CA1161757A - 4-amino-3-quinolinecarboxylic acids and esters- antisecretory, anti-ulcer compounds - Google Patents
4-amino-3-quinolinecarboxylic acids and esters- antisecretory, anti-ulcer compoundsInfo
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- CA1161757A CA1161757A CA000416431A CA416431A CA1161757A CA 1161757 A CA1161757 A CA 1161757A CA 000416431 A CA000416431 A CA 000416431A CA 416431 A CA416431 A CA 416431A CA 1161757 A CA1161757 A CA 1161757A
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Abstract
ABSTRACT OF THE DISCLOSURE
Pharmaceutical compositions for inhibiting secretion of gastric acids and for treating peptic ulcers in mammals, which are comprised of a pharmaceutical carrier and an effective amount of a compound having the formula
Pharmaceutical compositions for inhibiting secretion of gastric acids and for treating peptic ulcers in mammals, which are comprised of a pharmaceutical carrier and an effective amount of a compound having the formula
Description
This application is a divisional application of our copending Canadian Patent Application Serial No. 348,417, filed March 26, 1980.
BACKGROUND OF THE INVENTION
1. Field of Invention The present invention and its parent application Serial No. 348,417 relate to certain 4-amino-3-quinolinecarboxylic acids and esters and novel pharmaceutical use and compositions therefor.
More particularly, the inventions relate to certain 4-amino-3-quinolinecarboxylic acids and esters which reduce gastric secretionstimulated by secretagogues such as histamine, tetragastrin, and food and as such are useful in preventing or treating peptic ulcers in mammals. Application No. 348,417 refers to certain of the compounds which are novel, while this application deals with known compounds which have not been previously used in the novel pharmaceutical compositions of this invention.
BACKGROUND OF THE INVENTION
1. Field of Invention The present invention and its parent application Serial No. 348,417 relate to certain 4-amino-3-quinolinecarboxylic acids and esters and novel pharmaceutical use and compositions therefor.
More particularly, the inventions relate to certain 4-amino-3-quinolinecarboxylic acids and esters which reduce gastric secretionstimulated by secretagogues such as histamine, tetragastrin, and food and as such are useful in preventing or treating peptic ulcers in mammals. Application No. 348,417 refers to certain of the compounds which are novel, while this application deals with known compounds which have not been previously used in the novel pharmaceutical compositions of this invention.
2. Description of the Prior art Diuretic and antidepressant activity in certain 4-anilino-
3-quinolinecarboxylic acid esters and 6-chloro derivatives thereof have been disclosed by Hanifin, J. W. in United States Patent 3,470,186 and _. Med. Chem. 1969, 12~6), 1096-7._ Kermack et al., J. Chem. Soc., 1951, 1389-92 appears to disclose the preparation of 6-substituted 4-anilino-3-quinoline-carboxylic acids and esters therefrom. Sen et al., J. Indian Chem.
Soc., 34, 906~8 (1957) appears to disclose the preparation of 7-substituted 4-amino-3-quinolinecarboxylic amides. Elslager et al., J. Med. Pharm. Chem. 5, 546-58 (1962) discloses the preparation of 7~7
Soc., 34, 906~8 (1957) appears to disclose the preparation of 7-substituted 4-amino-3-quinolinecarboxylic amides. Elslager et al., J. Med. Pharm. Chem. 5, 546-58 (1962) discloses the preparation of 7~7
4-anilino-7-chloro-3-quinolinecarboxylic ac:id and its ethyl es-ter.
Antisecretory or anti-ulcer activ:ities for 4-amino-3-quinolinecarboxylic acids and esters have not been disclosed prior to this invention.
SUMMARY OF THE INVENTION
Our Application Serial No. 348,417 is directed to novel compounds which are 4-amino-3-quinolinecarboxylic acids and estexs which have the formula (Rl~n ~ ~ C2R3 wherein;
Rl is selected from the group consisting of loweralkyl, phenyl, O-loweralkyl, S-loweralkyl, halogen, trifluoromethyl, cyano and dialkylamino, R2 is selected ~rom the group consisting of loweralkyl, phenyl, phenylloweralkyl or phenyl substituted by 1-3 radicals taken from among loweralkyl, O-loweralkyl, S loweralkyl, halogen, cyano, hydroxy, carbamoyl, carboxy, acetyl, trifluoromethyl, and nitro, R3 is selected from the group consisting of hydrogen, loweralkyl, omega-dimethylamino-loweralkyl, loweralkoxy- loweralkyl, and allyl, n is 0, 1 or 2, provided that when n is 0 or n is 1 and Rl is chlorine or methoxy in -the 6-position or chlorine in the '7 7-position ancl R3 i5 hydrogen or ethyl, then if R2 i9 a phenyl group it is mono-substituted in the 2-position of the phenyl ring or is di-substituted in the 2- and ~-positions of the phenyl ring, and the pharmaceutically acceptable addition salts thereof.
This present application is directed to pharmaceutical compositions for inhibiting secretion of gastric acid or treating peptic ulcer in mammals which comprises a pharmaceutical carrier and an effective amount of a compound having the formula NHC6~15 or pharmaceutically acceptable salt thereof wherein R is hydrogen or methoxy, Rl is hydrogen, chlorine or methoxy and R3 is hydrogen or ethyl, provided that R and Rl are not both hydrogen.
The antisecretory effect of reduced flow of gastric juice and hydrochloric acid in pyloric-ligated rats was demonstrated when the esters of ~l-amino-3-~uinolinecarboxylic acids were administered orally, subcutaneously, intraperitoneally, intraduodenally and intravenously. Effective ulceration reduction was also demonstrated in pyloric-ligated rats. The compounds of the invention also were shown to reduce gastric secretion induced, for example, by histamine, tetragastrin and methacholine. Gastric acid output in Heidenhain pouch dogs stimulated with food was also reduced.
7;~,7 The term "loweralkyl" as used in the speclfication and claims includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exempli~ied by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like.
Representative of "phenylloweralkyl" radicals are benzyl (phenylmethyl), a-methylbenzyl, phenylethyl, phenylpropyl, phenyl-butyl, and the like.
The compounds of this div:lsional application and the compounds of the parent application can be made by similar methods.
Thus, the compounds are prepared from appropriate 4-chloro-3-quinolinecarboxylic acid esters as represented by the following equation:
Cl NHR2 ~ O2R3 ~ C2R3 (Rl)n~\NJ (Rl)n~N
wherein Rl, R2, and n are as hereinabove de~ined, and R3 is loweralkyl.
The Formula II compounds were prepared by chlorinating appropriate 4~hydroxy-3-quinolinecarboxylic acid esters with phosphorous oxychloride generally by the method described by 2~ Kermack & Storey, J. Chem. Soc. 1951, pp 1389-92. The equation is:
L'7~;~'7 ( R~ J C02R3 (R ) ~ C2R3 III II
wherein Rl and n are as defined hereinabove, and R3 is loweralkyl.
The Formula III compounds wherein R3 is ethyl were prepared by heating a mixture of appropriately substituted anilines and diethyl ethoxymethylenemalonate to Eorm an intermediate anilinoacrylate and thereafter cyclizing in a high boiling solvent such as diphenyloxide as described by Price and Roberts in J. Amer, Chem. Soc. 68, 1204-8. The reaction is represented by the following equation:
( ~)n ~ + C2H5OcN=c(co2c2~5)2 ~ 2C2~5 214-250C~
~ ~2 IV
OH
l)n ~ ~ ~ CO2C2H5 III
L`7~3;' Acids (R3=~I) of the compound~ may be prepared from es-ters (R3=loweralkyl) by usual methods of hydrolysis and other esters of the compounds may be prepared by usual methods of re-esterifi-cation.
Utilizing the foregoing method described by Price and Roberts, the following ethyl-4-hydroxy-3-quinolinecarboxylates of Formula II were prepared from diethylethoxymethoxymalonate and aniline or known aniline derivatives as follows:
Ethyl 4 hydroxyquinoline-3-carboxylate from aniline;
10 m.p. 280-283C.
Ethyl 4-hydroxy-8-methoxy-3-quinolinecarboxylate from 2-methoxyaniline; m.p. 243-246C.
Ethyl 4-hydroxy-8-ethoxy-3-quinolinecarboxylate from 2-ethoxyaniline; m.p. 198-200C.
Ethyl 4-hydroxy-5,8-dimethoxy-3-quinolinecarboxylate from 2,5-dimethoxyaniline; m.p. 197-199.5C~
Ethyl 4-hydroxy-8-methoxy-5-methyl-3-quinolinecarboxylate from 2-methoxy-5-methylaniline; m.p. 180-182C.
Ethyl 4-hydroxy-8-phenyl-3-quinolinecarboxylate from 202-aminobiphenyl; m.p. 250-252.5C.
Ethyl 4-hydroxy-8-methyl-3-quinolinecarboxylate from 2-methylaniline; m.p. 271-274C.
Ethyl 4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylate from 2-trifluoromethylaniline; m.p. 211-213.5C.
Ethyl 4-hydroxy-8-methylthio-3-quinolinecarboxylate from 2-methylthioaniline; m.p. 201-204C.
Ethyl 4~hydroxy-8-chloro-3-quinolinecarboxylate from 2-chloroaniline; m.p. 255-259C.
Ethyl 4-hydroxy-6r8-dimethyl-3-quinolinecarboxylate from 2,4-dimethylaniline;
Ethyl 4-hydroxy-6-methoxy-3-quinolinecarboxylate from 4-methoxyaniline; m.p. 283 287C.
Ethyl 4-hydroxy-8-cyano-3-quinolinecarboxylate from 2-cyanoaniline; m.p. 234-236C.
Ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate from 3-methoxyaniline; m.p. 280-282.5C.
Ethyl 4-hydroxy-8-dimethylamino-3-quinolinecarboxylate from 2-dimethylaminoaniline; m.p. 176-180C.
Preparation 1 illustrates the synthesis procedure used to make the 4-chloro compounds of Formula II which are the starting materials used in makiny active compounds.
Preparation Eth l 4-chloro-8-methox~3-quinolinecarboxylate.
A stirred mixture of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate, 66.63 g (0.269 mole) and phosphorous oxychloride (350 ml) was warmed until all the solid had dissolved and then heated at reflux temperature for two hours. After cooling to below 100C. the mixture was concentrated in a rotary evaporator. The residual oil was dissolved in 100 ml acetone and the solution poured onto an ice water mixture (800 ml). The mixture was neutralized with 6N sodium hydroxide solution and the solid product extracted successively wi-th 450 ml, 250 ml and 100 ml portions of methylene chloride. The extracts were combined, washed with wa-ter, dried over anhydrous magnesium sulfate and concentrated to yield 7~ 7 68.16 g crude product. This crude product was dissolved in 500 ml hot toluene and filtered to remove a small quantity of insoluble material. The toluene solution was filtered through a bed of 250 g fluorisil followed by two liters of toluene and four liters of chloroform. The purified solution was concentrated to give 64.17 g of oil (89%) which crystallized to an off-white solid on cooling.
The solid melted at 75-77C.
Analysis: Calculated for C13H12NO3CL: C, 58.77; H, 4.55; N, 5.27 Found : C, 58.58; ~I, 4.61; N, 5.33 Preparatlon 2-15 Utilizing the procedure of Preparation ], and substituting appropriate ethyl 4-hydroxy-3-quinolinecarboxylates listed above III, the following ethyl 4-chloro-quinoline-3-carboxylates were prepared and used directly.
