituted with 1 or 2 substituents, wherein the substituents are lower alkyl, O- (lower alkyl), S- (lower alkyl), cyano, kaibamoyl, carboxyl, acetyl, trifluoromethyl, hydroxy, nitro or halogen 1 R ₃ is hydrogen, lower alkyl; of the general formula 4-Chloro-3-cinnolinecarboxylic acid ester in a compound of formula VII. with an amine of formula ( _II) wherein R 1 and R _{2 are} as defined above and R _{3 is} lower alkyl 1, and the resulting compound of formula I wherein R ₃ is lower alkyl is optionally hydrolyzed to a compound of formula I wherein R ₃ is hydrogen and optionally converting a compound of formula I into a pharmaceutically acceptable salt. (Priority: March 28, 1979). 3. A process according to claim 1 wherein the starting material is a compound of formula II. A compound of formula 2 is used which is a III. the compound of formula is prepared wherein R, and R ₃ are as defined in claim 1 and the chlorination with phosphorus oxychloride. (Priority: March 4, 1980) 3 A process for the preparation of a compound of formula I according to claim 1, wherein R ₃ is ethyl and R ₁ and R ₂ are as defined in claim 1, characterized in that starting material is a compound of formula II. and VII. compounds of the general formula wherein I < ₃ is as defined above and R ₁ and R ₂ are as defined in claim 1. (Priority: March 4, 1980) A process for the preparation of a compound of formula I according to claim 1, wherein 4 R 1 is methoxy, R ₃ is ethyl and R ₂ is as defined in claim 1, characterized in that the starting materials are IL and VII. They are used compounds of formula wherein R and R ₃ are as defined above, and R ₂ are as defined in claim 1 4. (Priority: March 4, 1980) - 6. A process for the preparation of a compound according to claim 1 wherein R 1 is methoxy, R ₃ is ethyl, and R ₂ is phenyl, 2-methylphenyl, 2-methoxyphenyl, 2-methylthiophenyl, 2-trifluoromethylphenyl, 2-ethoxyphenyl, 2-ethylphenyl, 2,6-dichlorophenyl, 2-chlorophenyl, 2-cyano phenyl, 2-aminocarbonylphenyl, 2-fluorophenyl, 2-acetylphenyl, n-butyl, 3-methylphenyl, 4-methylphenyl, 2-methoxybenzyl -, 2,6-dimethyl-ethyl-phenyl, 1-phenylethyl, 2-chloro-5-methoxyphenyl, 3-methylthiophenyl, benzyl, 2,4-dimethoxyphenyl- , 2-methyl-4-methoxyphenyl, 2-methyl-5-nitrophenyl, 2-methylbenzyl, 2-isopropylphenyl, 2,3-dimethylphenyl or 2-nitro- phenyl group, characterized in that the starting materials are II. and VII. Compounds of formula (I) are used wherein R 1, R 1 and R ₃ are as defined above. (Priority: March 4, 1980) A process for the preparation of a compound of formula I according to claim 2 wherein R 1 is ethoxy, R ₃ is ethyl and R ₂ is 2-methylphenyl, 2-trifluoromethylphenyl, 2-methoxy. phenyl or 2-methylthiophenyl; and VII. using a compound of formula, wherein, Ri, _R2 and _R3 are as defined above. (Priority: March 28, 1979) 8. The method of claim 2 embodiment of the preparation of a compound of formula I, wherein R represents a trifluoromethyl, methylthio, methyl, cyano, phenyl or chloro, R ₂ is 2-methylphenyl , 2-methoxyphenyl, 2-thiomethyl-phenyl, 2-methyl-benzyl, phenyl, 2-carboxyphenyl or benzyl and R ₃ is ethyl, wherein the starting materials II as. and VII. They are used compounds of formula wherein Ri, R _2, and R ₃ is as defined above. (Priority: March 28, 1979) A process for the preparation of a compound of formula I according to claim 2, wherein R 1 is dimethylamino, R ₂ is phenyl or 2-methylphenyl, and R ₃ is ethyl. as starting materials for such II. and VII. are used compounds of formula wherein Ri, R ₂ and R ₃ are as defined above. (Priority: March 28, 1979) 10. The process of claim 1 for the preparation of a compound of formula I wherein R 1 is methoxy, R ₂ is 2-methylphenyl and R ₃ is hydrogen, isopropyl or methoxyethyl. that the starting materials are II. and VII. are used compounds of formula wherein R, R ₂ and R ₃ are as defined above. (Priority: March 4, 1980) 11. A process according to claim 1 for the preparation of the salts of ethyl 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate and the hydrobromide with ethyl 4-chloro-8. -methoxy-3-quinolinecarboxylate is reacted with o-toluidine and the resulting ethyl 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride is optionally neutralized to give the free base. (Priority: March 4, 1980) 12. A process according to claim 1 wherein the starting material is ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate which is ethyl 4-hydroxy-8-methoxy-3-quinoline. was prepared by chlorination of the carboxylate with phosphorus oxychloride. (Priority: March 4, 1980) 13. A process for the preparation of a pharmaceutical composition which inhibits secretion and gastric ulcer, characterized in that a compound of formula I according to claim 1, wherein R ₁ , R ₂ and R ₃ are as defined in claim 1, is a conventional additive and / or medicament. or processed into a pharmaceutical composition with excipients. (Priority: March 4, 1980)