CS216527B2 - Method of making the 4-amino-3-chinolincarboxyl avids and the esters thereof - Google Patents

Description

The present invention relates to 4-amino-3-quinolinecarboxylic acids and esters and to new pharmaceutical uses of mixtures containing these compounds. In particular, the invention relates to certain 4-amino-3-quinolinecarboxylic acids and esters that reduce gastric secretion stimulated by secretagogues, such as histamine, tetragastrine and food, and which can be used to prevent or treat formation gastric ulcers in mammals. The compounds of the present invention are novel compounds.

In the prior art, the effects, specifically the diuretic effect and antidepressant effect, of certain esters of 4-aniline-3-quinolinecarboxylic acids and 6-chloro derivatives of these compounds are known, such as have been published, for example, by JW Hanifin in the United States patent No. 3,470,186 and J. Med. Chem., 1969, 12 (6), 1096-7.

J. Chem. Soc., 1951, 1389-92, reported by Kermack et al. the preparation of 6-substituted 4-aniline-3-quinolinecarboxylic acids and esters thereof. Sen et al. reported in J. Indian Chem. Soc., 34, 906-8 (1957) for the preparation of 7-substituted 4-amino-3-ehinolinecarboxylic amides. Elslager et al. reported in J. Med. Pharm. Chem. 5, 548-58 (1962) to prepare 4-aniline-7-chloro-3-quinolinecarboxylic acids and ethyl esters thereof.

However, the antisecretory or anti-ulcer effect of 4-araino-3-quinoimarboxylic acids has not been known and reported.

The compounds which are used according to the invention in a novel process for inhibiting hydrochloric acid secretion and in the treatment of gastric ulcers in mammals are according to the invention 4-amino-3-quinolinecarboxylic acids and their esters.

The present invention relates to a process for the preparation of 4-amino-3-quinolinecarboxylic acids and their esters of formula (I)

where

R1 represents a methyl group, a phenyl group, a methoxy group, an ethoxy group, a methylthio group, a halogen, a trifluoromethyl group, a cyano group and a dimethylamino group,

R 2 represents butyl, phenyl, phenylmethyl, phenylethyl or phenyl substituted with 1 to 3 substituents selected from methyl, methoxy, ethoxy, methylthio, halogen, cyano, hydroxy, carbamoyl, carboxyl, acetyl, trifluoromethyl and nitro,

R 3 is hydrogen, ethyl, propyl, ethyldimethylamino, propyldimethylamino, ethylmethoxy and allyl, n is 0, 1 or 2, and pharmaceutically acceptable addition salts thereof. The process according to the invention consists in treating 4-hydroxy-3-quinolinecarboxylic acid esters of the general formula III with phosphorus oxychloride

wherein R 1 and n are as defined above and R 3 is ethyl, propyl or allyl. The reactants are heated to dissolve and the reaction is completed at reflux temperature. The ester formed

The 4-chloro-3-quinolinecarboxylic acids of formula II are separated. Then, the compound of formula II is reacted with a substituted amine of formula

R2NH2, wherein R2 is as defined above, in a polar aprotic solvent at room temperature for 18 hours,

Cl

(ll)

wherein R 1, R 2 and n are as defined above and R 5 is ethyl, propyl or allyl. The compounds of formula (I) are optionally converted into an addition salt by pharmaceutically acceptable acids or the resulting ester is hydrolyzed. '·· ’-' or

R 6 is a substituent selected from the group consisting of hydrogen, lower alkyl, lower alkyldimethylamino, lower alkyl-lower alkoxy and allyl, n is 0, 1 or 2, and pharmaceutically acceptable addition salts of the above compounds.

The antisecretoric effect of decreased gastric fluid and hydrochloric acid flow has been demonstrated in pylorus-bound rats administered the 4-amino-3-quinolinecarboxylic acid esters of the present invention by oral, subcutaneous, intraperitoneal, intraduodenal and intravenous administration. . Pylorus-bound rats have also been shown to effectively reduce ulceration. A decrease in gastric secretion caused, for example, by histamine has also been observed with the compounds of formula (I). tetragastroin and methachinoline. The present invention also found a reduced amount of gastric acid produced in Heidenhain dogs, which was stimulated by food.

It is clear from the above that it is an object of the present invention to provide a new method for controlling the production of excess stomach acids in mammals, comprising administering compounds of the above formula I wherein R 1, R 2, R 3 and n are the same as above. in an effective amount, that is, an amount that inhibits gastric ulceration.

It is a further object of the present invention to provide novel 4-amino-3-quinolinecarboxylic acids and esters thereof which are particularly effective for the treatment and prevention of gastric ulceration.

Finally, it is an object of the present invention to provide pharmaceutical compositions for achieving the above objectives, comprising suitable pharmaceutical carriers suitable for various routes of administration of certain compounds of the present invention.

Other objects and advantages of the invention will be apparent to those skilled in the art from the following description and individual embodiments of the invention and from the appended definition of the subject matter of the invention.

The term " lower alkyl " as used in both the specification and the definition refers to a straight or branched chain group containing up to and including 8 carbon atoms, such as methyl, ethyl propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like.

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

The compounds of the present invention are prepared from suitable 4-chloro-3-quinolinecarboxylic acid esters as illustrated by the following reaction scheme:

wherein R 1, R 2 and n have the same meaning as above, and R 3 is a lower alkyl group.

The compound of formula (II) is prepared by chlorination of a suitable 4-hydroxy-3-quinolinecarboxylic acid ester with phosphorus oxychloride, the general preparation of which is described and reported by Kermack and Storey in J. Chem. Soc. 1951, pp. 1389—92. The reaction scheme is as follows:

that _of R ₅ in which R n is as defined above and R3 is lower alkyl.

The compound of formula III above wherein R 3 is an ethyl group is prepared by heating a mixture of an appropriately substituted aniline and diethyl ethoxymethylene malonate to give the intermediate anilinacrylate, followed by cyclization in a high boiling solvent such as diphenyloxide as exemplified by Pric and Roberts in J. Amer. Chem. Soc. 68, 1204—8. This reaction can be illustrated by the following reaction scheme:

1 6 5 2 7 to

NH,

a small amount of heat

(III)

The acids of the invention (i.e., compounds in which R 3 = H) can be prepared from esters (compounds in which R 3 is a lower alkyl group) by conventional methods, and the other esters of the invention can be prepared by conventional re-esterification methods.

Preferred compounds, in view of their effectiveness in controlling gastric secretion and / or treating or preventing gastric ulceration in mammals, are compounds of the formula:

wherein R 1 is a radical selected from the group consisting of lower alkyl, phenyl, O-lower alkyl, S-lower alkyl, halogen, trifluoromethyl, cyano and dialkylamino, R a is a substituent selected from lower alkyl, phenyl, phenyl-lower alkyl or phenyl substituted by one to three substituents selected from the group consisting of lower alkyl, O-lower alkyl, S-lower alkyl, halogen, cyano, carbamoyl substituted with one to three nu, trifluoromethyl and nitro.

R 3 is a substituent selected from the group consisting of hydrogen, lower alkyl, lower alkyldimethylamino, lower alkyl-lower alkoxy and allyl, and pharmaceutically acceptable acid addition salts thereof.

For example, it has been found that the effect of ethyl {8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate} hydrochloride on histamine-induced gastric secretion is more than 43% greater, than ethyl {6-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate}, at half the dosing amount.