(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-quinoline-carboxylate (6) Ethyl 4-chloro-8-phenyl-3-quinolinecarboxylate (7) Ethyl 4-chloro-8-methyl-3-quinolinecarboxylate (8) Ethyl 4-chloro-8-trifluoromethyl-3-quinoline-carboxylate (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 (lS) Ethyl 4-chloro-8-(dimethylamino)-3-quinoline-carboxylate.
A general procedure for preparing esters (R3=loweralkyl) of the invention is to react an appropriate 4-chloro-3-quinoline-carboxylic acid ester with an appropriate amine in a polar aprotic solvent such as tetrahydrofuran or dioxane, following the reaction by thin-layer chromatography and modifying temperature and time to complete the reaction. In some instances the reacting amine may be used as the reaction solvent. Various solvents are used for recrystallizing. To prepare the free base from a salt the salt is dissolved and a base such as sodium hydroxide is added and the free base is extracted into a suitable organic solvent. To prepare additional salts the free base is mixed with an alcoholic solution of an acid, for example, phosphoric acid or sulfuric acid.
The foregoing is a general description of how to prepare the esters of the invention. The following Examples 1 and 2 generally illustrate the preparation of the ester compounds. The esters of Examples 3 to 71 and 74 to 80 were also prepared by reacting the appropriate amine with the appropriate ethyl 4-chloro-3-quinolinecarboxylate selected from Preparations 1 to 15.
Examples 81-84 and 89 illustrate the preparation of esters wherein R3 is loweralkyl, loweralkyldimethylamino, loweralkyl-loweralkoxy or allyl by the trans-esterification of esters wherein R3 is loweralkyl. ~reparation of the acids and acid salts thereof of the invention (R3=H) is illustrated in Examples 72 and 73, wherein _ g _ L 7~
the ester is hydrolyzed to -the acid. I~etal salts of the acids such as alkali metal salts may also be prepared by usual methods of reacting with an alkali metal base and isolating the salts.
Examples 85-88 further illustrate the conversion of free bases of esters of this invention to their acid addition salts. Physical data and analysis obtained are in Tables 1 and 2. The presentation of examples, however, shall not be construed as a limitation of the scope of the invention.
_arnple _ hyl 8-Methoxy-4-[(2-methylphenyl)arnino~-3-quinoline-carboxy ate Hydrochloride.
To a solution of 5.31 g l19.98 mmoles) of ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate dissolved in 40 ml oE tetrahydro-furan was added 2.15 g (20.06 mmoles) of o toluidine dissolved in 40 ml of tetrahydrofuran. The solution was stirred with exclusion of moisture at 60C. for 18 hours. The yellow solid precipitate was filtered and washed with isopropyl ether; yield 7.13 g (95.7%).
The product was recrystallized three times from methylene chloride:
ethyl acetate, m.p. 191-193.5C.
Analysis: Calculated for C20H21ClN2O3: C, 64.43; H, 5.68; N, 7.51 Found : C, 64.36; H, 5.65; N, 7.62 Ex _ple 2 Eth~l 4-(Phenylamino)-8-methoxy-3-quinolinecarboxylate.
-To a solution of 6.0 g (22.5 mmoles) of ethyl ~-chloro-8-methoxy-3-quinolinecarboxylate in 80 ml of tetrahydrofuran was added 2.3 g (24.8 mmoles) of aniline in 60 ml of tetrahydrofuran.
The solution was briefly warmed and after standing for 10 minutes, '7~
a yellow solid began to prec:ipitate. The mixture was kept at room temperature for 18 hours. The solvent was rotary evaporated. The residue dissolved in 200 ml of methanol and the pH made slightly basic (pH 8) with sodium bicarbonate. Water (700 ml) was added and an oil formed which solidified and after standing, additional solid crystallized. The solid was filtered and air-dried to give 6.9 g (95~) of crude material. The solid ~as dissolved in 300 ml of hot isooctane and the solution was charcoaled and filtered. The volume of the filtrate was reduced to 150 ml. Upon cooling, pale yellow needles separated; 6.5 g (89~); m.p~ 120-121C.
Analysis: Calculated for ClgH18N2O3: C, 70.79; H, 5.63; N, 8.69 Found : C, 70.91; H, 5.65; N, 8.77 Examples 3 to 71 3. Ethyl 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate by neutralization of Example 1.
4. Ethyl 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate sulfate (1:1) from Example 3 and sulfuric acid.
Antisecretory or anti-ulcer activ:ities for 4-amino-3-quinolinecarboxylic acids and esters have not been disclosed prior to this invention.
SUMMARY OF THE INVENTION
Our Application Serial No. 348,417 is directed to novel compounds which are 4-amino-3-quinolinecarboxylic acids and estexs which have the formula (Rl~n ~ ~ C2R3 wherein;
Rl is selected from the group consisting of loweralkyl, phenyl, O-loweralkyl, S-loweralkyl, halogen, trifluoromethyl, cyano and dialkylamino, R2 is selected ~rom the group consisting of loweralkyl, phenyl, phenylloweralkyl or phenyl substituted by 1-3 radicals taken from among loweralkyl, O-loweralkyl, S loweralkyl, halogen, cyano, hydroxy, carbamoyl, carboxy, acetyl, trifluoromethyl, and nitro, R3 is selected from the group consisting of hydrogen, loweralkyl, omega-dimethylamino-loweralkyl, loweralkoxy- loweralkyl, and allyl, n is 0, 1 or 2, provided that when n is 0 or n is 1 and Rl is chlorine or methoxy in -the 6-position or chlorine in the '7 7-position ancl R3 i5 hydrogen or ethyl, then if R2 i9 a phenyl group it is mono-substituted in the 2-position of the phenyl ring or is di-substituted in the 2- and ~-positions of the phenyl ring, and the pharmaceutically acceptable addition salts thereof.
This present application is directed to pharmaceutical compositions for inhibiting secretion of gastric acid or treating peptic ulcer in mammals which comprises a pharmaceutical carrier and an effective amount of a compound having the formula NHC6~15 or pharmaceutically acceptable salt thereof wherein R is hydrogen or methoxy, Rl is hydrogen, chlorine or methoxy and R3 is hydrogen or ethyl, provided that R and Rl are not both hydrogen.
The antisecretory effect of reduced flow of gastric juice and hydrochloric acid in pyloric-ligated rats was demonstrated when the esters of ~l-amino-3-~uinolinecarboxylic acids were administered orally, subcutaneously, intraperitoneally, intraduodenally and intravenously. Effective ulceration reduction was also demonstrated in pyloric-ligated rats. The compounds of the invention also were shown to reduce gastric secretion induced, for example, by histamine, tetragastrin and methacholine. Gastric acid output in Heidenhain pouch dogs stimulated with food was also reduced.
7;~,7 The term "loweralkyl" as used in the speclfication and claims includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exempli~ied by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like.
Representative of "phenylloweralkyl" radicals are benzyl (phenylmethyl), a-methylbenzyl, phenylethyl, phenylpropyl, phenyl-butyl, and the like.
The compounds of this div:lsional application and the compounds of the parent application can be made by similar methods.
Thus, the compounds are prepared from appropriate 4-chloro-3-quinolinecarboxylic acid esters as represented by the following equation:
Cl NHR2 ~ O2R3 ~ C2R3 (Rl)n~\NJ (Rl)n~N
wherein Rl, R2, and n are as hereinabove de~ined, and R3 is loweralkyl.
The Formula II compounds were prepared by chlorinating appropriate 4~hydroxy-3-quinolinecarboxylic acid esters with phosphorous oxychloride generally by the method described by 2~ Kermack & Storey, J. Chem. Soc. 1951, pp 1389-92. The equation is:
L'7~;~'7 ( R~ J C02R3 (R ) ~ C2R3 III II
wherein Rl and n are as defined hereinabove, and R3 is loweralkyl.
The Formula III compounds wherein R3 is ethyl were prepared by heating a mixture of appropriately substituted anilines and diethyl ethoxymethylenemalonate to Eorm an intermediate anilinoacrylate and thereafter cyclizing in a high boiling solvent such as diphenyloxide as described by Price and Roberts in J. Amer, Chem. Soc. 68, 1204-8. The reaction is represented by the following equation:
( ~)n ~ + C2H5OcN=c(co2c2~5)2 ~ 2C2~5 214-250C~
~ ~2 IV
OH
l)n ~ ~ ~ CO2C2H5 III
L`7~3;' Acids (R3=~I) of the compound~ may be prepared from es-ters (R3=loweralkyl) by usual methods of hydrolysis and other esters of the compounds may be prepared by usual methods of re-esterifi-cation.
Utilizing the foregoing method described by Price and Roberts, the following ethyl-4-hydroxy-3-quinolinecarboxylates of Formula II were prepared from diethylethoxymethoxymalonate and aniline or known aniline derivatives as follows:
Ethyl 4 hydroxyquinoline-3-carboxylate from aniline;
10 m.p. 280-283C.
Ethyl 4-hydroxy-8-methoxy-3-quinolinecarboxylate from 2-methoxyaniline; m.p. 243-246C.
Ethyl 4-hydroxy-8-ethoxy-3-quinolinecarboxylate from 2-ethoxyaniline; m.p. 198-200C.
Ethyl 4-hydroxy-5,8-dimethoxy-3-quinolinecarboxylate from 2,5-dimethoxyaniline; m.p. 197-199.5C~
Ethyl 4-hydroxy-8-methoxy-5-methyl-3-quinolinecarboxylate from 2-methoxy-5-methylaniline; m.p. 180-182C.
Ethyl 4-hydroxy-8-phenyl-3-quinolinecarboxylate from 202-aminobiphenyl; m.p. 250-252.5C.
Ethyl 4-hydroxy-8-methyl-3-quinolinecarboxylate from 2-methylaniline; m.p. 271-274C.
Ethyl 4-hydroxy-8-trifluoromethyl-3-quinolinecarboxylate from 2-trifluoromethylaniline; m.p. 211-213.5C.
Ethyl 4-hydroxy-8-methylthio-3-quinolinecarboxylate from 2-methylthioaniline; m.p. 201-204C.
Ethyl 4~hydroxy-8-chloro-3-quinolinecarboxylate from 2-chloroaniline; m.p. 255-259C.
Ethyl 4-hydroxy-6r8-dimethyl-3-quinolinecarboxylate from 2,4-dimethylaniline;
Ethyl 4-hydroxy-6-methoxy-3-quinolinecarboxylate from 4-methoxyaniline; m.p. 283 287C.
Ethyl 4-hydroxy-8-cyano-3-quinolinecarboxylate from 2-cyanoaniline; m.p. 234-236C.
Ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate from 3-methoxyaniline; m.p. 280-282.5C.
Ethyl 4-hydroxy-8-dimethylamino-3-quinolinecarboxylate from 2-dimethylaminoaniline; m.p. 176-180C.
Preparation 1 illustrates the synthesis procedure used to make the 4-chloro compounds of Formula II which are the starting materials used in makiny active compounds.
Preparation Eth l 4-chloro-8-methox~3-quinolinecarboxylate.
