Note: Descriptions are shown in the official language in which they were submitted.
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.
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
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
NHR2
(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
-- 2
'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
II R2NH2
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
OH C1
( 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:
2 5 2
( ~)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,
-- 10 --
'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
-- 11 --
~ 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.
- 12 -
737
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.
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-
- 13 -
7~
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.
- 14 -
~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.
15 -
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.
- 16 -
-~,
,
~ 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-
- 18 -
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-
-- 19 --
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.
- 20 -
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)
NHR2
(Rl)n _ ~ ~ 2 3
ample Rl R2 R3 Salt M.P., C.
.
1 8-CH30- 2-CH3-C6H4- c~2H5 HCl 191-193.5
2 8-CH30- C6H5- 2 5 L20-121
3 8-CH30- 2-CH3-C6H ~ 2 5 138.5-140
4 8-CH30- 2-CH3-C6H4- C2H5- H2S04 192-194
8-CH30- 2 CH3C6H4 C2H5- H3P04 99-102
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
O 4C2H50H
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
- 22 -
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
CH30H
8-CH30- 2,4(CH30)2-C6H3- C2H5 128-131
26 8-CH30- 2-C2H50-C6H4-C2H5- HCl 20~d
27 8-CH30- 2-CH3-4-CH30-C6H3-2H5 175-176
28 8-CH30- 2-C2H5-C H4- 2 5 152-153
29 8-CH30- 2-C2H5-C H - C2H5- 2H3P04 140 142
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
34 8-C2H50- 2 CH3-C H4- C2H5- HCL 208-209
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.)
- 23 -
'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
46 8-CF3- 2-CH3-C6H4- C2H5 147-148
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
8-C6H5- C6H5- C2H5 - 123-125
56 8 C6H5 2 COOH-C6H4- C2H5-HCl.~H2O 213-214
57 8-C6H5- 6H5CH2 C2 5 130-131
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.)
- 24 -
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
8-CN C6H5- 2 5 194-196
71 8-CH30- 2-OH-C6H4- C2 5 229-231
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
C6H4-
76 8-C1 2-CH -C H4- 2 5 189-191
77 8-CH30- 2-CH3-C H4- C2H5- HC1 207-209
78 8-CH30- 2,3-(CH3)2- C2H5- H2S04 177-181
C6H3-
79 8-CH30- 2-N0 -C H ~ C2H5 180-182
8-CH30- 2-N0 -C H - C2H5- C2H50H 85-90
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
- 25 -
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
87 8-CH30- 3 6 4 C2H5- CH3CH2- 113-116
SO 20H
88 8-CH30- 2-CH -C H C2H5- HO-CH2 142-145
CH2S020H
(a)Compares with m.p. 99-100C. given in J. Pharm~ Chem.
Soc. 1389 (1951).
- 26 -
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)
- 27 -
';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)
- 28 -
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)
- 29 -
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
- 32 -
~.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
338
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.
- 34 -