Using the above method described by Pric and Roberts, the following ethyl 4-hydroxy-3-quinolinecarboxylate of formula II is prepared starting from diethyl ethoxymethoxymalonate and aniline or from known aniline derivatives:

ethyl (4-hydroxyquinoline-3-carboxylate) prepared from aniline, m.p. 280-283 ° C; ethyl (4-hydroxy-8-methoxy-3-quinolinecarboxylate) prepared from 2-methoxyaniline, Melting point: 243 to 246 ° C, Ethyl 4-hydroxy-8-ethoxy-3-quinolinecarboxylate, prepared from 2-ethoxyaniline, o

Melting point: 198 DEG-200 DEG C. Ethyl 4-hydroxy-5,8-dimethoxy-3-quinolinecarboxylate, prepared from 2,5-dimethoxyaniline, melting point: 197-199.5. ° C, ethyl (4-hydroxy-8-methoxy-5-methyl-3-quinolinecarboxylate) prepared from 2-methoxy-5-methylanine, m.p. 180 ^DEG- 182 ^DEG C., ethyl (4-hydr) oxy-8-phenyl-3-quinolinecarboxylate), prepared from 2-aminobiphenyl, m.p. 250-252.5 ° C, ethyl (4-hydroxy-8-methyl-3-quinolinecarboxylate), prepared from 2-methylaminimide, m.p. 271-274 ° C, ethyl (4-hydroxy-8-trifluoromethyl-1-3-quinolinecarboxylate), prepared from 2-trifluoromethylaniline, m.p. 211-213, 5 ° C, ethyl (4-hydroxy-8-methylthio-3-quinolinecarboxylate), prepared from 2-methylthioaniline, m.p. 201-204 ° C; ethyl (4-hydroxy-8-chloro); 3-quinolinecarboxylate, prepared from 2-chloroaniline, m.p. ranges from 255 to 259 ° C, ethyl (4-hydroxy-6,8-dimethyl-3-quinolinecarboxylate), prepared from 2,4-dimethylaniline, ethyl (4-hydroxy-6-methoxy-3-quinolinecarboxylate) prepared from 4-methoxyaniline, m.p. 283-287 ° C, ethyl 4-hydroxy-8-cyano-3-quinolinecarboxylate, prepared from 2-cyanoaniline, m.p. 234-236 ° C, ethyl (4-hydroxy-7-methoxy-3-quinolinecarboxylate), prepared from 3-methoxyaniline, m.p. 280-282.5 ° C, ethyl (4-hydroxy-8-dimethylamino-3) (quinolinecarboxylate) prepared from 2-dimethylaminoaniline, m.p. 176-180 ° C.

In the following embodiment, designated as Preparation 1, the synthesis method used to prepare the 4-chloro compound of formula II, which is the starting compound used in the invention for the preparation of the compound of formula I, is illustrated.

Prepared

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

In this embodiment, the stirred mixture of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate (66.63 grams (0.269 moles)) and phosphorus oxychloride (350 ml) was heated and allowed to cool until the solid is not dissolved, and then the mixture is heated to reflux and maintained at this temperature for two hours. After cooling to less than 100 ° C, the mixture was concentrated in a rotary evaporator. This procedure yields residual oily hmo / ζ J? ?

which is dissolved in 100 ml of acetone and the solution obtained is poured onto a mixture of water and ice (800 ml). The mixture was neutralized with 6 N sodium hydroxide and the solid product was extracted with methylene chloride (450 mL, 250 mL, and 100 mL). The extracts are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a yellow solid.

68.16 grams of crude product. This crude product was then dissolved in 500 ml of hot toluene and then filtered to remove a small amount of insoluble residue. The toluene solution thus obtained is filtered again using a bed containing 250 grams of fluorisil, followed by washing with two liters of toluene and four liters of chloroform. The purified solution was then concentrated to give 64.17 grams of an oily matter (89 percent) from which a white solid crystallized upon cooling: This solid began to melt at a temperature in the range of 75-77 ° C.

For C13H12NO3Cl calculated:

% C, 58.77;% H, 4.55;% N, 5.27%

H, 4.61; N, 5.33.

Preparation 2 to 15

In these embodiments, the same procedure of Preparation 1 is carried out using the appropriate ethyl (4-hydroxy-3-quinolinecarboxylates) of the above formula (III), and the following ethyl (4-chloroquinoline) is prepared and used directly for the next procedure. -3-carboxylates j:

(2) ethyl (4-chloro-3-quinolinecarboxylate), (3) ethyl (4-chloro-8-ethoxy-3-quinolinecarboxylate), (4) ethyl (4-chloro-5,8-dimethoxy- (5) ethyl (4-chloro-8-methoxy-5-methyl-3-quinolinecarboxylate), (6j ethyl- (4-chloro-8-phenyl-3-quinolinecarboxylate), (7j) ethyl (4-chloro-8-methyl-3-quinolinecarboxylate), (8) ethyl (4-chloro-8-trifluoromethyl-3-quinolinecarboxylate), (9) ethyl (4-chloro-8-methylthio-3) (10) ethyl (4,8-dichloro-3-quinolinecarboxylate), (11) ethyl (4-chloro-6,8-dimethyl-3-quinolinecarboxylate), (12) ethyl (4-chloro), -8-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).

A general process for preparing esters of formula I (wherein R 3 is lower alkyl) is to react the appropriate 4-chloro-3-quinolinecarboxylic acid ester with a suitable amine in a polar aprotic solvent such as for example tetrahydrofuran or dioxane, followed by a thin layer chromatographic reaction and adjusting the temperature and time to complete the reaction. In some cases, the reaction amine can be used as the reaction solvent. A variety of solvents can be used to effect recrystallization. The process for preparing a free base compound from a salt is accomplished by dissolving the salt and adding a base compound such as sodium hydroxide to the solution and extracting the free base compound into a suitable organic solvent. In the preparation of addition salts, the free base compound is mixed with an alcoholic acid solution, for example a phosphoric acid solution or a sulfuric acid solution.

The foregoing provides a general preparation procedure for preparing esters of the compounds of the present invention. The following Examples 1 and 2 generally illustrate the preparation of ester compounds. The esters of Examples 3 to 71 and 74 to 80 are also prepared by reacting a suitable amine with a suitable ethyl 4-chloro-3-quinolinecarboxylate selected from the group of products prepared according to Preparation 1 to 15. Examples 81 to 84 and 89 illustrate preparation esters in which R3 is lower alkyl, lower alkyldimethylamino, lower alkyl-lower alkoxy or allyl, which is carried out by re-esterification of esters in which R3 is lower alkyl. R 3 is hydrogen), illustrated by Examples 72 and 73, in which the ester is hydrolyzed to the acid Metal salts derived therefrom, such as alkali metal salts, can also be prepared by conventional methods of reaction with a base of the alkali metal and the resulting salt are separated, Examples 85-88 below illustrate the conversion of the free base esters of the present invention into their acid addition salts. Tables 1 and 2 below show the physical values and analyzes performed. Obviously, the following examples are not intended to limit the scope of the present invention given by the structure and process of preparing the compounds of Formula I.

He did

Ethyl {8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate} hydrochloride

To a solution of 5.31 g (19.98 mmol) of ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate, dissolved in 40 ml of tetrahydrofuran, was added 2.15 g. grams (20.06 mmol) of O-toluidine, which is dissolved in 40 ml of tetrahydrofuran. The solution was stirred at 60 ° C for 18 hours with the exclusion of moisture. A yellow solid precipitate was obtained, which was filtered and washed with isopropyl ether. The product yield is 7.13 grams (95.7%) and the product is recrystallized three times from methylene chloride and ethyl acetate, mp 191-193.5 ° C.