A stirred mixture of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate, 66.63 g (0.269 mole) and phosphorous oxychloride (350 ml) was warmed until all the solid had dissolved and then heated at reflux temperature for two hours. After cooling to below 100C. the mixture was concentrated in a rotary evaporator. The residual oil was dissolved in 100 ml acetone and the solution poured onto an ice water mixture (800 ml). The mixture was neutralized with 6N sodium hydroxide solution and the solid product extracted successively wi-th 450 ml, 250 ml and 100 ml portions of methylene chloride. The extracts were combined, washed with wa-ter, dried over anhydrous magnesium sulfate and concentrated to yield 7~ 7 68.16 g crude product. This crude product was dissolved in 500 ml hot toluene and filtered to remove a small quantity of insoluble material. The toluene solution was filtered through a bed of 250 g fluorisil followed by two liters of toluene and four liters of chloroform. The purified solution was concentrated to give 64.17 g of oil (89%) which crystallized to an off-white solid on cooling.
The solid melted at 75-77C.
Analysis: Calculated for C13H12NO3CL: C, 58.77; H, 4.55; N, 5.27 Found : C, 58.58; ~I, 4.61; N, 5.33 Preparatlon 2-15 Utilizing the procedure of Preparation ], and substituting appropriate ethyl 4-hydroxy-3-quinolinecarboxylates listed above III, the following ethyl 4-chloro-quinoline-3-carboxylates were prepared and used directly.
(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-quinoline-carboxylate (6) Ethyl 4-chloro-8-phenyl-3-quinolinecarboxylate (7) Ethyl 4-chloro-8-methyl-3-quinolinecarboxylate (8) Ethyl 4-chloro-8-trifluoromethyl-3-quinoline-carboxylate (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 (lS) Ethyl 4-chloro-8-(dimethylamino)-3-quinoline-carboxylate.
A general procedure for preparing esters (R3=loweralkyl) of the invention is to react an appropriate 4-chloro-3-quinoline-carboxylic acid ester with an appropriate amine in a polar aprotic solvent such as tetrahydrofuran or dioxane, following the reaction by thin-layer chromatography and modifying temperature and time to complete the reaction. In some instances the reacting amine may be used as the reaction solvent. Various solvents are used for recrystallizing. To prepare the free base from a salt the salt is dissolved and a base such as sodium hydroxide is added and the free base is extracted into a suitable organic solvent. To prepare additional salts the free base is mixed with an alcoholic solution of an acid, for example, phosphoric acid or sulfuric acid.
The foregoing is a general description of how to prepare the esters of the invention. The following Examples 1 and 2 generally illustrate the preparation of the ester compounds. The esters of Examples 3 to 71 and 74 to 80 were also prepared by reacting the appropriate amine with the appropriate ethyl 4-chloro-3-quinolinecarboxylate selected from Preparations 1 to 15.
Examples 81-84 and 89 illustrate the preparation of esters wherein R3 is loweralkyl, loweralkyldimethylamino, loweralkyl-loweralkoxy or allyl by the trans-esterification of esters wherein R3 is loweralkyl. ~reparation of the acids and acid salts thereof of the invention (R3=H) is illustrated in Examples 72 and 73, wherein _ g _ L 7~
the ester is hydrolyzed to -the acid. I~etal salts of the acids such as alkali metal salts may also be prepared by usual methods of reacting with an alkali metal base and isolating the salts.
Examples 85-88 further illustrate the conversion of free bases of esters of this invention to their acid addition salts. Physical data and analysis obtained are in Tables 1 and 2. The presentation of examples, however, shall not be construed as a limitation of the scope of the invention.
_arnple _ hyl 8-Methoxy-4-[(2-methylphenyl)arnino~-3-quinoline-carboxy ate Hydrochloride.
To a solution of 5.31 g l19.98 mmoles) of ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate dissolved in 40 ml oE tetrahydro-furan was added 2.15 g (20.06 mmoles) of o toluidine dissolved in 40 ml of tetrahydrofuran. The solution was stirred with exclusion of moisture at 60C. for 18 hours. The yellow solid precipitate was filtered and washed with isopropyl ether; yield 7.13 g (95.7%).
The product was recrystallized three times from methylene chloride:
ethyl acetate, m.p. 191-193.5C.
Analysis: Calculated for C20H21ClN2O3: C, 64.43; H, 5.68; N, 7.51 Found : C, 64.36; H, 5.65; N, 7.62 Ex _ple 2 Eth~l 4-(Phenylamino)-8-methoxy-3-quinolinecarboxylate.
-To a solution of 6.0 g (22.5 mmoles) of ethyl ~-chloro-8-methoxy-3-quinolinecarboxylate in 80 ml of tetrahydrofuran was added 2.3 g (24.8 mmoles) of aniline in 60 ml of tetrahydrofuran.
The solution was briefly warmed and after standing for 10 minutes, '7~
a yellow solid began to prec:ipitate. The mixture was kept at room temperature for 18 hours. The solvent was rotary evaporated. The residue dissolved in 200 ml of methanol and the pH made slightly basic (pH 8) with sodium bicarbonate. Water (700 ml) was added and an oil formed which solidified and after standing, additional solid crystallized. The solid was filtered and air-dried to give 6.9 g (95~) of crude material. The solid ~as dissolved in 300 ml of hot isooctane and the solution was charcoaled and filtered. The volume of the filtrate was reduced to 150 ml. Upon cooling, pale yellow needles separated; 6.5 g (89~); m.p~ 120-121C.
Analysis: Calculated for ClgH18N2O3: C, 70.79; H, 5.63; N, 8.69 Found : C, 70.91; H, 5.65; N, 8.77 Examples 3 to 71 3. Ethyl 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate by neutralization of Example 1.
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-quinoline-carboxylate 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-methylthiophenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 1 and ~ t7 2-methylthioaniline.
9. Ethyl 4-[(2~chlorophenyl)amino]-8-methoxy-3-quinolinecarboxylate hydrochloride Erom Preparation 1 and 2-chloroaniline.
10. Ethyl 4-[(2-cyanophenyl)amino]-8-methoxy-3-quinolinecarboxylate hydrochloride from Preparation 1 and 2-amino-benzonitrile.
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-quinolinecarboxylate monohydrochloride ethanol (5:2) from Preparation 1 and anthranilamide.
13. Ethyl 4-[(2-fluorophenyl)amino]-8-methoxy-3-quinoline-carboxylate hydrochloride from Preparation 1 and 2-fluoro-analine.
14. Ethyl 4-[(2-acetylphenyl)amino]-8-methoxy-3-quinoline-carboxylate 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-quinoline-carboxylate hydrochloride monohydrate from Preparation 1 and m-toluidine.
17. Ethyl 8-methoxy-4-[(4-methylphenyl)amino]-3-quinoline-carboxylate 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-climethylphenyl)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 Hsr.
21. Ethyl 8-methoxy-4-[(1 phenylethyl)amino]-3-quinolinecarboxylate monohydrate from Preparation 1 and ~-methyl-benzylamine.
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-ethoxy~
aniline.
aniline.
27. Ethyl 8-methoxy-4-[~-methoxy-2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 1 and 2-methyl-4-methoxy-aniline.
28. Ethyl 4-[(2-ethylphenyl)amino]-8-methoxy-3-quinoline-carboxylate from Preparation 1 and 2-ethylaniline.
29. Ethyl 4-[(2-ethylphenyl)amino]-8-methoxy-3-quinoline-carboxylate phosphate (1:2) from Example 28 and anhyd, H3PO4.
30. Ethyl 4-[(2-ethylphenyl)amino]-8-methoxy-3-quinoline-7~
carboxylate sulfate (1:1) from Example 28 and alcoholic H2SO4.
carboxylate sulfate (1:1) from Example 28 and alcoholic H2SO4.
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)amin ~ 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 hydrochloride.
34. Ethyl 8-ethoxy-4-[(2-methylphenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 3 and o-toluidine.
35. Ethyl 8-e-thoxy-4-[2-(trifluoromethylphenyl)amino]-3-quinolinecarboxylate hydrobromide from Preparation 3 and o-trifluoro-methylaniline.
36. Ethyl 8-ethoxy-4-[(2-methoxyphenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 3 and o-anisidine.
37. Ethyl 8-ethoxy-4-[2-(methylthiophenyl)amino]-3-quinolinecarboxylate phosphate (1:1) from Preparation 3 and methyl-thioaniline and alcoholic H3PO4.
38. Ethyl 5,8-dimethoxy-4-(phenylamino)-3-quinoline-carboxylate hydrochloride hemihydrate from Preparation 4 and aniline.
39. Ethyl 5,8-dimethoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 4 and o-toluidine.
4~. Ethyl 7-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 14 and o-toluidine.
41. Ethyl 4-(phenylamino)-6-methoxy-3-quinolinecarboxylate from Preparation 12 and aniline.
~1''7'~'7 42. Ethyl 6-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 12 and o-toluidine.
43. Ethyl 8-methoxy-4-[(2-methoxyphenyl)amino]-5-methyl-3-quinolinecarboxylate dihydrochloride from Preparation 5 and o-anisidine.
44. Ethyl 8-methoxy-5-methyl-4-[2-(methylthiophenyl) amino]-3-quinolinecarboxylate phosphate (2:3) from Preparation 5 and 2-methylthioaniline.
45. Ethyl 8 methoxy-5-methyl-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 5 and o-toluidine.
46. Ethyl 4-[2-(methylphenyl)amino]-8-trifluoromethyl-3-quinolinecarboxylate from Preparation 8 and o-toluidine.
47. Ethyl 4-[(2-methylphenyl)amino]-8-methylthio-3-quinolinecarboxylate from Preparation 9 and o-toluidine.
48. Ethyl 4-[(2-methoxyphenyl)amino]-8-methylthio-3-quinolinecarboxylate hydrochloride from Preparation 9 and o-toluidine.
49. Ethyl 8-methylthio-4-[(2-methylthiophenyl)amino]-3-quinolinecarboxylate from Preparation 9 and 2-methylthioaniline.
50. Ethyl 8-methyl-4-[2-(methylthiophenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 7 and 2-methyl-thioaniline.
51. Ethyl 4-[(2-methoxyphenyl)amino]-8-methyl-3-quinolinecarboxylate hydrochloride from Preparation 7 and o-anisidine.
52. Ethyl 8-methyl-4-[(2-methylphenyl)methyl]amino-3-quinolinecarboxylate hydrobromide from Preparation 7 and 2-methyl-benzylamine.
7~7 53. Ethyl 8-chloro~4-[(2-methoxyphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 10 and o-anisidine.
54. Ethyl 8-cyano-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 13 and aniline.
55. Ethyl 4-(phenylamino)--8-phenyl-3-quinolinecarboxylate from Preparation 6 and aniline.
56. Ethyl 4-[(2-carboxyphenyl)amino]-8-phenyl-3-quinolinecarboxylate hydrochloride hemihydrate from Preparation 6 and 2-aminobenzoic acid.
57. Ethyl 4-benzylamino 8-phenyl-3-quinolinecarboxylate from Preparation 6 and benzylamine.
58. Ethyl 4-(phenylamino)-6,8-dlmethyl-3-quinoline-carboxylate from Preparation 11 and aniline.
59. Ethyl 4-(phenylamino)-3-quinolinecarboxylate from Preparation 2 and aniline.
60. Ethyl 4-(phenylamino)-3-quinolinecarboxylate hydro-chloride from Preparation 2 and aniline.
61. Ethyl 4-benzylamino-3-quinolinecarboxylate hydro-chloride from Preparation 2 and benzylamine.
62. Ethyl 4-[(2-methylphenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 2 and o-toluidine.
63. Ethyl 4-[2-(trifluoromethylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 2 and 2-tri-fluoromethylaniline.
64. Ethyl 4-[(2-methoxyphenyl)amino]-3-quinolinecarboxy-late hydrochloride from Preparation 2 and o-anisidine.
-~, , ~ 3 7 65. Ethyl 4-[(2-methylthiophenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 2 and 2-methyl-thioaniline.
