KR840000768B1 - Process for preparing 4-amino-3-quinolinecarboxylic acids and eaters - 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

Method for preparing 4-amino-3-quinolinecarboxylic acid and ester

The present invention provides 4-amino-3-quinoline carboxylic acids, esters and their pharmaceutically toxic additions which reduce gastric juice secretion stimulated by secretion promoters such as histamine, tetragastrin and food and are useful for the prevention or treatment of peptic ulcers in mammals. It relates to a method for preparing a salt.

The diuretic and antidepressant actions of some 4-anilino-3-quinolinecarboxylic acid esters and their 6-chloro derivatives have been described by Hanifin, J.W. in the United States, in particular US Pat. Nos. 3,470,186 and J. Med. chem. 1939, 12 (6), 109-7.

Kermack et al., J. chem. Soc. 1951, 1389-92 describe the preparation of 6-substituted 4-anilino-3-carboxylic acids and their esters and described in Sen et al., J. Indian chem. Soc. 34,906-8 (1957) describe the preparation of 7-substituted 4-amino-3-quinoline-carboxylamides. Elslager et al., J. Med. Pharm chem. 5,546-58 (1962) describes the preparation of 4-janilino-7-chloro-3-quinolinecarboxylic acid and its ethyl esters. Secretion inhibitory or antiulcer activity of 4-amino-3-quinolinecarboxylic acids and esters according to the invention is not known in the art.

The present invention provides a 4-amino-3-quinolinecarboxylic acid and ester of general formula (I) useful for inhibiting hydrochloric acid secretion and treating peptic ulcer in a mammal, and a method for preparing a pharmaceutically toxic addition salt thereof.

R ₁ is selected from lower alkyl, phenyl, O-lower alkyl, S-lower alkyl, halogen, trifluoromethyl, cyano and dialkylamino, and R ₂ is lower alkyl, phenyl, phenyl lower alkyl or Lower alkyl, O-lower alkyl, S-lower alkyl, halogen, cyano, hydroxy, carbamoyl, carboxy, acetyl, trifluoromethyl and nitro selected from phenyl substituted with one to three radicals, R ₃ is selected from hydrogen, lower alkyl, lower alkyl dimethylamino, lower alkyl-lower alkoxy and allyl and n is 0, 1 or 2;

The oral, subcutaneous, intraperitoneal, duodenal and intravenous administration of the 4-amino-3-quinoline-carboxylic acid of the present invention showed a secretory inhibitory effect of decreased secretion of gastric juice and hydrochloric acid in pyloric mice. In addition, an effective ulcer reduction effect was shown in pyloric rats. As mentioned above, compounds of general formula (I) have also been found to reduce gastric juice secretion induced by histamine, tetragastrin and methacholine. Food-stimulated gastric acid secretion was also reduced in HEIDENHAIN-CLA.

The present invention also provides a method for controlling excess gastric acid secretion by administering an effective amount of the gastric acid secretion inhibitor to a mammal.

The present invention also relates to a method of treating peptic ulcer by administering an inhibitory amount of peptic ulcer of the compound of general formula (I) to a mammal.

The present invention also provides a pharmaceutical composition containing the compound of the present invention and a suitable pharmaceutical carrier.

Other objects and advantages of the invention will be apparent to those skilled in the art, and will be apparent from the following description and claims of how best to implement the invention.

As used in the specification and claims, the term `` lower alkyl '' includes straight chain and branched radicals having up to 8 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, Examples thereof include heptyl, octyl and the like.

Representative of ″ phenyl lower alkyl ″ radicals include benzyl (phenylmethyl), α-methylbenzyl, phenylmethyl, phenylpropyl, phenylbutyl and the like.

Compounds of the present invention are prepared from suitable 4-chloro-3-quinolinecarboxylic acid esters as shown in the following reactions.

In the above general formula

R ₁ , R ₂ and n are as defined above,

R ₃ is lower alkyl.

Compound (II) is prepared by chlorination of an appropriate 4-hydroxy-3-quinolinecarboxylic acid ester with phosphorus oxychloride (Kermack & Storey, J. chem. Soc. 1951, pp 1389-92), and the reaction process thereof. Is as follows.

In the above general formula

R ₁ and n are as defined above,

R ₃ is lower alkyl.