For C 20 H 21 ClN 2 O 3 calculated:

% C, 64.43;% H, 5.68;% N, 7.51.

H, 5.65; N, 7.62.

Example 1 a d 2

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

In this example, 6.0 grams (corresponding to < tb >

22.5 mmol) of ethyl (4-chloro-8-methoxy-3-quinolinecarboxylate) in 80 ml of tetrahydrofuran, 2.3 g (24.8 mmol) of aniline in 60 ml of tetrahydrofuran are added. The solution was then heated rapidly and allowed to stand for 10 minutes, whereupon a solid yellow solid began to precipitate. The mixture is then maintained at ambient temperature for 18 hours. The solvent was evaporated in a rotary evaporator. The residue thus obtained was dissolved in 200 ml of methanol and the pH was adjusted to slightly basic (pH 8) with sodium bicarbonate. Water (700 ml) was then added to give an oily matter which solidified, and after further standing of the crystal there was another solid matter. The solid thus prepared is filtered and air-dried to form

6.9 g (95%) of crude material. The solid obtained above was dissolved in 300 ml of hot isooctane and treated with charcoal and filtered. The volume of the filtrate obtained is then reduced to 150 ml. Upon cooling, light yellow needle-like crystals formed, which separated. 6.5 g of product (89%), melting at 120-121 ° C, were obtained.

For C 18 H 18 N 2 O 5 calculated:

% C, 70.79;% H, 5.63;% N, 8.69.

H, 5.65; N, 8.77.

8527 obtained from the product of Preparation 1 and from 2‘-aminoacetophenone.

15. Ethyl [4- (butylamino) -8-methoxy-3-quinolinecarboxylate] hydrochloride obtained from the product of Preparation 1 and from n-butylamine.

Example 3 to 71

3. Ethyl {8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate), obtained by neutralizing the product of Example 1.

4. Ethyl 1- (8-methoxy-4 - [(2-ethylphenyl) amino] -3-quinolinecarboxylate), in the form of sulfate (1: 1), obtained from the product of Example 3 and from sulfuric acid.

5. Ethyl (8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate), in the form of phosphate (1: 1), obtained from the product of Example 3 and from phosphoric acid.

6. Ethyl (8-methoxy-4- (phenylamino) -3-quinolinecarboxylate], in the form of the hydrochloride obtained from the product of Preparation 1 and aniline.

7. Ethyl {8-methoxy-4 - [(2-methoxyphenyl) amino) -3-quinolinecarboxylate), in the form of the hydrochloride obtained from the product of Preparation 1 and o-anisidine.

8. Ethyl (8-methoxy-4 - [(2-methylthiophenyl) amino] -3-quinolinecarboxylate) hydrochloride obtained from the product of Preparation 1 and 2-methylthioaniline.

9. Ethyl {4 - [(2-chlorophenyl) amino] -8-methoxy-3-quinolinecarboxylate) hydrochloride, obtained from the product of Preparation 1 and from 2-chloroaniline.

10. Ethyl {4 - [(2-cyanophenyl) amino] -8-methoxy-3-quinolinecarboxylate) hydrochloride, obtained from the product of Preparation 1 and from 2-aminobenzonitrile.

11. Ethyl {4 - [(2-trifluoromethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate) hydrochloride, obtained from the product of Preparation 1 and from 2-trifluoromethylaniline.

12. Ethyl 1- (4 - ((2- (aminocarbonyl) phenyl) amino) -8-methoxy-3-quinolinecarboxylate), monohydrochlorideethanol (5: 2), obtained from the product of Preparation 1 and from anthranilamide.

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

14. Ethyl {4 - [(2-acetylphenyl) amino] -8-methoxy-3-quinolinecarboxylate) hydrochloride,

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

17. Ethyl (8-methoxy-4 - [(4-methylphenyl) amino) -3-quinolinecarboxylate) hydrochloride monohydrate, obtained from the product of Preparation 1 and from p-toluidine.

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

19. Ethyl (8-methoxy-4 - [(2,6-diethylphenyl) amino] -3-quinolinecarboxylate), obtained in the product of Preparation 1 and from 2,6-dimethylaniline.

20. Ethyl (8-methoxy-4 - [(2,6-dimethylphenyl) amino] -3-quinolinecarboxylate) hydrobromide, obtained from the product of Example 18 and from HBr.

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

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

23. Ethyl (8-methoxy-4 - [(3-methylthio) phenylamino] -3-quinolinecarboxylate), obtained from the product of Preparation 1 and from 3-methylmercaptoaniline.

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

25. Ethyl (8-methoxy-4 - ((2,4-dimethoxyphenyl) amino) -3-quinolinecarboxylate ', obtained from the product of Preparation 1 and 2,4-dimethoxyaniline.

26. Ethyl {4 - [(2-ethoxyphenyl) amino] -8-methoxy-3-quinolinecarboxylate) hydrochloride, also obtained from the product of Preparation 1 and from 2-ethoxyaniline.

27. Ethyl (8-methoxy-4- [methoxy-2-methylphenyl) amino] -3-quinolinecarboxylate), obtained from the product of Preparation 1 and from 2-methyl-4-methoxyaniline,

28. Ethyl {4 - [(2-ethylphenyl] amino] -8-methoxy-3-quinolinecarboxylate}, obtained from the product of Preparation 1 and from 2-ethylaniline.

29. Ethyl {4 - [(2-ethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate}, phosphate (1: 2), obtained from the product of Example 28 and anhydrous phosphoric acid.

30. Ethyl {4 - [(2-ethylphenyl) amino] -8-methoxy-3-quinolinecarboxylate}, sulfate (1: 1), obtained from the product of Example 28 and from an alcoholic sulfuric acid solution.

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

32. Ethyl {8-methoxy-4 - [(2-methyl-5-nitrophenyl) amino] -3-quinolinecarboxylate}, obtained from the product of Preparation 1 and from 2-methyl-5-nitroaniline.

33. Ethyl <8-methoxy-4 - {[(2-methylphenyl) methyl] amino} -3-quinolinecarboxylate) hydrochlorideethanol (2: 1), obtained from the product of Preparation 1 and from o-methylbenisylamine, ethanol and hydrogen chloride.

34. Ethyl {8-ethoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 3 and from o-toluidine.

35. Ethyl (8-ethoxy-4- [2- (trifluoromethylphenyl) amino] -3-quinolinecarboxylate}, hydrobromide obtained from the product of Preparation and from o-trifluoromethylaniline.

36. Ethyl {8-ethoxy-4 - [(2-methoxyphenyl) amino] -3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 3 and from o-anisidine.

37. Ethyl {8-ethoxy-4- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate}, phosphate (1: 1), obtained from the product of Preparation 3 and methylthioaniline and from an alcoholic phosphoric acid solution.

38. Ethyl [5,8-dimethoxy-4- (phenylamino) -3-quinolinecarboxylate], hydrochloride hemihydrate, obtained from the product of Preparation and from aniline.

39. Ethyl {5,8-dimethoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate), obtained from the product of Preparation 4 and from o-toluidine.