66. Ethyl 4-[(4-methoxy-2-methylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 2 and 2-methyl-4-methoxyaniline.
67. Ethyl 4-[(2-chlorophenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 2 and 2-chloroaniline.
68. Ethyl 8-(dimethylamino)-4-(phenylamino)-3-quinoline-carboxylate hydrochloride from Preparation 15 and aniline.
69. Ethvl 8-(dimethylamino)-4~ (2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 15 and o-toluidine.
70. Ethyl 8-cyano-4-(phenylamino)-3-quinolinecarboxylate from Preparation 13 and aniline.
71. Ethyl 4-[(2-hydroxyphenyl)amino]-8-methoxy-3-quinolinecarboxylate from Preparation 1 and o-hydroxyaniline.
Example 72 8-Methoxy-4-_[(2-methylphenyl)amino]-3-quinoline-carboxylic acid.
A mixture of Ethyl 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate, 15.00 g (0.0445 mole), 100 ml of 3N sodium hydroxide solution and 100 ml of ethanol was stirred at room temperature for 16 hou~s. The mixture was diluted with 300 ml of water and acidified to pH 6.8 with 6N hydrochloric acid solution.
The precipitate was collected by filtration, washed in succession with water and acetone and air dried for about 1.5 hr. Weight o~
solid was 13.41 g (98%), m.p. 272C (d).
7 ~7 Analysis: Calculated for C18H16N203: C, 70.12; H, 5.23; N, 9.09 Found ~I C, 70.10; H, 5.27; N, 9.09 Example 73 8-Methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylic Acid Hydrochloride.
A portion of the 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylic acid, 4.35 g from Example 72 was triturated with 100 ml hot absolute ethanol. After cooling, the solid was collected by filtration and air dried to give 3.87 g. The solid was suspended in 25 ml of absolute ethanol and excess ethereal hydrogen chloride solution added. A clear solution was obtained.
Addition of isopropyl ether produced a yellow precipitate ~hich was collected and recrystallized from absolute ethanol-isopropyl ether to yield 3.14 g solid m.p. 257C. (d).
Analysis: Calculated for C18H17N203Cl: C, 62.70; H, 4.97, N, 8.12 Found : C, 62.53, H, 4.93; N, 8.18 Examples 74-80 74. Ethyl 8-methyl-4-[(2-methylphenyl)amino]-3-quinoline-carboxylate monohydrochloride from Preparation 7 and o-toluidine.
75. Ethyl 8-methoxy-4-[[2-(1-methylethyl)phenyI]amino-3-quinolinecarboxylate from Pr~paration 1 and o-isopropylaniline.
76. Ethyl 8-chloro-4-[(2-methylphenyl)amino]-3-quinoline-carboxylate from Preparation 10 and o-toluidine.
77. Ethyl [(2-chloro-6-methylphenyl)amino]-8-methoxy-3-quinolinecarboxylate monohydrochloride from Preparation 1 and 2-chloro-6-methylaniline.
78. Ethyl 8-methoxy-4-[(2,3-dimethylphenyl)amino]-3-7~
quinolinecarboxylate monosulfa~e from Preparation 1 and 2,3-dimethylaniline.
79. Ethyl 8-methoxy-4-[(2-nitrophenyl)amino]-3-quinolinecarboxylate from Preparation 1 and 2-nitroaniline.
80. Ethyl 8-methoxy-4-[(2-nitrophenyl)amino]-3-quinolinecarboxylate, ethylsulfate (1:1), ethanol (1:1) from Example 79 and concentrated sulfuric acid in absolute ethanol.
Example 81 l-Me-t_ylethyl 8-Methoxy-4--[(2 methylphenyl)amino]-3-quinolinecarboxylate, Monohydrochloride, Monohydrate.
To 150 ml oE dry 2-propanol was added 2 sodium pellets followed by 5.38 g (15.99 mmoles) of ethyl 8-methoxy-4-[(2-methyl-phenyl)amino]-3-quinolinecarboxylate dissolved in 50 ml of dry 2-propanol. The solution was stirred and refluxed with exclusion of moisture for 6 hrs. during which time 120 ml of distillate was collected in a Dean-Starke trap and discarded. The solvent was evaporated and the residue was dissolved in 50 ml of 2.9 M hydro-chloric acid and 100 ml of water added thereto. The solution was adjusted to a pH of 8 with 1 M aqueous sodium bicarbonate and the oil which separated was extracted three times with 100 ml of methylene chloride. The combined extracts were dried over magnesium sulfate. The solvent was evaporated to give 4.60 g (82~) of the free base of the titled compound having a m.p. of 120-122C. after recrystallization from acetone-hexane.
The free base was dissolved in isopropyl ether and ethereal hydrogen chloride added thereto. The solvent was evaporated and the residue recrystallized from methylene chloride-7~
acetone to obtain the titled compound as a yellow crys-talline solid having a m.p. of 140-143C.
Example 82 3 Methoxyethyl-8-methoxy-4-[(2-methylphenyl)amino]~
3-quinolinecarboxylate.
-Following the procedure of Example 81, the compound ofExample 3 was trans-esterified with 2-methoxyethanol to give the titled compound.
Example 83 3-Dimethylamino ethyl 8-Methoxy-4 [(2-methylpheny1) amino]-3-quinolinecarboxylate.
Following a procedure similar to that given in Example 81, the compound of Example 3 was trans-es-terified with 2-dimethylamino-ethanol substitu-ting sodium ethoxide catalyst and -toluene solvent to give the titled compound.
Example 84 3-Dimethylamino prop~l 8-Methoxy-4-~(2-methylphenyl) aminol-3-~uinolinecarboxylate.
Following a procedure similar to that given in Example 81, the compound of Example 3 was trans-esterified with 3-dimethylamino-l-propanol substituting toluene solvent to give the titled compound.
Example 85 2-Dime-thylamino ethyl 8-Methoxy-4-[(2-methylphenyl) amino]-3-quinolinecarboxylate, Fumarate (1:1.5).
The titled compound was prepared from the compound of Example 83 and fumaric acid.
75~
Example_86 3-Dimethylamino propyl 8-Methoxy-4-[(2-methylphenyl) amino]-3~quinolinecarboxylate, Dihydrochloride, Monohydrate.
. . ~
The titled compound was prepared from the compound of Example 84 and ethereal hydrogen ch]oride.
Example 87 Ethyl 8-Methoxy-4-~(2-methylphenyl)amino]-3-quinoline~
carboxylate, ethanesulfonate (l:l)(salt).
The titled compound was prepared from the compound of Example 3 and ethanesulfonic acid in absolute ethanol.
Example 88 Ethyl 8-Methoxy-4-[(2-methylphenyl)amino]-3-quinoline-carboxylate, 2-~Iydroxye-thanesulfonate (l:l)(salt).
The titled compound was prepared from the compound of Example 3 and 2-hydroxyethylsulfonic ac:id in absolute ethanol.
Example 89 All~l 8-Methoxy-4-[(2-me-thylphenyl)amino]-3-q_inoline-carboxylate.
Following a procedure similar to Example 81, substituting allyl alcohol for 2-propanol, the titled compound is prepared.
7~
Table (Examples 1-88) (Rl)n _ ~ ~ 2 3 ample Rl R2 R3 Salt M.P., C.
.
1 8-CH30- 2-CH3-C6H4- c~2H5 HCl 191-193.5 3 8-CH30- 2-CH3-C6H ~ 2 5 138.5-140 6 8-CH30- C6H5- C2H5- HCl 165.5-168 7 8-CH30- 2-CH30-C6H4- C2H5- HCl 204-207 8 8-CH30- 2-CH3S-C6H - C2H5- HCl 275-278 9 8-CH30- 2-Cl-C H - C2H5- HCl 193-194.5 8-CH30- 2-C~-C H - C2H5- HCl 204-206.5 11 8-CH30- 2-CF -C H C2H5- HCl 199-201d 12 8-CH30- 2-NH2oc-c6H4-C2H5- 1 HCl- 251-154 13 8-CH30- 2-F-C6H4- C2H5- HCl 204 206 14 8-CH30- 2-CH3C0-C6H4-C2~-I - HCl 203-204d 8-CH30~ CH3(-CH2)3- C2H5- HC1 171-172d 16 8-CH30- CH3C6H4 C2H5- HCl.H20 156-158d 17 8-CH30- 4-CH3C6H4- C2H5- HCl.H20 155-156d 18 8-CH30- 2~CH3~C6H4CH2 C2H5 132-137 7~
Table 1 (cont) Ex- R R R Salt M.P., C.
ample 1 2 3 19 8-CH30- 2,6(CH3)2C6H3-C2~15 160-163 8-CH30- 2,6~CH3)2C6H3-C2H5- HBr 182-184 21 8-CH30 C6H5(CH3)CH-C2H5- H20 97-99 22 8-CH30- 2-cl-5-cH3o~c6H3-C2H5- HBr 160-162 23 8-CH30- 3-CH3S-C6H4- C2H5 123-124.5 24 8-CH30- C6H5CH2- C2H5- H3P04. 221-223 8-CH30- 2,4(CH30)2-C6H3- C2H5 128-131 26 8-CH30- 2-C2H50-C6H4-C2H5- HCl 20~d 8-CH30- 2-C2H5-C6H4- C2H5- H2S04 177-178.5 31 8-CH30- 2,6-Cl-C6H3- 2 5 178-180 32 8-CH30- 2-CH3-5-No2-C6H3-C2H5 251.5-253 33 8-CH30- 2-CH3-C6H4CH2-C2H5- ~C2II50H
8-C2H50 2-CF3-C6H4- C2H5- HBr 185-19ld 36 8 C2H5 2-CH30-C6H4- C2H5- HCl 205-206.5 37 8-C2H50- 2-CH3S-C H ~C2H5- H3P04 185-190 38 5,8(CH30)2 C6H5 C2H5- HCl.~H20 166-167 39 5,8(CH30)2- 2-CH3 C6H4C2H5 156-158d 7-CH30- 2-CH3-C6H4- C2H5- HCl 147-159d 41 b CH 0 C6H5- C2H5 99~5-102.5 (cont.) '71;~7 Table l(cont) Ex- R R R3 Salt M.P., C.