Formula (III), wherein R ₃ is ethyl, heats a mixture of suitably substituted aniline and diethyl ethoxymethylene malonate to produce an intermediate anilinoacrylate, which is closed in a high boiling solvent such as diphenyloxide. (Price and Roberts in J. Amer. Chem. Soc. 68, 1204-8).

This reaction is represented by the following scheme.

Acids (R ₃ = H) of the present invention may be prepared from esters (R ₃ = lower alkyl) by hydrolysis, which is a conventional method, and other esters of the present invention may be prepared by conventional re-esterification methods. Can be.

The present invention relates in particular to the following general formula (Ia) compounds and methods for the preparation of pharmaceutically toxic addition salts thereof.

In the above general formula

R ₁ is selected from lower alkyl, phenyl, O-lower alkyl, S-lower alkyl, halogen, trifluoromethyl, cyano and dialkylamino;

R ₂ is 1 to 3 selected from lower alkyl, phenyl, phenyl lower alkyl, or lower alkyl, O-lower alkyl, S-lower alkyl, halogen, cyano, carbamoyl, carboxy, acetyl, trifluoromethyl and nitro Selected from radicals substituted with phenyl,

R ₃ is selected from hydrogen, lower alkyl, lower alkyl dimethylamino, lower alkyl-lower alkoxy and allyl.

For example, ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride is induced by histamine and ethyl 6-methoxy-4- at 1/2 the dose for gastric acid secretion. It was found to be 43% more effective than [(2-methylphenyl) amino] -3-quinoline carboxylate.

Ethyl-4-hydroxy-3-quinolinecarboxylate of formula II is prepared from diethylethoxymethoxy malonate and aniline or known aniline derivatives using the methods of Price and Roberts described above:

Ethyl 4-hydroxyquinoline-3-carboxylate (from aniline);

Melting Point: 280 to 283 ° C

Ethyl 4-hydroxy-8-methoxy-3-quinolinecarboxylate (from 2-methoxyaniline);

Melting Point: 243-246 ° C

Ethyl 4-hydroxy-8-ethoxy-3-quinolinecarboxylate (from 2-ethoxyaniline);

Melting Point: 198 to 200 ° C

Ethyl 4-hydroxy-5,8-dimethoxy-3-quinolinecarboxylate (from 2,5-dimethoxyaniline);

Melting Point: 197 to 199.5 ° C

Ethyl 4-hydroxy-8-methoxy-5-methyl-3-quinolinecarboxylate (from 2-methoxy-5-methylaniline);

Melting Point: 189-182 ° C

Ethyl 4-hydroxy-8-phenyl-3-quinolinecarboxylate (from 2-aminobiphenyl);

Melting Point: 250-252.5 ° C

Ethyl 4-hydroxy-8-methyl-3-quinoline carboxylate (from 2-methylaniline);

Melting Point: 271 to 274 ° C

Ethyl 4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylate (from 2-trifluoromethylaniline)

Melting Point: 211 to 213.5 ° C

Ethyl 4-hydroxy-8-methylthio-3-quinolinecarboxylate (from 2-methylthioaniline);

Melting Point: 201 to 204 ° C

Ethyl 4-hydroxy-8-chloro-3-quinolinecarboxylate (from 2-chloroaniline);

Melting Point: 255 to 259 ° C

Ethyl 4-hydroxy-6,8-dimethyl-3-quinolinecarboxylate (from 2,4-dimethylaniline);

Ethyl 4-hydroxy-6-methoxy-3-quinolinecarboxylate (from 4-methoxyaniline);

Melting Point: 283-287 ° C

Ethyl 4-hydroxy-8-cyano-3-quinolinecarboxylate (from 2-cyanoaniline);

Melting Point: 234-236 ° C

Ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate (from 3-methoxyaniline);

Melting Point: 280 to 282.5 ° C

Ethyl 4-hydroxy-8-dimethylamino-3-quinolinecarboxylate (from 2-dimethylaminoaniline);

Melting Point: 176-180 ° C

Preparation Example 1 illustrates the synthesis of 4-chloro compounds of the general formula (II) which is a starting material in the preparation of the general formula (I) compounds.