40. Ethyl {7-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 14 and from o-toluidine.

41. Ethyl [4- (phenylamino) -6-methoxy-3-quinolinecarboxylate], obtained from the product of Preparation 12 and from aniline.

42. Ethyl (6-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate}, obtained from the product of Preparation 12 and from o-toluidine.

43. Ethyl {8-methoxy-4 - [(2-methoxyphenyl) amino] -5-methyl-3-quinolinecarboxylate], dihydrochloride, obtained from the product of Preparation 5 and from o-anisidine.

44. Ethyl (8-methoxy-5-methyl-4- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate}, phosphate (2: 3), obtained from the product of Preparation 5 and from 2-methylthioaniline.

45. Ethyl {8-methoxy-5-methyl-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate}, obtained from the product of Preparation 5 and from o-toluidine.

46. Ethyl {4- [2- (methylphenyl) amino] -8-trifluoromethyl-3-quinolinecarboxylate}, obtained from the product of Preparation 8 and from o-toluidine.

47. Ethyl {4 - [(2-methylphenyl) amino] -8-methylthio-3-quinolinecarboxylate), obtained from the product of Preparation 9 and from o-toluidine.

48. Ethyl {4 - [(2-methoxyphenyl) amino] -8-methylthio-3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 9 and from o-toluidine.

49. Ethyl 8-methylthio-4 - [(2-methylthiophenyl) amino] -3-quinolinecarboxylate}, obtained from the product of Preparation 9 and from 2-methylthioaniline.

50. Ethyl {8-methyl-4- [2- (methylthiophenyl) amino] -3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 7 and from 2-methylthioaniline.

51. Ethyl {4 - [(2-methoxyphenyl] amino] -8-methyl-3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 7 and from o-anisidine.

52. Ethyl (8-methyl-4 - [(2-methylphenyl) methyl] amino-3-quinolinecarboxylate}, hydrobromide obtained from the product of Preparation 7 and from 2-methylbenzylamine.

53. Ethyl (8-chloro-4 - [(2-methoxyphenyl) amino] -3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 10 and o-anisidine.

54. Ethyl (8-cyano-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 13 and from aniline.

55. Ethyl [4- (phenylamino) -8-phenyl-3-quinolinecarboxylate], obtained from the product of Preparation 6 and from aniline.

218527

56. Ethyl {4 - [(2-carboxyphenyl) amino] -8-phenyl-3-quinolinecarboxylate}, hydrochloride hemihydrate, obtained from the product of Preparation 6 and from 2-aminobenzoic acid.

57. Ethyl (4-benzylamino-8-phenyl-3-quinolinecarboxylate), obtained from the product of Preparation 6 and from benzylamine.

58. Ethyl [4- (phenylamino) -6,8-dimethyl-3-quinolinecarboxylate], obtained from the product of Preparation 11 and from aniline.

59. Ethyl [4- (phenylamino) -3-quinolinecarboxylate), prepared from the product of Preparation 2 and from aniline.

60. Ethyl [4- (phenylamino) -3-quinolinecarboxylate] hydrochloride, obtained from the product of Preparation 2 and from aniline.

61. Ethyl (4-benzylamino-3-quinolinecarboxylate) hydrochloride obtained from the product of Preparation 2 and benzylamine.

62. Ethyl {4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate, hydrochloride, obtained from the product of Preparation 2 and from o-toluldine.

63. Ethyl 4- [2- (trifluoromethylphenyl) amino] -3-quinolinecarboxylate, hydrochloride, obtained from the product of Preparation 2 and from 2-trifluoromethylaniline.

64. Ethyl {4 - [(2-methoxyphenyl) amino] -3-quinolinecarboxylate}, hydrochloride, obtained from the product of Preparation 2 and o-anisidine.

65. Ethyl {4 - [(2-methylthiophenyl) amino] -3-quinolinecarboxylate, hydrochloride, obtained from the product of Preparation 2 and from 2-methylthioaniline.

66. Ethyl [4 - [(4-methoxy-2-methylphenyl) amino] -3-quinolinecarboxylate, hydrochloride, obtained from the product of Preparation 2 and from 2-methyl-4-methoxyanilm.

67. Ethyl 1- (4 - ((2-chlorophenyl) amino) -3-quinolinecarboxylate} hydrochloride, obtained from the product of Preparation 2 and from 2-chloroaniline.

68. Ethyl [8- (dimethylamino) -4- (phenylamino) -3-quinolinecarboxylate] hydrochloride, obtained from the product of Preparation 15 and from aniline.

69. Ethyl {8- (dimethylamino) -4 - ((2-methylphenyl) amino] -3-quinolinecarboxylate}, obtained from the product of Preparation 15 and from o-toluidine.

70. Ethyl [8-cyano-4- (phenylamino) -3-quinoline-carboxylate], obtained from the product of Preparation 13 and from aniline.

71. Ethyl {- [(2-hydroxyphenyl) amino] -8-methoxy-3-quinolinecarboxylate}, obtained from the product of Preparation 1 and from o-hydroxyaniline.

Example 72

8-Methoxy-4 - [(2-methylphenyl jamino) -3-quinolinecarboxylic acid

A mixture of ethyl (8-methoxy-4 - [(2-methylphenyl) amino) -3-quinolinecarboxylate], 15.00 grams (corresponding to 0.0445 moles), was further added. 100 ml of 3 N sodium hydroxide solution and 100 ml of ethanol are stirred at ambient temperature for 16 hours. The mixture was then diluted with 300 mL of water and acidified to pH 6.8 with 6 N hydrochloric acid. The precipitate was collected by filtration, washed with plenty of water and acetone and air-dried for 1.5 hours. The total weight of the solid obtained was 13.41 g (98% yield), and the melting point of the product thus obtained was 272 ° C (dec.).

For C18HJ6N2O3:

calculated:

70.12 θ / ο C, 5.23% H, 9.09% N,

T * | Q 1 Π17ΡΠ Π ¹

H, 5.27; N, 9.09. Example 73

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

An aliquot of 8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylic acid (4.35 g from Example 72) was triturated with 100 mL of hot absolute ethanol. After cooling, the resulting solid was collected by filtration and then air dried to give 3.77 g. This solid was suspended in 25 mL of absolute ethanol and excess ethereal hydrogen chloride solution was added. A pure solution is obtained. Isopropyl ether was then added to form a yellow precipitate which was collected and recrystallized ^! from absolute ethanol mixed with isopropyl ether to give 3.14 g of a 3.14 g solid. Mp 257 DEG C. (dec.).

For C 18 H 17 N 2 O 3 Cl calculated:

% C, 62.70;% H, 4.97;% N, 8.12.

% C, 62.53;% H, 4.93;% 8.18.

Examples 74 to 80

74. Ethyl {8-methyl-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate), monohydrochloride, obtained from the product of Preparation 7 and from o-toluidine.

75. Ethyl (8-methoxy-4 - {[2- (1-methylethyl) phenyl] amino) -3-quinolinecarboxylate), obtained from the product of Preparation 1 and from o-isopropylaniline.

76. Ethyl {8-chloro-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate), obtained from the product of Preparation 10 and from o-toluidine.

77. Ethyl {[(2-chloro-6-methylphenyl) amino] -8-methoxy-3-quinolinecarboxylate) monohydrochloride, obtained from the product of Preparation 1 and from 2-chloro-6-methylaniline.