ampl~ 1 2 42 6-CH30- 2-C~13-C6H4- C2H5- HCI, 193d 43 5-cH3-8-cH3o- 2-CH3O C6H4 C2H5- 2HC1 183-185d 44 5-CH3-8-CH3O- 2-CH3S C6 4 C2H5-.5~l3PO4 204 205 5 CH3 8 CH30 2 CH3 C6H4 C2H5- ~ 167.5-169 47 8-CH3S~ 2-CH3-C6H4 C2H5 168-170 48 8-CH3S- 2-CH3O-C6H4- C2H5- HCl 169-172 49 8-CH3S- 2-CH3S-C6H - C2H5- - 140.5-142 8-CH3- 2-CH3S-C6H - C2H5- HCl 172-174d 51 8-CH3- 2-CH3O-C6H4- C2H5- HCl 186-188 52 8-CH3- 2-CH3-C6H4cH2 C2H5- HBr 182-183 53 8-Cl- 2-CH3O-C6H4- C2H5- HCl 203-205d 54 8-CN- 2-CH3-C H4- C2H5- HCl 215-219 56 8 C6H5 2 COOH-C6H4- C2H5-HCl.~H2O 213-214 58 6,8(CH3)2- C6H5- C2H5 164.5-165 59 H- C6H5- C2H5 100-102(a) H- C6H5- C2H5- HC1 193-195d 61 H- C6H5CH2- C2H5- HC1 195.5-196 62 H- 2-CH -C H4- C2H5- HC1 170-171d 63 H- 2-CF3-C6H4- C2H5- HC1 168.5-170 64 H- 2-CH3O-C6H4- C2H5- HCl 172-174.5 H- 2-CH3S-C H4- C2H5- HC1 186-187d 66 H- 2-CH3-4-OCH3- C2H5- HC1 178-179d C6H3- (cont.) Table l(cont) Ex- R R R Sal-t M.P., C.
ample 1 2 3 _ 67 H- 2-Cl-C6H4- C2H5- HC1 204-205d 68 ( 3)2 C6H5 C2H5- HCl 179-181 69 ( 3)2 2-CH -C H4- 2 5 110-114 72 8-CH30- 2-CH3-C H4- H _ 272(d) 73 8-CH30 2-CH -C H4- H HCl 257 74 8-CH3- 2-C~13-C H4- C2H5- HC1 162-164 8-CH30- ( 3)2CH 2 5 136-138 78 8-CH30- 2,3-(CH3)2- C2H5- H2S04 177-181 79 8-CH30- 2-N0 -C H ~ C2H5 180-182 81 8-CH30- 2-CH3-C6H ~ tCH3)2 HCl.H20 140-143 HC-82 8-CH30- 2 CH3-C6H4- CH30 HCl 184-187 (CH2)2 83 8-CH30- 2-CH ~C H4- (CH3)2 100-103 N(CH2)2-84 8-CH30- 2-CH3-C6H4- (CH3)2 N(CH2) - - 95-97 5 7~
Table 1 (cont) _ Ex- R R R Salt M.P., C.
ample 1 2 3 8-CH30- 3 6 4 ( 3)2 N(CH2)2 fumarate 186-189 86 8-CH30~ 3 6 4 ( 3)2 !H20 177-180 ( 2)3 .HCl (a)Compares with m.p. 99-100C. given in J. Pharm~ Chem.
Soc. 1389 (1951).
Tahle 2 Analytical Data on Examples 1~88 Empirical Calculated E'ound Ex. Formula C H N C H N
20 21 lW20364.63 5.68 7.51 64.36 5.65 7.62 2 Cl9H18N23 70.79 5.63 8.69 70.91 5.65 8.77 3 C20H20N2 3 71.41 5.99 8.33 71.52 5.94 8.35 20 22 2 7 55.29 5.]0 6.45 55.68 5.02 6.42 C20H23N27 55.30 5.34 6.45 54.92 5.37 6.53 19 19 2 3 63.60 5.34 7.81 63.25 5.33 7.69 7 20 21 2 4 61.78 5.44 7.20 61.55 5.57 7.07 8 C20H21ClN203S59-33 5.23 6.92 59.04 5.38 6.87 9 ClgH18C12N20358.03 4.61 7.12 57.89 4.69 7.13 20 18 3 3 62.59 4.73 lO.9S 62.23 4.95 10.73 11 C20H18N203F3C1 56.28 4.25 6.56 56.33 4.34 6.60 12 C104H112ClsN15022 59.25 5.21 10.03 13 ClgH18N203FC160.56 4.81 7.43 60.28 4.87 7.32 14 21 21 2 4 62.92 5.28 6.99 62.56 5.48 6.76 17 23 2 3 60.26 6.84 8.26 59.39 6.80 8.20 16 20 23 2 4C 61.46 5.93 7.17 61.40 5.92 7.21 17 20 23 2 4C61.46 5.93 7.17 61.73 5.76 7.33 18 21 22 24 68.84 6.05 7~65 68.61 6.04 7.51 19 21 22 2 3 71.98 6.33 7.99 72.16 6.33 8.01 21 23 2 3 58.48 5.37 6.49 58.48 5.41 6.52 21 21 24 2 4 68.46 6.57 7.60 68.47 6.51 7.59 22 C20H20N204ClBr 51.35 4.31 5.99 51.27 4.30 6.04 (cont'd) ';7~7~
Table 2 (cont'd) An~lytical Data on Ex~mples 1-88 . _ Empirical Calculated Found Ex.Formula C H _ _ _ N
2320 20 2 3 65.20 5.47 7.60 65.18 5.48 7.66 2421 27 2 8 54.08 5.84 6.01 54.32 5.58 6.23 2521 22 2 5 65.96 5.80 7.33 66.06 5.75 7.28 26C21H23N204C1 62.61 5.75 6.95 62.61 5.84 6.94 2721 22N2 4 68.84 6.05 7.65 68.94 6.06 7.68 2821 22N203 71.98 6.33 7.99 72.02 6.29 8.03 2gC21H28N2011P2 46.16 5.17 5.13 46.07 5.22 5.12 21 24 27 56.24 5.39 6.25 56.09 5.43 6.24 31ClgH16N203C12 58.33 4.12 7.16 58.52 4.13 7.21 3220 19 3 5 62.99 5.02 11.02 63.02 5.08 11.03 33C44H52N47C 2 64.46 6.39 6.83 64.09 6.22 6.96 21 23 2 3 65.20 5.99 7.24 65.25 6.01 7.26 21 20 2 3 3 51.97 4.15 5.77 52.22 4.14 5.89 36C21H23N204C1 62.61 5.75 6.95 62.67 5.76 7.05 21 25 2 7 52.50 5.75 5.83 52.08 5.35 5.77 38C20H21ClN24 60.37 5.57 7.04 60.22 5.55 7.05 3921 22 2 4 68.84 6.05 7.67 69.19 6.09 7.70 20 21 2 3C1 64.43 5.68 7~51 64.71 5.76 7.54 4119 18 2 3 70.79 5.63 8.69 70.96 5.66 8.62 4220 21 2 3C1 64.43 5.68 7.51 64040 9.67 7.62 43C21H24N204C12 57.41 5.50 6.38 57.02 5.79 6.25 44C42H53N4018S2 3 47.64 5.04 5.29 48.06 5.08 5.43 (cont'd) Table 2 (cont'd) An~lytical Data on Examples 1-88 _ Empirical Calculated Found Ex. Formula _ _ N _ _ N
C21H22N2 3 71.98 6.33 7.9972.326.35 8.02 46 20 17 3 2 264.17 4.58 7.4864.164.62 7.49 20 20 2 2 68.16 5.72 7.9568.195.76 8.14 48 C20H21ClN203S59.335.23 6.9259.555.32 6.86 49 C20H20N22 2 62.47 5.24 7.2962.165.16 7.12 20 21 2 2 61.77 5.44 7.2061.845.41 7.31 51 20 2lClN20364.73 5.68 7.5164.475.61 7.50 52 C21H23BrN20260.73 5.58 6.9360.765.60 6.82 19 18 23Cl258.03 4.61 7.1257.974.65 7.11 54 C20H17N3 2 72.49 5.17 12.68 72.16 5.26 12.54 C24H20N22 78.24 5.47 7.6078.225.47 7.50 56 C50H44C12N40965.574.84 6.1166.045.00 6.09 5? 25 23N22 78.32 6.05 7.3178.52S.90 7.30 58 20 20 2 2 74.98 6.71 8.7475.226.37 8.77 59 C18Hl6N22 73.96 5.52 9.5874.125.64 9.42 18 17 2 2 65.75 5.21 8.5265.855.29 8.56 61 19 l9 N2 2 66.56 5.59 8.1766.805.61 8.12 62 ClgHlgN202C166.57 5.59 8.1766.805.70 8.19 63 19 16 2 2 357.51 4.06 7.0657.854.08 7.13 64 ClgHlgClN20363.60 5.34 7.8163.675.30 7.78 ClgHlgN202SCl60.875.11 7.4760.975.30 7.39 66 C20H2lN203C164.43 5.68 7.5164.145.70 7.52 67 C18Hl6N202Cl259.524.44 7.7159.264.42 7.67 (cont'd) 7~''7 Table 2 (cont'd) Analyt_ al Data on Examples 1- 88 Empirical Calculated ~ound Ex. Formula C H N C H N
.
68 C20H22N302C1 64~60 5~96 11~30 64~60 5~96 11~39 69 21 23N32 72~18 6~63 12~03 72~24 6~57 12~09 70 Cl9H15N32 71 ~ 91 4 ~ 76 13 ~ 24 71 ~ 95 4 ~ 86 13 ~ 26 7119 18 2 4 67~45 5~36 8~78 67~495~38 8~50 7218 16 2 3 70~12 5~23 9~09 70~105~27 9~09 18 17 2 3C~ 62~70 4~97 8~12 62~534~93 8~18 7420 21 N2 2 67~32 5~93 7~85 67~225~92 7~83 75C22H24N23 72~51 6~64 7~69 72~566~55 7~67 7619 17 2 2 66~90 5~03 8~22 66~605~14 8~20 77C20H20N203C12 58~98 4~95 6~88 58~904~94 6~90 7821 24N207S 56~24 5~39 6~25 56~375~42 6~28 79ClgH17N305 62~12 4~66 11~44 62~05 4~66 11~54 8023 29 3 10 51 ~ 20 5 ~ 42 7 ~ 79 51 ~ 20 5 ~ 36 8 ~ 01 8121 25 24 62~30 6~22 6~92 62~49 6~23 6~94 8221 23ClN204 62~61 5~75 6~95 62~72 5~76 7~04 8322 25 33 69~64 6~64 11~07 69~73 6~64 11~07 8423 27 3 3 70~21 6~92 10~68 70~42 6~95 10~67 8528 31 3 9 60~75 5~64 7~59 60~89So69 7~53 86C23H31C12N304 57~03 6~45 8~67 57~056~31 8~79 8722 26 2 6 59~18 5~87 6~27 59~165~93 6~25 8822 26 2 7S 57~13 5~67 6~06 57~085~71 6~10 ~ 30 ~
~ t~ 7 Pharmacology The action of 4-amino-3-quinolinecarboxylic acids and esters of this invention on gastric secretion was studied in rats and dogs. Inhibition of secretion was measured and expressed in terms of percent of gastric acid output. Anti-ulcer studies were also done in rats. The results of studies with a preferred com-pound of this invention are described below. Other compounds of this invention show qualitatively similar effects in one or more of these tests.
Table 3 Effect of Compound of Example 1 on Stimulated Gastric Secretion .. . . . _ . _ _ Dose Stimulating Inhibition Species(~Jmoles/kg) RouteAgen* (~) Rat 0.3 - 8.1 IVHistamine 43 - 96 Rat 0.3 - 10.7 IDHistamine 40 - 70 Rat 0.3 - 8.1 IVTetragastrin 27 - 85 Rat 0.9 - 8.1 IVMethacholine 25 - 76 Dog 2~7 and 8.1 IVFood 50 and 83 Dog 32.4 POFood 56 l Inhibition was measured as output of gastric acid.