Production Example 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 is warmed with stirring to dissolve all solids and then heated at reflux for 2 hours. Cool down to 100C and mix the mixture on a rotary evaporator. The residual oil is dissolved in 100 ml of acetone and the solution is poured into 800 ml of ice-water mixture. The mixture is neutralized with 6N sodium hydroxide and then the solid product is continuously extracted with 450 ml, 230 ml and 100 ml methylene chloride, respectively. The extracts are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 68.16 g of crude product.

The crude product is dissolved in 500 ml of hot toluene to filter off a small amount of insoluble matter. The toluene solution is filtered through 250 g of fluorylsilic layer and then passed through 2 liters of toluene and 4 liters of chloroform. The purification solution is concentrated to give 64.17 g (89%) of oil which crystallizes to an off-white solid upon cooling.

Melting point is 75-77 degreeC.

Elemental Analysis of C ₁₃ H ₁₂ NO ₃ Cl

Calculated Value: C 58.77, H 4.55, N 5.27

Found: C 58.58, H 4.61, N 5.33

[Production Examples 2 to 15]

The following 4-chloro-quinoline-3-carboxylate was prepared directly using ethyl 4-hydroxy-3-quinolinecarboxylate of general formula (III) according to the method of Preparation Example 1 and used immediately.

(2) ethyl 4-chloro-3-quinolinecarboxylate

(3) ethyl 4-chloro-8-ethoxy-3-quinolinecarboxylate

(4) ethyl 4-chloro-5,8-dimethoxy-3-quinolinecarboxylate

(5) ethyl 4-chloro-8-methoxy-5-methyl-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

(11) ethyl 4-chloro-6,8-dimethyl-3-quinolinecarboxylate

(12) ethyl 4-chloro-6-methoxy-3-quinolinecarboxylate

(13) ethyl 4-chloro-8-cyano-3-quinolinecarboxylate

(14) ethyl 4-chloro-7-methoxy-3-quinolinecarboxylate

(15) ethyl 4-chloro-8- (dimethylamino) -3-quinolinecarboxylate.

General preparations of the esters of general formula (I) of the invention (R ₃ = lower alkyl) are prepared by the preparation of a suitable 4-chloro-3-quinoline carboxylic acid ester in a suitable amine and a polar aprotic solvent such as tetrahydrofuran or dioxane. The reaction is completed by adjusting the temperature and time while keeping track of the reaction by thin layer chromatography.

In some cases, the amine itself may be used as the reaction solvent. Several solvents can be used for recrystallization. To prepare the free base from the salt, the salt is dissolved, a base such as sodium hydroxide is added, and the free base is extracted with a suitable organic solvent. Other salts may be prepared by mixing the free base with an alcoholic solution of an acid such as phosphoric acid or sulfuric acid.

Examples 1 and 2 which follow illustrate the general method of preparing ester compounds. The esters of Examples 3 to 71 and 74 to 80 are also prepared by reacting the appropriate amine with the appropriate ethyl 4-chloro-3-quinolinecarboxylate selected from Preparation Examples (1) to (15). Examples 81 to 84 and 89 is R ₃ is in the lower alkyl ester will be described a production method of an ester of a lower alkoxy, or allyl-esterification with R ₃ is lower alkyl, lower alkyl, dimethylamino lower alkyl. Methods of preparing acids of formula (I) (R ₃ -H) and their acid salts are described in Examples 72 and 73 where the esters are hydrolyzed to acids.

Metal salts of acids, such as alkali metal salts, can also be prepared by the general method of reacting with an alkali metal base to separate the salts. Examples 85 to 88 illustrate a process for converting the free bases of the esters of the invention to their acid addition salts. The analysis and physical property data measured are listed in Tables 1 and 2. The following examples illustrate the invention but do not limit it.

Example 1

Ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinoline-carboxylate hydrochloride

In a solution of 5.31 g (19.98 mmol) of ethyl 4-chloro-8-methoxy-3-quinoline carboxylate in 40 ml of tetrahydrofuran, 2.15 g (20.06 mmol) of 0-toluidine in 40 ml of tetrahydrofuran The dissolved solution is added. The mixture is stirred while dehumidifying at 60 ° C. for 18 hours. The yellow precipitate is filtered off and washed with isopropyl ether to give 7.13 g of product (95.7). The product is recrystallized three times with methylene chloride and ethyl acetate.