78. Ethyl {8-methoxy-4 - [(2,3-dimethylphenyl) amino] -3-quinolinecarboxylate), monosulfate, obtained from the product of Preparation 1 and 2,3-diroethylaniline.

79. Ethyl 18-methoxy-4 - [(2-nitrophenyl) amino] -3-quinolinecarboxylate), obtained from the product of Preparation 1 and from 2-nitroaniline.

80. Ethyl {8-methoxy-4 - [(2-nitrophenyl] amino] -3-quinolinecarboxylate), ethyl sulfate (1: 1), ethanol (1: 1), obtained from the product of Example 79 and concentrated sulfuric acid absolute ethanoia.

Example 81 1-methylethyl {8-methoxy-4 - [(2-methylphenyl) amino] -3-quinolinecarboxylate) monohydrochloride monohydrate ¹ »

I ··

To this, 2 sodium pellets were added to 150 ml of dry 2-propanol and then 5.38 g (corresponding to 15.99 mmol) of ethyl [8-methoxy-4 - [(2-methylphenol)] was added. enyl) amino] -3-quinolinecarboxylate), which is dissolved in 50 ml of dry 2-propanol. The solution was stirred and heated to reflux for 6 hours, during which time it was collected in a Dean-Stark trap and removed 120 ml of distillate. The solvent is evaporated and the residue is dissolved in 50 ml of 2.9 M hydrochloric acid and 100 ml of water which is added after hydrochloric acid. The pH of the above solution was then adjusted to 8 with 1M aqueous sodium bicarbonate solution, and the oily matter was separated and extracted three times with 100 ml of methylene chloride. The combined extracts obtained above were then dried over magnesium sulfate. The solvent was evaporated to give 4.60 g (82% yield) of the free base of the title compound, mp 120-122 ° C after recrystallization from acetone / hexane .

The free base compound is then dissolved in isopropyl ether and ethereal hydrogen chloride is added to the mixture. The solvent was evaporated and the residue was recrystallized from methylene chloride / acetone to give the title compound as a yellow crystalline solid, mp 140-143 ° C.

Example 82

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

Example 81 was followed by recrystallization from 2-methoxyethanol to give the title compound as described in Example 3.

Example 83

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

Example 81 was recrystallized from 2-dimethylaminoethanol to replace sodium ethoxide catalyst and toluene solvent to give the title compound.

Example 84

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

Following the same procedure as in Example 81, the compound of Example 3 was re-esterified with 3-dimethylamino-1-propanol to replace toluene as the solvent to give 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 obtained in Example 83 and fumaric acid.

Example 86

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

The title compound was prepared from Example 84 and ethereal hydrogen chloride.

Example 87

Ethyl (8-methoxy-4 - [(2-methylphenyl-lamino) -3-quinolinecarboxylate}, ethanesulfonate (1: 1) (salt). of ethanesulfonic acid in absolute ethanol.

Example 88

Ethyl {8-methoxy-4 - [(2-methylphenyl) amino) -3-quinolinecarboxylate, 2-hydroxyethanesulfonate (1: 1) (salt)

The title compound was prepared from the compound obtained in Example 3 and 2-hydroxyethylsulfonic acid in absolute ethanol.

Example 89

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

The procedure of Example 81 was followed, substituting allyl alcohol for 2-propanol, to give the title compound.

· '· ··· • w,; a

With cd + - »o

and ω

H cn tí

CC c \ l <

> -3

E

(Examples 1 to 88)

Td ed

Td X3 ad cd cd cd honors

uo what Ή O CM 00 Lx what ΙΌ Tff ΙΩ uo 3 N Three WHAT tí Ň r — M tí N tí N 3 N Γχ WHAT Tti 03 / CM uo TT WHAT rH * 2 © WHAT in Ol to O 03 / CM Tfl 03 / O WHAT O rx 03 / O O V3 O O O O O what WHAT 00 what CM CM what J21> uo v 0- what rH rH τ-H t-H τ — 1 rH CM CM rH CM řn CM CM ř-i ř-4 f-4 rH iH rH 03 / rH rH CM rH tí ^H rH iH tH rH > S5 > S3 > b-3 > t-9 > N> > b3 > N3 > N3 > S3 > S3 > S1 > K '-' - ' '-' '· -' > b5 > N1 > S3 > S3 > N > b3 > b3 S * 2 * 2 * 4> b4 CD CD CD CD ca CD CD CD CD H ca ca Tfl CM QO WHAT Honors ca CD CD CD CD CD CD S ^rt CD and that CD i-H O in CM 03 / If) Tt < in what O Ή Tí * O CM rx ΙΓ3 ( 1T3 r-H CM O CM rx O WHAT • rH 00 · —'In CM 2 y 00 □ 3 CM 03 / 03 / * · O Cx. 03 / O CM it O WHAT what 00 03 / what CM CM CM m ir* rH rH what what τ — 1 rH Lij WHAT rH CM CM rH CM > N Honors CM CM > N CD > N CD > N CD > N CD tH rH r-) τ — 1 rH CM tH O ^H Od rH 4 ° H rH

CO rH co uo o t in in Μ Η Η H

E o

LO

E co □ l im £ u5S5u5 ^ u5c E ^{1 1} g «ΕΕΕΕΕΕΕο'ΕΕΕ i — 4

CJ

E

o o it tm EE | m cž S-t (33 E 1 1 § 1 1 § 1-4 i-M ' ¹ Ε E E ¹ E ^{1 1} E CJ CJ Ε E O Om CM

it

E

O cn

- - m w ίο irt w w ιο ιο ιο ίο ir> ιλ w tn ιη w irt

EEEEEEEEEKEEEEEEEEEEEEEEEEEEEEEEE f! N «NNN« NN «« NN Μ H PI N Μ NNNNNN «« N ouuouooooouooouoouuoooouuououuo ΐΛΐηΐΛίΛΏίαιηιηΐΛ ¹ TU

E

4ffi eekč ^ *} <Tjf

Ε Ε Ε E _r O „O O ® _{w w w w w w w w w} J

I HH ι I-M M m M CO F5 to U * J '1-, r \ ri ri ΓΊ t *..

u o cj u

O]

CM CM CM

FE E κ-i to to 'i

SeeE ®

I U - * --- *

O <ίο <O J? 'J ί V EC <o tO E ώΰ'ίΐ ^ ΰΗδφ, φ, ί?

CJ o

CM CM

O

UUE ^N CM CM Z

CD

O> 0

E ω

CM

EE £ <99 u m m *

E ¹ _»and 5SgOpŠss §S SgáGgToo ^ ₉ g cqccI U» C-; X ^<1 cm ncmcmN cm ^for T. CJ

CM Cd

CM

QOOaOOOOOOOOOOOOOOOOOaOOOOOÓQÓQQÓ to do it to K) to do it to it to it to do it to it to do it to ro ιο ro to do it to K> »O ΪΟ P)

EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE cjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcjcj

I t l I | I 1 | 1 I I t I t I t I t I t I t I t I t I

OOoOOOOOOOOOOOCOOOOOCOOOOOOOCOCOOOOOOOQOOOOOOOQOOOOOOOeOOOCOdO rHCMCO- ^ inCOt ^ COO ^ OTHCMCO ^ lOCOt ^ fipCnOrHCMo ^ incOt ^ eOOJQH

HrHrHrlHHHHrlr-INNCMNNNCQMNNMCO

Example R1 R2 R3 Salt Melting point (° C)