2 Rats were studied according to a modification of the method of Ghosh and Shield, 1958, BritO J. Pharmacol. 13:54-61.
3 Dogs were Heidenhain pouch dogs.
The compound of Example 1 was administered to pyloric-ligated rats having no artificial stimulation of gastric secretion. The doses ~ 3 ~
used were 33 to 134 ~moles/kg; acid output was inhibited by 38-55%.
The gastric anti-ulcer effects of the compound of Example 1 were examined in rats studied according to the method of Shay et al., 1945, Gastroenterology 5:43-61. Protection against ulceration of 4-90~ was provided by doses of 12-198 ~moles/kg.
Effective quantities of the foregoing compounds repre-sented by Formula I may be administered to a living animal body for therapeutic purposes relating to the control of acid release due to histamine stimulation and peptic ulcer control or combat-ting peptic ulcers in rnammals according to usual modes of adminis-tration for pharmaceuticals in usual forms such as orally in solution, emulsions, suspensions, pills, tablets, troches, lozenges, pellets, capsules and the like in pharmaceutically acceptable carriers; parenterally in the form of sterile solutions or mix-tures.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, a~ar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, arachis oil, water or any parenterally acceptable liquid.
Although very small quantities of the active materials of the present invention are effective when minor therapy for gas-tric irritation is involved or in cases of administration to sub-jects having a low body weight, unit dosages will usually contain the active ingredient in an amount to supply 2 to 6 mg/kg to the ~.t~
host. Unit dosages may vary Erom 100 to 500 mg active agent, pre-ferably for an adult human from 200 to 500 mg. The active ingre-dient will preEerably be administered in equal doses one to four times per day. The daily dosage regimen will vary from about 100 to about 1200 mg, most pre~erably from about 300 to 900 mg/day.
It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. The exact individual dosages as well as daily dosages will, o~ course, be determined according to standard medical pr:inciples under the direction of a physician or veterinarian.
The following formulations are representative:
1. Capsules Ingredients Amount, mg.
Active ingredient, 200 e.g., Example 2 = Ethyl 8-methoxy-4-(phenyl) amino-3-quinolinecarboxylate Sucrose 100 Starch 30 Talc 5 Stearic Acid 3 slend and fill into gelatin capsulesO
2. Tablets Amount mg.
Ingredients per tablet Active ingredient 350.0 e.g., Example 2 = Ethyl 8-methoxy-4-(phenyl) amino-3-quinol.inecarboxylate 180.0 Alginic acid 20.0 Calcium and ammoniwm alginate 40.0 Starch 54.0 ~actose 75.0 Magnesium stearate 2.2 721.2 '7~7 The mixture, all except the magnesium stearate and one half of the calcium ammonium alginate, is blended and granulated with ethanol and passed through a number eight mesh screen and the mixture dried 16 hours at 140F. The dried granulated material is then blended thoroughly with the remainder of the calcium ammonium alginate and magnesium stearate and tableted.
3. Intravenous Injection Ingredients Amounts,~
Active ingredient 200 e.g., Example 2 = Ethyl 8-methoxy-4-(phenyl) amino-3-quinolinecarboxylate Water 2,000 Preservative, e.g., chlorobutanol 20 Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, com-positions and methods of the present invention without departing from the spirit and scope thereof, and it is therefore understood that the invention is to be limited only by the scope of the appended claims.
4~. Ethyl 7-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 14 and o-toluidine.
41. Ethyl 4-(phenylamino)-6-methoxy-3-quinolinecarboxylate from Preparation 12 and aniline.
~1''7'~'7 42. Ethyl 6-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 12 and o-toluidine.
43. Ethyl 8-methoxy-4-[(2-methoxyphenyl)amino]-5-methyl-3-quinolinecarboxylate dihydrochloride from Preparation 5 and o-anisidine.
44. Ethyl 8-methoxy-5-methyl-4-[2-(methylthiophenyl) amino]-3-quinolinecarboxylate phosphate (2:3) from Preparation 5 and 2-methylthioaniline.
45. Ethyl 8 methoxy-5-methyl-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 5 and o-toluidine.
46. Ethyl 4-[2-(methylphenyl)amino]-8-trifluoromethyl-3-quinolinecarboxylate from Preparation 8 and o-toluidine.
47. Ethyl 4-[(2-methylphenyl)amino]-8-methylthio-3-quinolinecarboxylate from Preparation 9 and o-toluidine.
48. Ethyl 4-[(2-methoxyphenyl)amino]-8-methylthio-3-quinolinecarboxylate hydrochloride from Preparation 9 and o-toluidine.
49. Ethyl 8-methylthio-4-[(2-methylthiophenyl)amino]-3-quinolinecarboxylate from Preparation 9 and 2-methylthioaniline.
50. Ethyl 8-methyl-4-[2-(methylthiophenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 7 and 2-methyl-thioaniline.
51. Ethyl 4-[(2-methoxyphenyl)amino]-8-methyl-3-quinolinecarboxylate hydrochloride from Preparation 7 and o-anisidine.
52. Ethyl 8-methyl-4-[(2-methylphenyl)methyl]amino-3-quinolinecarboxylate hydrobromide from Preparation 7 and 2-methyl-benzylamine.
7~7 53. Ethyl 8-chloro~4-[(2-methoxyphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 10 and o-anisidine.
54. Ethyl 8-cyano-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 13 and aniline.
55. Ethyl 4-(phenylamino)--8-phenyl-3-quinolinecarboxylate from Preparation 6 and aniline.
56. Ethyl 4-[(2-carboxyphenyl)amino]-8-phenyl-3-quinolinecarboxylate hydrochloride hemihydrate from Preparation 6 and 2-aminobenzoic acid.
57. Ethyl 4-benzylamino 8-phenyl-3-quinolinecarboxylate from Preparation 6 and benzylamine.
58. Ethyl 4-(phenylamino)-6,8-dlmethyl-3-quinoline-carboxylate from Preparation 11 and aniline.
59. Ethyl 4-(phenylamino)-3-quinolinecarboxylate from Preparation 2 and aniline.
60. Ethyl 4-(phenylamino)-3-quinolinecarboxylate hydro-chloride from Preparation 2 and aniline.
61. Ethyl 4-benzylamino-3-quinolinecarboxylate hydro-chloride from Preparation 2 and benzylamine.
62. Ethyl 4-[(2-methylphenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 2 and o-toluidine.
63. Ethyl 4-[2-(trifluoromethylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 2 and 2-tri-fluoromethylaniline.
64. Ethyl 4-[(2-methoxyphenyl)amino]-3-quinolinecarboxy-late hydrochloride from Preparation 2 and o-anisidine.
-~, , ~ 3 7 65. Ethyl 4-[(2-methylthiophenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 2 and 2-methyl-thioaniline.
66. Ethyl 4-[(4-methoxy-2-methylphenyl)amino]-3-quinolinecarboxylate hydrochloride from Preparation 2 and 2-methyl-4-methoxyaniline.
67. Ethyl 4-[(2-chlorophenyl)amino]-3-quinoline-carboxylate hydrochloride from Preparation 2 and 2-chloroaniline.
68. Ethyl 8-(dimethylamino)-4-(phenylamino)-3-quinoline-carboxylate hydrochloride from Preparation 15 and aniline.
69. Ethvl 8-(dimethylamino)-4~ (2-methylphenyl)amino]-3-quinolinecarboxylate from Preparation 15 and o-toluidine.
70. Ethyl 8-cyano-4-(phenylamino)-3-quinolinecarboxylate from Preparation 13 and aniline.
71. Ethyl 4-[(2-hydroxyphenyl)amino]-8-methoxy-3-quinolinecarboxylate from Preparation 1 and o-hydroxyaniline.
Example 72 8-Methoxy-4-_[(2-methylphenyl)amino]-3-quinoline-carboxylic acid.
A mixture of Ethyl 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate, 15.00 g (0.0445 mole), 100 ml of 3N sodium hydroxide solution and 100 ml of ethanol was stirred at room temperature for 16 hou~s. The mixture was diluted with 300 ml of water and acidified to pH 6.8 with 6N hydrochloric acid solution.
The precipitate was collected by filtration, washed in succession with water and acetone and air dried for about 1.5 hr. Weight o~
solid was 13.41 g (98%), m.p. 272C (d).
7 ~7 Analysis: Calculated for C18H16N203: C, 70.12; H, 5.23; N, 9.09 Found ~I C, 70.10; H, 5.27; N, 9.09 Example 73 8-Methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylic Acid Hydrochloride.
A portion of the 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylic acid, 4.35 g from Example 72 was triturated with 100 ml hot absolute ethanol. After cooling, the solid was collected by filtration and air dried to give 3.87 g. The solid was suspended in 25 ml of absolute ethanol and excess ethereal hydrogen chloride solution added. A clear solution was obtained.
Addition of isopropyl ether produced a yellow precipitate ~hich was collected and recrystallized from absolute ethanol-isopropyl ether to yield 3.14 g solid m.p. 257C. (d).
Analysis: Calculated for C18H17N203Cl: C, 62.70; H, 4.97, N, 8.12 Found : C, 62.53, H, 4.93; N, 8.18 Examples 74-80 74. Ethyl 8-methyl-4-[(2-methylphenyl)amino]-3-quinoline-carboxylate monohydrochloride from Preparation 7 and o-toluidine.
75. Ethyl 8-methoxy-4-[[2-(1-methylethyl)phenyI]amino-3-quinolinecarboxylate from Pr~paration 1 and o-isopropylaniline.
76. Ethyl 8-chloro-4-[(2-methylphenyl)amino]-3-quinoline-carboxylate from Preparation 10 and o-toluidine.
77. Ethyl [(2-chloro-6-methylphenyl)amino]-8-methoxy-3-quinolinecarboxylate monohydrochloride from Preparation 1 and 2-chloro-6-methylaniline.
78. Ethyl 8-methoxy-4-[(2,3-dimethylphenyl)amino]-3-7~
quinolinecarboxylate monosulfa~e from Preparation 1 and 2,3-dimethylaniline.
79. Ethyl 8-methoxy-4-[(2-nitrophenyl)amino]-3-quinolinecarboxylate from Preparation 1 and 2-nitroaniline.
80. Ethyl 8-methoxy-4-[(2-nitrophenyl)amino]-3-quinolinecarboxylate, ethylsulfate (1:1), ethanol (1:1) from Example 79 and concentrated sulfuric acid in absolute ethanol.
Example 81 l-Me-t_ylethyl 8-Methoxy-4--[(2 methylphenyl)amino]-3-quinolinecarboxylate, Monohydrochloride, Monohydrate.
To 150 ml oE dry 2-propanol was added 2 sodium pellets followed by 5.38 g (15.99 mmoles) of ethyl 8-methoxy-4-[(2-methyl-phenyl)amino]-3-quinolinecarboxylate dissolved in 50 ml of dry 2-propanol. The solution was stirred and refluxed with exclusion of moisture for 6 hrs. during which time 120 ml of distillate was collected in a Dean-Starke trap and discarded. The solvent was evaporated and the residue was dissolved in 50 ml of 2.9 M hydro-chloric acid and 100 ml of water added thereto. The solution was adjusted to a pH of 8 with 1 M aqueous sodium bicarbonate and the oil which separated was extracted three times with 100 ml of methylene chloride. The combined extracts were dried over magnesium sulfate. The solvent was evaporated to give 4.60 g (82~) of the free base of the titled compound having a m.p. of 120-122C. after recrystallization from acetone-hexane.