Melting point is 191-193.5 degreeC.

Elemental Analysis of C ₂₀ H ₂₁ ClN ₂ O ₃

Calculated Value: C 64.63, H 5.68, N 7.51

Found: C 64.36, H 5.65, N 7.62

Example 2

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

In a solution of 6.0 g (22.5 mmol) of ethyl 4-chloro-8-methoxy-3-quinoline carboxylate in 80 ml of tetrahydrofuran, a solution of 2.3 g (24.8 mmol) of aniline in 60 ml of tetrahydrofuran was prepared. Add. After warming the mixture for 10 minutes, yellow solids start to precipitate. The mixture is left at room temperature for 18 hours. The solvent is removed by rotary evaporation to dissolve the residue in 200 ml of methanol and the pH is adjusted to 8 with sodium bicarbonate. Adding 700 ml of water gives a solid oil, which is left to continue to precipitate crystals. The solid is filtered and dried to yield 6.9 g (95%) of crude product. The solid is dissolved in 300 ml of hot isooctane, treated with charcoal and filtered. The volume of the filtrate is reduced to 150 ml. Cooling yields 6.5 g (89%) of pale yellow acicular crystals.

Melting point is 120-121 degreeC.

Elemental Analysis of C ₁₉ H ₁₈ N ₂ O ₃

Calculated Value: C 70.79, H 5.63, N 8.69

Found: C 70.91, H 5.65, N 8.77

[Examples 3 to 71]

3. Neutralize the compound of Example 1 to prepare ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinoline carboxylate.

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

5. Ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate phosphate (1: 1) is prepared from the compound of example 3 and phosphoric acid.

6. Preparation Ethyl 8-methoxy-4- (phenylamino) -3-quinoline carboxylate hydrochloride is prepared from the compound of Example 1 and aniline.

7. Preparation Ethyl 8-methoxy-4-[(2-methoxyphenyl) amino] -3-quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 1 and 0-anisidine.

8. Preparation Ethyl 8methoxy-4-[(2-methylthiophenyl) amino] -3-quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 1 and 2-methylthioaniline.

9. Preparation of ethyl 4-[(2-chlorophenyl) amino] -8-methoxy-3-quinoline carboxylate hydrochloride from the compound of Preparation Example 1 and 2-chloroaniline.

10. Preparation Ethyl 4-[(2-cyanophenyl) amino] -8-methoxy-3-quinoline carboxylate hydrochloride is prepared from the compound of Example 1 and 2-aminobenzonitrile.

11. Preparation ethyl 4-[(2-trifluoromethylphenyl) amino] -8-methoxy-3quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 1 and 2-trifluoromethylaniline.

12. Ethyl 4-{[(2-aminocarbonyl) phenyl] amino} -8-methoxy-3-quinoline carboxylate monohydrochlorideethanol (5: 2) was prepared from the compound of Preparation Example 1 and anthranylamide. Manufacture.

13. Production of ethyl 4-[(2-fluorophenyl) amino] -8-methoxy-3-quinoline carboxylate hydrochloride from the compound of Preparation Example 1 and 2-fluoroaniline.

14. Preparation of ethyl 4-[(2-acetylphenyl) amino] -8-methoxy-3-quinoline carboxylate hydrochloride from the compound of Preparation Example 1 and 2′-aminoacetophenone.

15. Ethyl 4- (butylamino) -8-methoxy-3-quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 1 and n-butylamine.

16. Preparation Ethyl 8-methoxy-4-[(3-methylphenyl) amino] -3-quinoline carboxylate hydrochloride monohydrate is prepared from the compound of Preparation Example 1 and m-toluidine.

17. Preparation of ethyl 8-methoxy-4-[(4-methyllophenyl) amino] -3-quinoline carboxylate hydrochloride monohydrate from the compound of Preparation Example 1 and P-Toluidine.

18. Preparation Ethyl 8-methoxy-4-{[(2-methoxyphenyl) -methyl] amino} -3-quinoline carboxylate is prepared from the compound of Example 1 and 2-methoxybenzylamine.

19. Preparation Ethyl 8-methoxy-4-[(2,6-dimethylphenyl) amino] -3-quinoline carboxylate is prepared from the compound of Example 1 and 2,6-dimethylaniline.