8-CH3O-2-CH3-5-NO2-C6H3-C2H5- 251.5 to 253

8-CH3O- 2-CH3-C6H4CH2- C2H5- HCl.1 / 2 C2H5OH 197.5 to 198

8-C2H5O-2-CH3-C6H4-C2H5-HCl 208-209

8-C2H5O- 2-CF3-C6H4- C2H5- HBr 185-191 (decomposition)

nd Ό rd Ό • d T3 in CD r2 3 3 CD CD ra IO <& O tS 1—4 N 3 N LO C \ T IT rS 3 N LO CD OO O CM CM 3 N what WHAT 3 N CD LO Ml t — 1 LO + 3 N 3 SS N O LO M ^ O CD WHAT 0 O O O O WHAT M ¹ ts rs M * O WHAT WHAT O rH CM rH WHAT WHAT O cn 0 ts CM rH rH f-4 f-l rH 3 N f-l CM rH rH rH r ^- 1 rH f-l rH τ — 1 f-l CM rH CM rH rH CM f-l Ή ÍH rH rH > N > N > N > N - ’ > N > N > N > N > N > N '-' > N > N , -, > N > N > N > IM > N O '-' > N '' > N > N CD CD CD 00 CD CD O f-l LO CD CD Honors CD CD CD M ¹ CD Honors LO CD CD CD Honors CD ri 10 ra, -t Honors CD LO it what it 1O rH IO WHAT _J ΪΌ ÍS 00 CD LIMB ÍS r * H what CM O CM 10 WHAT what O 10 > N CD CD r * i UO CM O what what r ~ i σΓ CD WHAT CD rH 0 fs. Ml what WHAT rj WHAT OO rH CM rH WHAT M ^ WHAT rH 10 ocT ts CM rH rd > N CD > tM CD > N CD CM WHAT rH τ — 1 rH rH M rH > N Honors rH rH > N CD CM rH CM rH 0 0 , L- | > N CD »3 what rH rH what tS what CM what what 0 LO what ts 0 CD IS rH t ~! rH rH CM rH rH

O

CM o

it

Pj to

CM rH u

to o

to o

OJ in

U to

U O PQ O O that's it

O to o

it is about it

it it it

To ίη ^ ΙΛΙΟΙΛΙΟίηΐΛΐηίΛΙΛΙΛΙΛΙΟίΟΙΛΙΛΙΛΙΛΙΟΙΛ ΙΟΙΛίΟΙΛΙΟ it this 'sorry' to tototototototototototototototototototototototo

N N M CM CM '· <Sl

Ttl -r this

O O

O ώ thats it o o

04 /

Til tíi to f 1 1 I I J *? I i I .- ^ I ^ ti Tff · 7 <T i ..

No tototoss * £ £ *? BP EOR ^ r ^ r tCOCOcor-ir ^ ni · Thr) ^ i U i Τ ι ι ηΓΊι ^^, i is ΚιΠ ^{1.5 and} about ¹⁰ Λ η ΓΊ it

II Tfi • that it that it that it _r <° t? <T!!,, / / / / / Ro ro ro / ro oto oto oto oto oto gg gg gg gg gg gg gg gg gg gg gg gg gg gg gg 9 oou ω X o 9 oO o 9 9 ooo

I 1

CM CM. ' O o 04 04 <| ^M ™ ™ C4-04 C4. <Ooo

CM CM to t čοοοοοΰΰβ> tO hp to t ^ ^ -r ro, CZ) CZ) CZ)

About ¹ 04 04

So to m m

UUUUU r> nr d-, vjujvj tn to i ','. ^M r. Ť t to tototototo ^^^ t ^ totototototoFl ^^^^ to [totototototooOCOWotototoQUQOu tocoto ^ t 00 00 00_ CO CD ggg CO (X) CO

LO LO | <I in lo lo

04 ^

4 «! Jh Jh i_Lh JJ ι i i o o o £ £ £ £ £ £ s

CO 00 00 CO co

H-2-CH3S-C6H4-C2H5-HCl 186 to 187 (decomposition)

H-2-CH3-4-OCH3-C6H3-C2H5-HCl 178-179 (dec.)

H- 2-CI-C6H4-C2H5 ´H1 204 to 205 (decomposition)

8- (CH3) 2N C6H5-C2H5-HCl 179-181

8- (CH 3) 2N 2-CH 3 -C 6 H 4 -C 2 H 5 - 110-114

COtSOOCDOrHCMCOMlLOCOISCOCDOrHCMCOMiLOCOlSCOCDOrHCMCOM LOCOt ^ ^ COO) CO CO CO CO M M ¹ * M ¹ M ¹ M ¹ M ¹ M ^{1 1} Μ ΙΟ LO LO LO LO LO LO LO LO ID CD CO CO CO CO CO CO CO CO CO

Example R 1 R 3 R 3 Salt Melting point (° C)

8-CN C6H5-C2H5- 194-196

8-CH 3 O-2-OH-C 6 H 4 -C 2 H 5 - 229-231

8-CH3O- 2-CH3-C6H4-H-272 (decomposition)

8-CH 3 O-2-CH 3 -C 6 H 4 -H HCl 257

Me 00 r-l cn rH CM what O, WHAT UO cn O WHAT UO WHAT WHAT 05 / 0 00 WHAT O Me 00 O 00 00 r-l Me rH r-l rH CM rH r-l cn rH r-1 rH cn T “í rH tH rd > N > N > N > N > N > N > N > N > N > N > N > N > N > N > N honors CD Honors Honors Honors Honors Honors Honors Honors Honors Honors Honors honors Honors Honors CM what cn l >> O tn O M ¹ O 10 WHAT !>. WHAT CM WHAT what 00 O WHAT 00 Me 00 O cn 00 r-l Me rH r-j rH CM rH rH r-l r-l r-l τ — 1 rd r-l tH

° ff °

^ffi ffi kpí O ^ffi ffi Offi tO ffi ffi ffi OO ^ OO »(Λ K 'tu N <M ti ffi ffi ffi

9i 4? 4? q-l 5 * ffi ffi ó ó ffi ffi, ά 12, ffi,>, 4} ffi? 4} ym 1 ffi ffi ffi (t 1 1 1 1 1 ffi ffi QO 0 0 ii 0 0 10 to mm 10 w 1 rt. Ιλ ιλ ffi ffi ffi ffi ffi ffi 2 of ^ Zffiffi youuuuuia, 2-, 2 < -uu

Eiffiffiffiffig oouoo ffi ⁶⁰

O

I ffi

M

Λ ffi ffi «eo ω

AND

CM. _ tji - <JI -ei ffitcuffiffiffiffiffiffiffiffiffiffi co (o2u (0 (0cococo (oeo (0 (0 <o ffiffiffiooffiffiffixtcffiffiffi) ωο ^ ΖΖοοοοοωωωω