The free base was dissolved in isopropyl ether and ethereal hydrogen chloride added thereto. The solvent was evaporated and the residue recrystallized from methylene chloride-7~
acetone to obtain the titled compound as a yellow crys-talline solid having a m.p. of 140-143C.
Example 82 3 Methoxyethyl-8-methoxy-4-[(2-methylphenyl)amino]~
3-quinolinecarboxylate.
-Following the procedure of Example 81, the compound ofExample 3 was trans-esterified with 2-methoxyethanol to give the titled compound.
Example 83 3-Dimethylamino ethyl 8-Methoxy-4 [(2-methylpheny1) amino]-3-quinolinecarboxylate.
Following a procedure similar to that given in Example 81, the compound of Example 3 was trans-es-terified with 2-dimethylamino-ethanol substitu-ting sodium ethoxide catalyst and -toluene solvent to give the titled compound.
Example 84 3-Dimethylamino prop~l 8-Methoxy-4-~(2-methylphenyl) aminol-3-~uinolinecarboxylate.
Following a procedure similar to that given in Example 81, the compound of Example 3 was trans-esterified with 3-dimethylamino-l-propanol substituting toluene solvent to give the titled compound.
Example 85 2-Dime-thylamino ethyl 8-Methoxy-4-[(2-methylphenyl) amino]-3-quinolinecarboxylate, Fumarate (1:1.5).
The titled compound was prepared from the compound of Example 83 and fumaric acid.
75~
Example_86 3-Dimethylamino propyl 8-Methoxy-4-[(2-methylphenyl) amino]-3~quinolinecarboxylate, Dihydrochloride, Monohydrate.
. . ~
The titled compound was prepared from the compound of Example 84 and ethereal hydrogen ch]oride.
Example 87 Ethyl 8-Methoxy-4-~(2-methylphenyl)amino]-3-quinoline~
carboxylate, ethanesulfonate (l:l)(salt).
The titled compound was prepared from the compound of Example 3 and ethanesulfonic acid in absolute ethanol.
Example 88 Ethyl 8-Methoxy-4-[(2-methylphenyl)amino]-3-quinoline-carboxylate, 2-~Iydroxye-thanesulfonate (l:l)(salt).
The titled compound was prepared from the compound of Example 3 and 2-hydroxyethylsulfonic ac:id in absolute ethanol.
Example 89 All~l 8-Methoxy-4-[(2-me-thylphenyl)amino]-3-q_inoline-carboxylate.
Following a procedure similar to Example 81, substituting allyl alcohol for 2-propanol, the titled compound is prepared.
7~
Table (Examples 1-88) (Rl)n _ ~ ~ 2 3 ample Rl R2 R3 Salt M.P., C.
.
1 8-CH30- 2-CH3-C6H4- c~2H5 HCl 191-193.5 3 8-CH30- 2-CH3-C6H ~ 2 5 138.5-140 6 8-CH30- C6H5- C2H5- HCl 165.5-168 7 8-CH30- 2-CH30-C6H4- C2H5- HCl 204-207 8 8-CH30- 2-CH3S-C6H - C2H5- HCl 275-278 9 8-CH30- 2-Cl-C H - C2H5- HCl 193-194.5 8-CH30- 2-C~-C H - C2H5- HCl 204-206.5 11 8-CH30- 2-CF -C H C2H5- HCl 199-201d 12 8-CH30- 2-NH2oc-c6H4-C2H5- 1 HCl- 251-154 13 8-CH30- 2-F-C6H4- C2H5- HCl 204 206 14 8-CH30- 2-CH3C0-C6H4-C2~-I - HCl 203-204d 8-CH30~ CH3(-CH2)3- C2H5- HC1 171-172d 16 8-CH30- CH3C6H4 C2H5- HCl.H20 156-158d 17 8-CH30- 4-CH3C6H4- C2H5- HCl.H20 155-156d 18 8-CH30- 2~CH3~C6H4CH2 C2H5 132-137 7~
Table 1 (cont) Ex- R R R Salt M.P., C.
ample 1 2 3 19 8-CH30- 2,6(CH3)2C6H3-C2~15 160-163 8-CH30- 2,6~CH3)2C6H3-C2H5- HBr 182-184 21 8-CH30 C6H5(CH3)CH-C2H5- H20 97-99 22 8-CH30- 2-cl-5-cH3o~c6H3-C2H5- HBr 160-162 23 8-CH30- 3-CH3S-C6H4- C2H5 123-124.5 24 8-CH30- C6H5CH2- C2H5- H3P04. 221-223 8-CH30- 2,4(CH30)2-C6H3- C2H5 128-131 26 8-CH30- 2-C2H50-C6H4-C2H5- HCl 20~d 8-CH30- 2-C2H5-C6H4- C2H5- H2S04 177-178.5 31 8-CH30- 2,6-Cl-C6H3- 2 5 178-180 32 8-CH30- 2-CH3-5-No2-C6H3-C2H5 251.5-253 33 8-CH30- 2-CH3-C6H4CH2-C2H5- ~C2II50H
8-C2H50 2-CF3-C6H4- C2H5- HBr 185-19ld 36 8 C2H5 2-CH30-C6H4- C2H5- HCl 205-206.5 37 8-C2H50- 2-CH3S-C H ~C2H5- H3P04 185-190 38 5,8(CH30)2 C6H5 C2H5- HCl.~H20 166-167 39 5,8(CH30)2- 2-CH3 C6H4C2H5 156-158d 7-CH30- 2-CH3-C6H4- C2H5- HCl 147-159d 41 b CH 0 C6H5- C2H5 99~5-102.5 (cont.) '71;~7 Table l(cont) Ex- R R R3 Salt M.P., C.
ampl~ 1 2 42 6-CH30- 2-C~13-C6H4- C2H5- HCI, 193d 43 5-cH3-8-cH3o- 2-CH3O C6H4 C2H5- 2HC1 183-185d 44 5-CH3-8-CH3O- 2-CH3S C6 4 C2H5-.5~l3PO4 204 205 5 CH3 8 CH30 2 CH3 C6H4 C2H5- ~ 167.5-169 47 8-CH3S~ 2-CH3-C6H4 C2H5 168-170 48 8-CH3S- 2-CH3O-C6H4- C2H5- HCl 169-172 49 8-CH3S- 2-CH3S-C6H - C2H5- - 140.5-142 8-CH3- 2-CH3S-C6H - C2H5- HCl 172-174d 51 8-CH3- 2-CH3O-C6H4- C2H5- HCl 186-188 52 8-CH3- 2-CH3-C6H4cH2 C2H5- HBr 182-183 53 8-Cl- 2-CH3O-C6H4- C2H5- HCl 203-205d 54 8-CN- 2-CH3-C H4- C2H5- HCl 215-219 56 8 C6H5 2 COOH-C6H4- C2H5-HCl.~H2O 213-214 58 6,8(CH3)2- C6H5- C2H5 164.5-165 59 H- C6H5- C2H5 100-102(a) H- C6H5- C2H5- HC1 193-195d 61 H- C6H5CH2- C2H5- HC1 195.5-196 62 H- 2-CH -C H4- C2H5- HC1 170-171d 63 H- 2-CF3-C6H4- C2H5- HC1 168.5-170 64 H- 2-CH3O-C6H4- C2H5- HCl 172-174.5 H- 2-CH3S-C H4- C2H5- HC1 186-187d 66 H- 2-CH3-4-OCH3- C2H5- HC1 178-179d C6H3- (cont.) Table l(cont) Ex- R R R Sal-t M.P., C.
ample 1 2 3 _ 67 H- 2-Cl-C6H4- C2H5- HC1 204-205d 68 ( 3)2 C6H5 C2H5- HCl 179-181 69 ( 3)2 2-CH -C H4- 2 5 110-114 72 8-CH30- 2-CH3-C H4- H _ 272(d) 73 8-CH30 2-CH -C H4- H HCl 257 74 8-CH3- 2-C~13-C H4- C2H5- HC1 162-164 8-CH30- ( 3)2CH 2 5 136-138 78 8-CH30- 2,3-(CH3)2- C2H5- H2S04 177-181 79 8-CH30- 2-N0 -C H ~ C2H5 180-182 81 8-CH30- 2-CH3-C6H ~ tCH3)2 HCl.H20 140-143 HC-82 8-CH30- 2 CH3-C6H4- CH30 HCl 184-187 (CH2)2 83 8-CH30- 2-CH ~C H4- (CH3)2 100-103 N(CH2)2-84 8-CH30- 2-CH3-C6H4- (CH3)2 N(CH2) - - 95-97 5 7~
Table 1 (cont) _ Ex- R R R Salt M.P., C.
ample 1 2 3 8-CH30- 3 6 4 ( 3)2 N(CH2)2 fumarate 186-189 86 8-CH30~ 3 6 4 ( 3)2 !H20 177-180 ( 2)3 .HCl (a)Compares with m.p. 99-100C. given in J. Pharm~ Chem.
Soc. 1389 (1951).