20. Preparation Ethyl 8-methoxy-4-[(2,6-dimethylphenyl) amino] -3-quinoline carboxylate hydrobromide is prepared from the compound of Example 18 and HBr.

21. Preparation Ethyl 8-methoxy-4-[(1-phenylethyl) amino] -3-quinoline carboxylate monohydrate is prepared from the compound of Example 1 and α-methylbenzylamine.

22. Ethyl 4-[(2-chloro-5-methoxyphenyl) amino] -8-methoxy-3-quinolinecarboxylate hydrobromide was prepared from the compound of Preparation Example 1 and 2-chloro-5-methoxyaniline. Manufacture.

23. Preparation Ethyl 8-methoxy-4-[(3-methylthiophenyl) amino] -3-quinoline carboxylate is prepared from the compound of Example 1 and 3-methylmercaptoaniline.

24. Preparation Ethyl 4-benzylamino-8-methoxy-3-quinoline carboxylate phosphate (1: 1) methanolate (1: 1) is prepared from the compound of Example 1 and benzylamine.

25. Preparation Ethyl 8-methoxy-4-[(2,4-dimethoxyphenyl) amino] -3-quinoline carboxylate is prepared from the compound of Example 1 and 2,4-dimethoxyaniline.

26. Ethyl 4-[(2-ethoxyphenyl) amino] -8-methoxy-3-quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 1 and 2-ethoxyaniline.

27. 8-methoxy-4- [4-methoxy-2-methylphenyl) amino] -3-quinoline carboxylate is prepared from the compound of Preparation Example 1 and 2-methyl-4-methoxyaniline.

28. Ethyl 4-[(2-ethylphenyl) amino] -8-methoxy-3-quinoline carboxylate is prepared from the compound of Preparation Example 1 and 2-ethylaniline.

29. Ethyl 4-[(2-ethylphenyl) amino] -8-methoxy-3-quinoline carboxylate phosphate (1: 2) is prepared from the compound of Example 28 and anhydrous H ₃ PO ₄ .

30. Ethyl 4-[(2-ethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate sulfate (1: 1) is prepared from the compound of example 28 and alcoholic H ₂ SO ₄ .

31. Ethyl 4-[(2,6-dichlorophenyl) amino] -8-methoxy-3-quinolinecarboxylate is prepared from the compound of Preparation Example 1 and 2,6-dichloroaniline.

32. Ethyl 8-methoxy-4-[(2-methyl-5-nitrophenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 1 and 2-methyl-5-nitroaniline.

33. Compound of Preparation Example 1 and ethyl 8-methoxy-4-[(2-methylphenyl) methyl] amino} -3-quinolinecarboxylate hydrochloride ethanol (2: 1 from 0-methylbenzylamine, ethanol and hydrogen chloride) ).

34. Ethyl 8-ethoxy-4-[(2-methylphenyl (amino) -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 3 and 0-toluidine.

35. Ethyl 8-ethoxy-4- [2- (trifluoromethylphenyl) amino] -3-quinolinecarboxylate hydrobromide is prepared from the compound of Preparation Example 3 and 0-trifluoromethylaniline.

36. Ethyl 8-ethoxy-4-[(2-methoxyphenyl) amino] -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 3 and 0-anisidine.

37. Ethyl 8-ethoxy-8- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate phosphate (1: 1) was prepared from the compound of Preparation Example 3 and methylthioaniline and alcoholic H ₃ PO ₄ . Manufacture.

38. Ethyl 5,8-dimethoxy-4- (phenylamino) -3-quinoline-carboxylate hydrochloride hemihydrate is prepared from the compound of Preparation Example 4 and aniline.

39. Ethyl 5,8-dimethoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 4 and 0-toluidine.

40. Ethyl 7-methoxy-4-[(2-methylphenyl) amino-3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 14 and 0-toluidine.

41. Ethyl-4- (phenylamino) -6-methoxy-3-quinolinecarboxylate is prepared from the compound of Preparation Example 12 and aniline.

42. Ethyl 6-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 12 and 0-toluidine.

43. Ethyl 8-methoxy-4-[(2-methoxyphenyl) amino] -5-methyl-3-quinolinecarboxylate dihydrochloride is prepared from the compound of Preparation Example 5 and 0-anisidine.