CMCM ^ CMCMCMCMCMCMCMCMCMM cm o ^ oooooooooooooo

Mottototototototototototooto

ZE Uk i Uh hU E-E Uh hU til 3h W ø · H-ι 3m 3h

CjOcoUOUOOOOOOOOO

I 1 (I I 1 1 «I t (t 1

00 OOCOOOOOOOCOOOOOOOOOOCOCO mi in co t> t 'M> ts

COmOHMCl 3 in. * .Oooooooooooooo

CO fv CO 00 what what

TABLE 2

Analytical values of Examples 1 to 88

Example Empirical formula 1 C20H21ClN2O3 2 C19H18N2O3 3 C20H20N2O3 4 C20H22N2O7S 5 C20H23N2O7P 6 C19H19ClN2O3 7 C20H21ClN2O4 8 C20H21ClN2O3S 9 C19H18Cl2N2O3 10 C20H18ClN3O3 Í1 C20H18N2O3F3Cl 12 CIO4H112Cl5N15O22 13 C19H18N2O3FCI 14 C21H21N2O4Cl 15 Dec C17H20N2O3Cl 16 C20H23N2O4Cl 17 C20H23N2O4Cl 18 C21H22N2O4 Í9 C21H22N2O3 20 May C21H23BrN2O3 21 C21H24N2O4 22nd C20H20N2O4ClBr 23 C20H20N2O3S 24 C21H27N2O8P 25 C21H22N2O5 26 C21H23N2O4Cl .: 27 .. C21H22N2O4 28 C21H22N2O3 29 C21H28N2O11P2 30 C21H24N2O7S 31 C19H16N2O3Cl2 32 C20H19N3O5 33 '. C44H52N4O7Cl2 . 34. C21H23N2O3Cl 35 C21H20N2O3F3Br 36 C31H23N2O.1Cl. 37. . C21H25N2O7SP . 38 ... . .C20H21CIN2O4 , 39 .... C21H22N2O4 r 40 . C20H21N2O3Cl 41. . .... C19H18N2O3 42 ..... C20II21N2O3CI 43 C21H24N2O4Cl2 44 C42H53N4O18S2P3 45 C21H22N2O3 46 C20H17F3N2O2 47 C20H20N2O2S .48. . C20H21ClN2O3S 49 C20H20N2O2S2 50 C20H21N2O2SCI 51 C20H21ClN2O3 52 C ₂ iH23BrNzO2 53 C19H18N2O3Cl2 54 C20H17N3O2 55 C24H20N2O2 56 C50H44Cl2N4O9 57 C25H23N2O2 58 C20H20N2O2 59 C18H16N2O2 60 C18H17N2O2Cl 61 C19H19ClN2O2

Calculated

C H N 64.63 5.68 7.51 70.79 5.63 8.69 71.41 5.99 8.33 55.29 5.10 6.45 55.30 5.34 6.45 63.60 5.34 7.81 61.78 5.44 7.20 59.33 5.23 6.92 58.03 4.61 7.12 62.59 4.73 10.95 56.28 4.25 6.56 59.44 5.37 10.00 60.56 4.81 7.43 62.92 5.28 6.99 60.26 6.84 8.26 61.46 5.93 7.17 61.46 5.93 7.17 68.84 6.05 7.65 71.98 6.33 7.99 58.48 5.37 6.49 68.46 6.57 7.60 51.35 4.31 5.99 65.20 5.47 7.60 54.08 5.84 6.01 65.96 5.80 7.33 62.61 5.75 6.95 68.84 6.05 7.65 71.98 6.33 7.99 46.16 . 5.17 5.13 56.24 5.39 6.25 58.33 4.12 7.16 62.99 5.02 11.02 64.46 6.39 6.83 . 65.20 . . 5.99 7.24 .51,97 . 4.15 . 5.77 '62, 61 5.75 6.95 52.50 5.75. 5.83 60.37 5,57 7.04 68.84. . 6.05 7.67 . 64.43 5.68 7.51 .. 70.79 5.63 8.69 • 64.43. 5.68 '7.51 57.41 5.50 6.38 47.64 5.04 5.29 71.98 6.33 7.99 64.17 4.58 7.48 68.16 5.72 7.95 59.33 5.23 6.92 62.47 5.24 7.29 61.77 5.44 7.20 64.73 5.68 7.51 60.73 5.58 6.93 58.03 4.61 7.12 72.49 5.17 12.68 78.24 5.47 7.60 65.57 4.84 6.11 78.32 6.05 7.31 74.98 6.71 8.74 73.96 5,52 9.58 65.75 5.21 8.52 66.56 5.59 8.17

Found

C H N 64.36 5.65 7.62 70.91 5.65 8.77 71.52 5.94 8.35 55.68 5.02 6.42 54.92 5.37 6.53 63.25 5.33 7.69 61.55 5,57 7.07 59.04 5.38 6.87 57.89 4.69 7.13 62.23 4.95 10.73 56.33 4.34 6.60 59.25 5.21 10,03 60.28 4.87 7.32 62.56 5.48 6.76 59.39 6.80 8.20 61.40 5.92 7.21 61.73 5.76 7.33 68.61 6.04 7.51 72.16 6.33 8.01 58.48 5.41 6.52 68.47 6.51 7.59 51.27 4.30 6.04 65.18 5.48 7.66 54.32 5.58 6.23 66.06 5.75 7.28 62.61 5.84 6.94 68.94 6.06 7.68 72.02 6.29 8.03 46.07 5.22 5.12 56.09 5.43 6.24 58.52 4.13 7.21 63.02 5.08 11.03 64.09 6.22 · 6.96 65.25 6.01 7.26 , 52.22 4.14 5.89 62.67 5.76 7.05 52.08 5.35 5.77 60.22 5.55 7.05 69.19 6.09 7.70 64.71 5.76 7.54 70.96 5.66 8.62 64.40 9.67 7.62 57.02 5.79 6.25 48.06 5.08 5.43 72.32 6.35 8.02 64.16 4.62 7.49 68.19 5.76 8.14 59.55 5.32 6.86 62.16 5.16 7.12 61.84 5.41 7.31 64.47 5.61 7.50 60.76 5.60 6.82 57.97 4.65 7.11 72.16 5.26 12.54 78.22 5.47 7.50 66.04 5.00 6.09 78.52 5.90 7.30 75.22 6.37 8.77 74.12 5.64 9.42 65.85 5.29 8.56 66.80 5.61 8.12

Example Empirical formula Calculated Found C Η N C H N

62 CigHigNaOzCl 66.57 5.59 8.17 66.80 5.70 8.19 63 C19H16N2O2F3Cl 57.51 4.06 7.06 57.85 4.08 7.13 64 C19H19ClN2O3 63.60 5.34 7.81 63.67 5.30 7.78 65 C19H19N2O2SCl 60.87 5.11 7.47 60.97 5.30 7.39 66 C20H21N2O3Cl 64.43 5.68 7.51 64.14 5.70 7.52 67 C18H16N2O2C12 59.52 4.44 7.71 59.26 4.42 7.67 68 C20H22N3O2Cl 64.60 5.96 11.30 64.60 5.96 11.39 69 C21H23N3O2 72.18 6.63 12.03 72.24 6.57 12.09 70 C19H15N3O2 71.91 4.76 13.24 71.95 4.86 13.26 71 C19H18N2O4 67.45 5.36 8.78 67.49 5.38 8.50 72 C18H16N2O3 70.12 5.23 9.09 70.10 5.27 9.09 73 C18H17N2O3Cl 62.70 4.97 8.12 62.53 4.93 8.18 74 C20H21ClN2O2 67.32 5.93 7.85 67.22 5.92 7.83 75 C22H24N2O3 72.51 6.64 7.69 72.56 6.55 7.67 76 C19H17N2O2Cl 66.90 5.03 8.22 66.60 5.14 8.20 77 C20H20N2O3C12 58.98 4.95 6.88 58.90 4.94 6.90 78 C21H24N2O7S 56.24 5.39 6.25 56.37 5.42 6.28 79 C19H17N3O5 62.12 4.66 11.44 62.05 4.66 11.54 80 C23H29N3O10S 51.20 5.42 7.79 51.20 5.36 8.01 81 C25H25ClN2O4 62.30 6.22 6.92 62.49 6.23 6.94 82 C21H23ClN2O4 62.61 5.75 6.95 62.72 5.76 7.04 83 C22H25N3O3 69.44 6.64 11.07 69.73 6.64 11.07 84 C23H27N3O3 70.21 6.92 10.68 70.42 6.95 10.67 85 C28H31N3O9 60.75 5.64 7.59 60.89 5.69 7.53 86 C23H31Cl2N3O4 57.03 6.45 8.67 57.05 6.31 8.79 87 C22H28N2O6S 59.18 5.87 6.27 59.16 5.93 6.25 88 C22H26N2O7S 57.13 5.67 6.06 57.08 5.71 6.10

Note to Table 1:

(a) In contrast to the melting point in the range of 99 to 100 ° C reported in J. Pharm. Chem. Soc. 1389 (1951).