Tahle 2 Analytical Data on Examples 1~88 Empirical Calculated E'ound Ex. Formula C H N C H N
20 21 lW20364.63 5.68 7.51 64.36 5.65 7.62 2 Cl9H18N23 70.79 5.63 8.69 70.91 5.65 8.77 3 C20H20N2 3 71.41 5.99 8.33 71.52 5.94 8.35 20 22 2 7 55.29 5.]0 6.45 55.68 5.02 6.42 C20H23N27 55.30 5.34 6.45 54.92 5.37 6.53 19 19 2 3 63.60 5.34 7.81 63.25 5.33 7.69 7 20 21 2 4 61.78 5.44 7.20 61.55 5.57 7.07 8 C20H21ClN203S59-33 5.23 6.92 59.04 5.38 6.87 9 ClgH18C12N20358.03 4.61 7.12 57.89 4.69 7.13 20 18 3 3 62.59 4.73 lO.9S 62.23 4.95 10.73 11 C20H18N203F3C1 56.28 4.25 6.56 56.33 4.34 6.60 12 C104H112ClsN15022 59.25 5.21 10.03 13 ClgH18N203FC160.56 4.81 7.43 60.28 4.87 7.32 14 21 21 2 4 62.92 5.28 6.99 62.56 5.48 6.76 17 23 2 3 60.26 6.84 8.26 59.39 6.80 8.20 16 20 23 2 4C 61.46 5.93 7.17 61.40 5.92 7.21 17 20 23 2 4C61.46 5.93 7.17 61.73 5.76 7.33 18 21 22 24 68.84 6.05 7~65 68.61 6.04 7.51 19 21 22 2 3 71.98 6.33 7.99 72.16 6.33 8.01 21 23 2 3 58.48 5.37 6.49 58.48 5.41 6.52 21 21 24 2 4 68.46 6.57 7.60 68.47 6.51 7.59 22 C20H20N204ClBr 51.35 4.31 5.99 51.27 4.30 6.04 (cont'd) ';7~7~
Table 2 (cont'd) An~lytical Data on Ex~mples 1-88 . _ Empirical Calculated Found Ex.Formula C H _ _ _ N
2320 20 2 3 65.20 5.47 7.60 65.18 5.48 7.66 2421 27 2 8 54.08 5.84 6.01 54.32 5.58 6.23 2521 22 2 5 65.96 5.80 7.33 66.06 5.75 7.28 26C21H23N204C1 62.61 5.75 6.95 62.61 5.84 6.94 2721 22N2 4 68.84 6.05 7.65 68.94 6.06 7.68 2821 22N203 71.98 6.33 7.99 72.02 6.29 8.03 2gC21H28N2011P2 46.16 5.17 5.13 46.07 5.22 5.12 21 24 27 56.24 5.39 6.25 56.09 5.43 6.24 31ClgH16N203C12 58.33 4.12 7.16 58.52 4.13 7.21 3220 19 3 5 62.99 5.02 11.02 63.02 5.08 11.03 33C44H52N47C 2 64.46 6.39 6.83 64.09 6.22 6.96 21 23 2 3 65.20 5.99 7.24 65.25 6.01 7.26 21 20 2 3 3 51.97 4.15 5.77 52.22 4.14 5.89 36C21H23N204C1 62.61 5.75 6.95 62.67 5.76 7.05 21 25 2 7 52.50 5.75 5.83 52.08 5.35 5.77 38C20H21ClN24 60.37 5.57 7.04 60.22 5.55 7.05 3921 22 2 4 68.84 6.05 7.67 69.19 6.09 7.70 20 21 2 3C1 64.43 5.68 7~51 64.71 5.76 7.54 4119 18 2 3 70.79 5.63 8.69 70.96 5.66 8.62 4220 21 2 3C1 64.43 5.68 7.51 64040 9.67 7.62 43C21H24N204C12 57.41 5.50 6.38 57.02 5.79 6.25 44C42H53N4018S2 3 47.64 5.04 5.29 48.06 5.08 5.43 (cont'd) Table 2 (cont'd) An~lytical Data on Examples 1-88 _ Empirical Calculated Found Ex. Formula _ _ N _ _ N
C21H22N2 3 71.98 6.33 7.9972.326.35 8.02 46 20 17 3 2 264.17 4.58 7.4864.164.62 7.49 20 20 2 2 68.16 5.72 7.9568.195.76 8.14 48 C20H21ClN203S59.335.23 6.9259.555.32 6.86 49 C20H20N22 2 62.47 5.24 7.2962.165.16 7.12 20 21 2 2 61.77 5.44 7.2061.845.41 7.31 51 20 2lClN20364.73 5.68 7.5164.475.61 7.50 52 C21H23BrN20260.73 5.58 6.9360.765.60 6.82 19 18 23Cl258.03 4.61 7.1257.974.65 7.11 54 C20H17N3 2 72.49 5.17 12.68 72.16 5.26 12.54 C24H20N22 78.24 5.47 7.6078.225.47 7.50 56 C50H44C12N40965.574.84 6.1166.045.00 6.09 5? 25 23N22 78.32 6.05 7.3178.52S.90 7.30 58 20 20 2 2 74.98 6.71 8.7475.226.37 8.77 59 C18Hl6N22 73.96 5.52 9.5874.125.64 9.42 18 17 2 2 65.75 5.21 8.5265.855.29 8.56 61 19 l9 N2 2 66.56 5.59 8.1766.805.61 8.12 62 ClgHlgN202C166.57 5.59 8.1766.805.70 8.19 63 19 16 2 2 357.51 4.06 7.0657.854.08 7.13 64 ClgHlgClN20363.60 5.34 7.8163.675.30 7.78 ClgHlgN202SCl60.875.11 7.4760.975.30 7.39 66 C20H2lN203C164.43 5.68 7.5164.145.70 7.52 67 C18Hl6N202Cl259.524.44 7.7159.264.42 7.67 (cont'd) 7~''7 Table 2 (cont'd) Analyt_ al Data on Examples 1- 88 Empirical Calculated ~ound Ex. Formula C H N C H N
.
68 C20H22N302C1 64~60 5~96 11~30 64~60 5~96 11~39 69 21 23N32 72~18 6~63 12~03 72~24 6~57 12~09 70 Cl9H15N32 71 ~ 91 4 ~ 76 13 ~ 24 71 ~ 95 4 ~ 86 13 ~ 26 7119 18 2 4 67~45 5~36 8~78 67~495~38 8~50 7218 16 2 3 70~12 5~23 9~09 70~105~27 9~09 18 17 2 3C~ 62~70 4~97 8~12 62~534~93 8~18 7420 21 N2 2 67~32 5~93 7~85 67~225~92 7~83 75C22H24N23 72~51 6~64 7~69 72~566~55 7~67 7619 17 2 2 66~90 5~03 8~22 66~605~14 8~20 77C20H20N203C12 58~98 4~95 6~88 58~904~94 6~90 7821 24N207S 56~24 5~39 6~25 56~375~42 6~28 79ClgH17N305 62~12 4~66 11~44 62~05 4~66 11~54 8023 29 3 10 51 ~ 20 5 ~ 42 7 ~ 79 51 ~ 20 5 ~ 36 8 ~ 01 8121 25 24 62~30 6~22 6~92 62~49 6~23 6~94 8221 23ClN204 62~61 5~75 6~95 62~72 5~76 7~04 8322 25 33 69~64 6~64 11~07 69~73 6~64 11~07 8423 27 3 3 70~21 6~92 10~68 70~42 6~95 10~67 8528 31 3 9 60~75 5~64 7~59 60~89So69 7~53 86C23H31C12N304 57~03 6~45 8~67 57~056~31 8~79 8722 26 2 6 59~18 5~87 6~27 59~165~93 6~25 8822 26 2 7S 57~13 5~67 6~06 57~085~71 6~10 ~ 30 ~
~ t~ 7 Pharmacology The action of 4-amino-3-quinolinecarboxylic acids and esters of this invention on gastric secretion was studied in rats and dogs. Inhibition of secretion was measured and expressed in terms of percent of gastric acid output. Anti-ulcer studies were also done in rats. The results of studies with a preferred com-pound of this invention are described below. Other compounds of this invention show qualitatively similar effects in one or more of these tests.
Table 3 Effect of Compound of Example 1 on Stimulated Gastric Secretion .. . . . _ . _ _ Dose Stimulating Inhibition Species(~Jmoles/kg) RouteAgen* (~) Rat 0.3 - 8.1 IVHistamine 43 - 96 Rat 0.3 - 10.7 IDHistamine 40 - 70 Rat 0.3 - 8.1 IVTetragastrin 27 - 85 Rat 0.9 - 8.1 IVMethacholine 25 - 76 Dog 2~7 and 8.1 IVFood 50 and 83 Dog 32.4 POFood 56 l Inhibition was measured as output of gastric acid.
2 Rats were studied according to a modification of the method of Ghosh and Shield, 1958, BritO J. Pharmacol. 13:54-61.
3 Dogs were Heidenhain pouch dogs.
The compound of Example 1 was administered to pyloric-ligated rats having no artificial stimulation of gastric secretion. The doses ~ 3 ~
used were 33 to 134 ~moles/kg; acid output was inhibited by 38-55%.
The gastric anti-ulcer effects of the compound of Example 1 were examined in rats studied according to the method of Shay et al., 1945, Gastroenterology 5:43-61. Protection against ulceration of 4-90~ was provided by doses of 12-198 ~moles/kg.
Effective quantities of the foregoing compounds repre-sented by Formula I may be administered to a living animal body for therapeutic purposes relating to the control of acid release due to histamine stimulation and peptic ulcer control or combat-ting peptic ulcers in rnammals according to usual modes of adminis-tration for pharmaceuticals in usual forms such as orally in solution, emulsions, suspensions, pills, tablets, troches, lozenges, pellets, capsules and the like in pharmaceutically acceptable carriers; parenterally in the form of sterile solutions or mix-tures.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, a~ar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, arachis oil, water or any parenterally acceptable liquid.
Although very small quantities of the active materials of the present invention are effective when minor therapy for gas-tric irritation is involved or in cases of administration to sub-jects having a low body weight, unit dosages will usually contain the active ingredient in an amount to supply 2 to 6 mg/kg to the ~.t~
host. Unit dosages may vary Erom 100 to 500 mg active agent, pre-ferably for an adult human from 200 to 500 mg. The active ingre-dient will preEerably be administered in equal doses one to four times per day. The daily dosage regimen will vary from about 100 to about 1200 mg, most pre~erably from about 300 to 900 mg/day.
It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. The exact individual dosages as well as daily dosages will, o~ course, be determined according to standard medical pr:inciples under the direction of a physician or veterinarian.
The following formulations are representative:
1. Capsules Ingredients Amount, mg.
Active ingredient, 200 e.g., Example 2 = Ethyl 8-methoxy-4-(phenyl) amino-3-quinolinecarboxylate Sucrose 100 Starch 30 Talc 5 Stearic Acid 3 slend and fill into gelatin capsulesO
2. Tablets Amount mg.
Ingredients per tablet Active ingredient 350.0 e.g., Example 2 = Ethyl 8-methoxy-4-(phenyl) amino-3-quinol.inecarboxylate 180.0 Alginic acid 20.0 Calcium and ammoniwm alginate 40.0 Starch 54.0 ~actose 75.0 Magnesium stearate 2.2 721.2 '7~7 The mixture, all except the magnesium stearate and one half of the calcium ammonium alginate, is blended and granulated with ethanol and passed through a number eight mesh screen and the mixture dried 16 hours at 140F. The dried granulated material is then blended thoroughly with the remainder of the calcium ammonium alginate and magnesium stearate and tableted.
3. Intravenous Injection Ingredients Amounts,~
Active ingredient 200 e.g., Example 2 = Ethyl 8-methoxy-4-(phenyl) amino-3-quinolinecarboxylate Water 2,000 Preservative, e.g., chlorobutanol 20 Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, com-positions and methods of the present invention without departing from the spirit and scope thereof, and it is therefore understood that the invention is to be limited only by the scope of the appended claims.
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Pharmaceutical compositions for inhibiting secretion of gastric acid or treating peptic ulcer in mammals which comprises a pharmaceutical carrier and an effective amount of a compound hav-ing the formula or a pharmaceutically acceptable salt thereof wherein R is hydro-gen or methoxy, R1 is hydrogen, chlorine or methoxy and R3 is hydrogen or ethyl, provided that R and R1 are not both hydrogen.
2. A composition according to claim 1 in which R1 is meth-oxy, R is hydrogen and R3 is ethyl.
3. A composition according to claim 1 in which R is methoxy, R1 is hydrogen and R3 is ethyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000416431A CA1161757A (en) | 1979-03-26 | 1982-11-25 | 4-amino-3-quinolinecarboxylic acids and esters- antisecretory, anti-ulcer compounds |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2398179A | 1979-03-26 | 1979-03-26 | |
| US127,153 | 1980-03-04 | ||
| US06/127,153 US4343804A (en) | 1979-03-26 | 1980-03-04 | 4-Amino-3-quinolinecarboxylic acids and esters-antisecretory anti-ulcer compounds |
| CA000348417A CA1147338A (en) | 1979-03-26 | 1980-03-26 | 4-amino-3-quinolinecarboxylic acids and esters-antisecretory, anti-ulcer compounds |
| CA000416431A CA1161757A (en) | 1979-03-26 | 1982-11-25 | 4-amino-3-quinolinecarboxylic acids and esters- antisecretory, anti-ulcer compounds |
| US023,981 | 1993-02-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1161757A true CA1161757A (en) | 1984-02-07 |
Family
ID=27426227
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000416431A Expired CA1161757A (en) | 1979-03-26 | 1982-11-25 | 4-amino-3-quinolinecarboxylic acids and esters- antisecretory, anti-ulcer compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1161757A (en) |
-
1982
- 1982-11-25 CA CA000416431A patent/CA1161757A/en not_active Expired
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