44. Ethyl 8-methoxy-5-methyl-4- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate phosphate (2: 3) was prepared from the compound of Preparation Example 5 and 2-methylthioaniline. Manufacture.

45. Ethyl 8-methoxy-5-methyl-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 5 and 0-toluidine.

46. Ethyl 4- [2- (methylphenyl) amino] -8-trifluoromethyl-3-quinolinecarboxylate is prepared from the compound of Preparation Example 8 and 0-toluidine.

47. Ethyl 4-[(2-methylphenyl) amino] -3-methylthio-3-quinolinecarboxylate is prepared from the compound of Preparation Example 9 and 0-toluidine.

48. Ethyl 4- [2-methoxyphenyl) amino] -8-methylthio-3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 9 and 0-toluidine.

49. Ethyl 8-methylthio-4-[(2-methylthiophenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 9 and 2-methylthioaniline.

50. Ethyl 8-methyl-4- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 7 and 2-methylthioaniline.

51. Ethyl 4-[(2-methoxyphenyl) amino] -8-methyl-3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 7 and 0-anisidine.

52. Ethyl 8-methyl-4-[(2-methylphenyl) methyl] amino-3-quinolinecarboxylate hydrobromide is prepared from the compound of Preparation Example 7 and 2-methylbenzylamine.

53. Ethyl 8-chloro-4-[(2-methoxyphenyl) amino] -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 10 and 0-anisidine.

54. Ethyl 8-cyano-4-[(2-methylphenyl) amino-3-quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 13 and aniline.

55. Ethyl 4- (phenylamino) -8-phenyl-3-quinolinecarboxylate is prepared from the compound of Preparation Example 6 and aniline.

56. Ethyl 4-[(2-carboxyphenyl) amino] -8-phenyl-3-quinolinecarboxylate hydrochloride hemihydrate is prepared from the compound of Preparation Example 6 and 2-aminobenzoic acid.

57. Ethyl 4-benzylamino-8-phenyl-3-quinolinecarboxylate is prepared from the compound of Preparation Example 6 and benzylamine.

58. Ethyl 4- (phenylamino) -6,8-dimethyl-3-quinolinecarboxylate is prepared from the compound of Preparation Example 11 and aniline.

59. Ethyl 4- (phenylamino) -3-quinolinecarboxylate is prepared from the compound of Preparation Example 2 and aniline.

60. Ethyl 4- (phenylamino) -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 2 and aniline.

61. Ethyl 4-benzylamino-3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 2 and benzylamine.

62. Ethyl 4-[(2-methylphenyl) amino-3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 2 and 0-toluidine.

63. Ethyl 4- [2- (trifluoromethylphenyl) amino] -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 2 and 2-trifluoromethyl aniline.

64. Ethyl 4-[(2-methoxyphenyl) amino] -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 2 and 0-anisidine.

65. Ethyl 4-[(2-methylthiophenyl) amino] -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 2 and 2-methylthioaniline.

66. Ethyl 4-[(4-methoxy-2-methylphenyl) amino] -3-quinolinecarboxylate hydrochloride is prepared from the compound of Preparation Example 2 and 2-methyl-4-methoxyaniline.

67. Ethyl 4-[(2-chlorophenyl) amino] -3-quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 2 and 2-chloroaniline.

68. Ethyl 8- (dimethylamino) -4- (phenylamino) -3-quinoline carboxylate hydrochloride is prepared from the compound of Preparation Example 15 and aniline.

69. Ethyl 8- (dimethylamino) -4-[(2-methylphenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 15 and 0-toluidine.

70. Ethyl 8-cyano-4- (phenylamino) -3-quinolinecarboxylate is prepared from the compound of Preparation Example 13 and aniline.

71. Ethyl [(2-hydroxyphenyl) amino] -8-methoxy-3-quinolinecarboxylate is prepared from the compound of Preparation Example 1 and 0-hydroxyaniline.

Example 72

8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylic acid

A mixture of 15.00 g (0.0445 mol) of ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate, 100 ml of 3N sodium hydroxide and 100 ml of ethanol is stirred at room temperature for 16 hours. The mixture is diluted with 300 ml of water and acidified to pH 6.8 with 6N hydrochloric acid solution. The precipitates are collected by filtration, washed successively with water and acetone and air dried for 1.5 hours. The weight of the solid is 13.41 g (98%) and the melting point is 272 ° C (d).