Pharmacological tests

The effect of 4-amino-3-quinolinecarboxylic acids and esters of these compounds on gastric secretion was investigated in rats and dogs. Inhibition of this secretion was found to be expressed as a percentage of gastric acid produced. The anti-ulcer effect of the compounds of this invention was also observed in rats. The results of these tests performed with the preferred compounds of the present invention are shown in the following table. The other compounds of the present invention exhibit quantitatively and qualitatively similar effects in one or more of these assays.

The compounds of Example 1 were administered to pylorus-bound rats that were not stimulated by artificial gastric secretion. The doses used ranged from 33 to 134 pmoles / kg, with the amount of acid produced being inhaled to 8-55%.

The gastric anti-ulcer effects of the compounds of Example 1 were tested in rats by the method described in: Gastroehterology 5, 43-81, by Shay et al. The ulcer protection was 4 to 90% with doses ranging from 12 to 198 µmoles / kg.

TABLE 3

Effect of the compounds of Example 1 on stimulation of gastric secretion

Species Dose Route of Administration Stimulator Inhibition ¹ (%) (y mol / kg)

rat ² 0.3— 8.1 IV histamine 43 - 96 rat ² 0.3—10.7 ID histamjp 40 - 70 rat ² 0.3— 8.1 IV tetragastrin 27-85 rat ² 0.9— 8.1 IV methachinoline 25 - 76 dog ³ 2.7 and 8.1 IV food 50 and 83 dog ³ 32.4 AFTER food 56

¹ inhibition was measured as gastric acid produced ² rats were tested according to a modified method: Ghosh and Shield, 195fi, Brit. J. Pharmacol., 13, 54-61 The ^three dogs were of the Heidenhain species.

216327

Effective amounts of the compounds of formula (I) above may be administered to a living animal with a therapeutic objective, by controlling the release of histamine-stimulated acid and peptic ulceration or combating peptic ulcers in mammals using conventional methods of administering pharmaceutical compositions which can be administered in conventional forms. such as orally in solution, in the form of an emulsion, suspension, pills, tablets, dragees, lozenges, pellets, capsules and the like, in pharmaceutically acceptable carriers, or parenterally in the form of sterile solutions or mixtures.

The above-mentioned pharmaceutical carriers can be, for example, in solid form or they can be liquids. Examples of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. As examples of liquid carriers, brew oil, water or any other parenterally acceptable liquid may be mentioned.

Although very small amounts of the active compounds of the present invention are effective in mild gastric irritation treatment, or when the compounds of the present invention are administered to a subject of low body weight, where small amounts of the compounds of the present invention are also effective, The compounds of the present invention contain the active ingredient in an amount ranging from 2 to 6 milligrams / kilogram body weight. Unit dosage amounts contain from 100 to 500 milligrams, preferably 200 to 500 milligrams. The active ingredient of the invention may preferably be administered in equivalent doses of one to four times a day. The prescribed daily dose may range from about 100 to about 1200 milligrams, most preferably from 300 to 900 milligrams / day. It is only important in this context that the active ingredient is present in an effective amount, i.e., that a suitable effective dose is prepared to suit the dosage form employed. Precise individual doses as well as daily doses are, of course, determined according to common medical principles under the supervision of a physician or veterinarian.

The following are examples of mixtures. network according to the invention.

1. Capsules

Components Quantity (mg)

active ingredient, see Example 1: 200 ethyl- [8-methoxy-4- (2-methylphenyl) amino-3-quinoline- carboxylate), hydrochloride 100 ALIGN! saeharosis starch 30 talc 5 stearic acid 3 338 The ingredients are mixed and it is created that latin capsules. 2. Tablets Folders Quantity (mg per tablet) active ingredient, see Example 1: 350.0 ethyl [8-methoxy-4- (2-methylphenyl) amino-3-quinolinecarboxylate] hydrochloride alginic acid 20.0 calcium and ammonium alginate 40.0 starch 54.0 laktčza 75.0 magnesium stearate 2.2

721.2

The ingredients of this mixture, with the exception of magnesium stearate and one-half of the calcium ammonium alginate, are mixed and granulated with ethanol, and the mixture is passed through a mesh eight sieve, and the mixture is then dried at 60 ° for 16 hours. C. The dried granular material is then mixed properly with the rest of the calcium-magnesium alginate and the magnesium stearate and formed into tablets.

3. Intravenous injection

Components Amounts (mg) active ingredient, see Example 1: 200 ethyl [8-methoxy-4- (2-methylphenyl) amino-3-quinolinecarboxylate), hydrochloride water 2000 preservative, i.

chlorobutanol 20

2220

Other modifications and modifications of the various embodiments of the present invention will be apparent to those skilled in the art, which modifications may relate to the compounds themselves, to the compositions themselves, and to the method of preparation and use thereof without departing from the scope of the invention. that this scope of the invention is given by the following definition of the subject matter of the invention.

Claims (1)

SUBJECT A process for the preparation of 4-amino-3-quinolinecarboxylic acids and their esters of general formula wherein R1 is methyl, phenyl, methoxy, ethoxy, methylthio, halogen, trifluoromethyl, cyano and dimethylamino, Ra is butyl, phenyl, phenylmethyl, phenylethyl or phenyl substituted with 1 to 3 substituents selected from the group consisting of methyl, methoxy, ethoxy, methylthio, halogen, cyano, hydroxy, carbamoyl, carboxyl, acetyl, trifluoromethyl a nitro group, R3 represents a hydrogen atom, an ethyl group, a propyl group, an ethyldimethylamino group, a propyldimethylamino group, an ethylmethoxy group and an allyl group, n is 0, 1 or 2, and pharmaceutically acceptable addition salts thereof, characterized in that the esters are 4-hydroxy-3 quinolinecarboxylic acids of formula III (III) wherein R 1 and n are as defined above and R 3 is ethyl, propyl or allyl, are treated with phosphorus oxychloride, the reagents are heated to dissolve and the reaction is completed at reflux temperature and the ester formed 4-chloro-3-quinolinecarboxylic acids of formula II wherein R 1, n is as defined above and R 3 is ethyl, propyl or allyl, is treated with a substituted amine of the formula R 2 NH 2, wherein R 2 is as defined above, in a polar aprotic solvent at room temperature for 18 hours, and optionally the resulting compounds of formula I are converted into pharmaceutically acceptable acids into addition salts, or the ester optionally formed is hydrolyzed.