Elemental Analysis of C ₁₈ H ₁₆ N ₂ O ₃

Calculated Value: C 70.12, H 5.23, N 9.09

Found: C 70.10, H 5.27, N 9.09

Example 73

8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylic acid hydrochloride

4.35 g of 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylic acid from Example 72 were polished with 100 ml of hot anhydrous ethanol. After cooling the solids were collected by filtration and air dried to yield 3.87 g. The solid is suspended in 25 ml of anhydrous ethanol and excess etheric hydrogen chloride solution is added. A clear solution is obtained. Isopropyl ether is added to produce a yellow precipitate, which is collected and recrystallized from anhydrous ethanol-isopropyl ether to give 3.14 g of a solid having a melting point of 257 ° C. (d).

Elemental Analysis of C ₁₈ R ₁₇ N ₂ O ₃ Cl

Calculated Value: C 62.70, H 4.97, N 8.12

Found: C 62.53, H 4.93, N 8.18

Example 74-80

74. Prepare ethyl 8-methyl-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate monohydrochloride from the compound of Preparation Example 7 and 0-toluidine.

75. Ethyl 8-methoxy-4- [2- (1-methylethyl) phenylamino-3-quinolinecarboxylate is prepared from the compound of Preparation Example 1 and 0-isopropylaniline.

76. Ethyl 8-chloro-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 10 and 0-toluidine.

77. Ethyl [(2-chloro-6-methylphenyl) amino] -8-methoxy-3-quinolinecarboxylate monohydrochloride is prepared from the compound of Preparation Example 1 and 2-chloro-6-methylaniline.

78. Ethyl-8-methoxy-4- [2,3-dimethylphenyl) amino-3-quinolinecarboxylate monosulfate is prepared from the compound of Preparation Example 1 and 2,3-dimethylaniline.

79. Ethyl 8-methoxy-4-[(2-nitrophenyl) amino] -3-quinolinecarboxylate is prepared from the compound of Preparation Example 1 and 2-nitroaniline.

80. Ethyl 8-methoxy-4-[(2-nitrophenyl) amino] -3-quinolinecarboxylate, ethyl sulfate (1: 1), ethanol (1: 1) from the compound of Example 79 and concentrated sulfuric acid in anhydrous ethanol 1) is prepared.

Example 81

1-methylethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate, monohydrochloride, monohydrate

Two sodium pellets were added to 150 ml of anhydrous 2-propanol and 5.38 g (15.99 mmol) of ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate was added to 50 ml of anhydrous 2-propanol. Add dissolved solution. The solution is stirred, dehumidified and refluxed for 6 hours, at which time 120 ml of distillate is collected in the Dean-Stark trap, which is discarded. The solvent is evaporated and the residue is dissolved in 50 ml of 2.9 M hydrochloric acid and 100 ml of water is added. To this solution is added 1M aqueous sodium bicarbonate solution to adjust the pH to 8, the separated oil is extracted three times with 100 ml of methylene chloride, and the combined extracts are dehydrated on magnesium sulfate. The solvent is evaporated and then recrystallized from acetone-hexane to give 4.60 g (82%) of the free base of the title compound.

The free base is dissolved in isopropyl ether and etheric hydrogen chloride is added. The solvent is evaporated and the residue is recrystallized from methylene chloride-acetone to give the title compound as a yellow crystal having a melting point of 140 to 143 ° C.

Example 82

2- (methoxyethyl) -8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate

According to the method of Example 81, the compound of Example 3 is reesterified with 2-methoxyethanol to give the title compound.

Example 83

3- (dimethylamino) ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate

In a similar manner to Example 81, the compound of Example 3 is reesterified with 2-dimethylaminoethanol using a sodium ethoxide catalyst and toluene to afford the title compound.

Example 84

3- (dimethylamino) propyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate

In a similar manner to Example 81, the compound of Example 3 is reesterified with 3-dimethylamino-1-propanol using toluene to afford the title compound.

Example 85

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 83 and fumaric acid.

Example 86

3- (dimethylamino) propyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinolinecarboxylate, dihydrochloride, monohydrate

The title compound is prepared from the compound of Example 84 and ethereal hydrogen chloride.

Example 87

Ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinoline-carboxylate, ethanesulfonate (1: 1) (salt)

The title compound is prepared from the compound of Example 3 and ethane sulfonic acid in ethanol anhydride.

Example 88

Ethyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinoline-carboxylate, 2-hydroxyethanolsulfonate (1: 1) (salt)

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

Example 89

Allyl 8-methoxy-4-[(2-methylphenyl) amino] -3-quinoline-carboxylate

In the same manner as in Example 81, the title compound is prepared using allyl alcohol instead of 2-propanol.

TABLE 1

TABLE 2

[Pharmacology]

The action of gastric secretion of 4-amino-3-quinolinecarboxylic acid and ester of the present invention was tested in rats and dogs. The secretion inhibitory activity was measured and expressed as% gastric acid secretion. Antiulcer tests were also performed in rats.

The results of testing with the preferred compounds of formula (Ia) of the present invention are described below. Other compounds of the present invention also exhibited qualitatively equivalent effects in one or more of these tests.

TABLE 3

Example 1 Compounds were administered to pyralized mice that did not artificially stimulate gastric juice secretion. The dose used was 33 to 134 μmoles / kg, with the result that the amount of acid secretion was suppressed 38 to 55%.

Example 1 The compound was tested according to the method of Shay et al., 1945, Gastroenterology 5: 42-61 in the above antiulcer activity. Protective effects of 4 to 90% against ulcers were seen at 12 to 198 μmoles / kg dose.

The effective amount of the compound of formula (Ia) may be adjusted according to conventional pharmaceutical administration methods, such as emulsions, suspensions, solutions, pills, tablets, troches, to control acid secretion due to histamine stimulation in mammals or to control or treat peptic ulcers. It can be administered orally in the form of, lozenges, summons, capsules, etc., or parenterally in sterile solutions or mixtures.

The pharmaceutical carrier used may, for example, be in solid or liquid form. 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, water or other parenterally nontoxic liquids.

When administered to patients with light weight therapy or small weight to treat gastric irritation, even a small amount of the active substance of the present invention is effective, but a unit dose usually contains an amount of 2 to 6 mg per kg of the active substance. The unit dose may contain 100 to 500 mg of active substance and 200 to 500 mg is preferred for adults. The active ingredient is preferably administered 1 to 4 times a day. The daily dose may vary from about 100 to 1200 mg, but preferably about 300 to 900 mg per day. It is necessary to ensure that the active ingredient is contained in an effective amount, that is, that the appropriate effective dose is consistent with the dosage form employed. The daily dose, as well as the exact individual dose, should be established according to standard medical principles under the direction of a physician or veterinarian.

The following formulation is representative.

1. Capsule

Mixed and filled into gelatin capsules.

2. Tablet

Half of all ingredients except magnesium stearate and calcium ammonium alginate are mixed and granulated with ethanol, passed through an 8 mesh sieve and the mixture is dried at 140 ° F. for 16 hours. The dried granules are mixed with the remaining calcium ammonium alginate and magnesium stearate and compressed into tablets.

3. Intravenous Injection

Those skilled in the art will appreciate that many modifications are possible and can be applied to the compound compositions and methods of the invention without departing from the spirit and scope of the invention. Therefore, the present invention is not limited to the claims.

Claims (1)

The reaction of a compound of formula (II) with an amine of formula (VI) to prepare 4-amino-3-quinolinecarboxylic acid of formula (Ia), an ester thereof and a pharmaceutically nontoxic salt thereof Way.

In the general formula, R ₁ is selected from lower alkyl, phenyl, 0-lower alkyl, S-lower alkyl, halogen, trifluoromethyl, cyano and dialkylamino, and R ₂ is lower alkyl, phenyl, phenyl lower alkyl Or phenyl substituted with 1 to 3 radicals selected from lower alkyl, 0-lower alkyl, S-lower alkyl, halogen, cyano, hydroxy, carbamoyl, carboxy, acetyl, trifluoromethyl and nitro; , R ₃ is selected from hydrogen, lower alkyl, lower alkyl dimethylamino, lower alkyl-lower alkoxy and allyl.