CA1128063A

CA1128063A - Anilinotropone derivatives

Info

Publication number: CA1128063A
Application number: CA324,928A
Authority: CA
Inventors: Takehiro Amano; Kensei Yoshikawa; Jiro Sawada; Michitada Sasajima
Original assignee: Taisho Pharmaceutical Co Ltd
Current assignee: Taisho Pharmaceutical Co Ltd
Priority date: 1979-04-05
Filing date: 1979-04-05
Publication date: 1982-07-20

Abstract

ABSTRACT OF THE DISCLOSURE
Anilinotropone derivatives represented by the following formula:

Description

~2~6~

Among the known anilinotropone derivatives, only 2-(p-aminoalkoxy) anilinotropones are known to have coronary vasodilating and anti-hypertensive - activity as described in Chem. Pharm. Bull 22,514 (1974).
. _ The present invention relates to anilinotropone derivatives repre-sented by the following general formula:

~ N~ ~ C~COO~

wherein R is hydrogen or methyl and the pharmaceutically acceptable salts thereof.
It has been discovered that the novel compounds of the present invention have excellent anti-inflammatory and analgesic activity and low gastrointestinal action which known anti-inflammatory agents have in proportion to their anti-inflammatory activity.
Accordingly, it is an object of the present invention to provide these novel compounds valuable as medicines possessing excellent anti-inflamma-tory and analgesic activity and reduced gastrointestinal action.
The anilinotropone derivatives of the present invention represented by the general formula (I) may be prepared by reacting a tropone derivative represented by the following general formula:

:
~ X
~ (II) ,:

.

~Z8~6~

wherein X is a halogen atom such as fluorine, chlorine or bromine, a sulfonyl-oxy group such as a tosyloxy group, or an alkoxy group such as methoxy with an aniline derivative represented by the following general formula:

2N ~ CH y (III) wherein R is hydrogen or methyl and Y is a carboxyl group or a group that can be converted to carboxyl group, such as an ester or nitrile group and subjecting the reaction product to hydrolysis or the like when Y is not a carboxyl group.
In practicing the above reaction, a basic condensing agent such as potassium carbonate, sodium acetate or triethylamine may be used and, in order that the reaction proceed easily, an iodide such as sodium iodide or potassium iodide or Ullmann catalyst such as activated copper or copper sulfate may also be used. As the reaction solvent, there may be used an organic solvent such as benzene, ethanol, tert-butyl alcohol, tetrahydrofuran, acetone, dimethylsulfoxide or N,N-dimethylformamide. It is preferred that the reaction be carried out at room temperature or at a refluxing temperature.
The pharmaceutically acceptable salts of the compounds of the formula (I) include, but are not limited to, the corr~sponding alkali metal salts such as sodium and potassium salts, alkaline earth metal salts, such as barium and calci~n salts, and unsubstituted and substituted annmonium salts.
A compound of the formula (I) may be converted into a desired salt by treating with alkali metal base, alkaline earth me~al base, or unsubstituted or substituted ammonium base in a known manner.

,:

llZ~

The compounds of the present invention may be used as anti-inflammatory, analgesic and anti-pyretic agents in mammals. For these purposes, a compound of the present invention may be administered orally in a conventional dosage form such as tablet> capsule or powder prepared accord-ing to conventional pharmaceutical practice. A single dose, or preferably

2 to 4 divided daily doses, provided on a basis of about 2 to 40 mg/kg/day, is appropriate.
The compounds of the present invention have extremely low toxicity.
The minimum lethal dose in mice or rats is in excess of 1000 mg/kg of the body weight.
Experiments made on pharmeceutical properties of the compounds of the present invention and on a prior art compound (phenylbutazone) are summarized below. In these experiments, "Cpd. 1", "Cpd. 2" and "Cpd. 3"
refer to 2-[p-~2-troponylamino)-phenyl~propionic acid, 2-[m-(2-troponylamino) phenyl] propionic acid and phenylbutazone, respectively.
Experiment 1: Anti-inflammatory activity Anti-inflammatory activity was evaluated by the method of rat paw edema (Winter et al, J. Pharmacol. Exp. Ther., 141, 369 ~1963)). Six male Wistar strain rats were used in each group and the volume of each paw was measured four hours after injection of carrageenin. The results are shown in Tables 1 and 2.

. '~--`

~Z~63 Table 1 _ _ . . . _ .
Dose (mg/kg, p.o.) Inhibition (%) Cpd. 1 25 56,8 Cpd. 1 50 50-9 Cpd. 1 100 61.0 Cpd. 3 25 22.4 Cpd. 3 50 34,7 Cpd. 3 100 54.5 Table 2 .
Dose (mg/kg, p.o.) Inhibition (%) . _ .
Cpd. 2 100 43.0 Cpd. 2-Ca salt 100 43.2 Cpd. 3 100 32.5 Experiment 2: Analgesic activity Male Wistar strain rats in groups of six each were used for the evalua-tion of analgesic activity by the method of Randall-Selitto (Arch. Intern.
i Pharmacodyn., 111, 409 (1957)) with slight modification. In a graph where the load was plotted on the ordi~late and the time was plotted an the absicissa, the cul~e obtained when Cpd. 1 was orally administered in a dose of 25 mg/kg was sub-stantially in agreement with the curve obtained when Cpd. 3 was orally admin-istered in a dose of 100 m~/kg. Similar results were obtained when Cpd. 1 was administered in a dose of 50 mg/kg and the Cpd. 3 was administered in a dose of 200 mg/kg.

Experiment 3: Analgesic activity Male ddY strain mice in groups of ten each were used for evaluation of analgesic activity by the acetic acid writhing test (Koster et al, Federation Proc., 18, 412 (1959). The results are shown in Tables 3 and 4.
Table 3 Dose (mg/kg, p.o.) Inhibition (~) Cpd. 1 100 54.8 Cpd. 3 200 18.5 .
Table 4 Dose (mg/kg, p.o.) Inhibition (%) .
Cpd. 2 100 31.2 Cpd. 2-Ca salt 100 31.2 Cpd. 3 100 10.7 ~ _ .
Experiment 4: Gastric uloe rogenicity Immediately after the completion of the test described in Experiment 1, the test compound was orally administered to the test rats in a dose twice the dose administered in E~periment 1, and fasting was continued for 18 hours prior to autopsy and evaluation of gastric lesions. The gastric lesions induced was expressed as incidence (number of rats with gastric lesions/number of the test rats) and lesion index (sum of areas damaged). The results are shown in Tables 5 and 6.

-.:

~2~3~63 Table 5 .
Dose ~mg/kg, p.o.) Incidence Lesion index (mm2) Cpd. 1 25 + 50 0/6 0 Cpd. 1 50 ~ 100 1/60.02 ~ 0.017 Cpd. 1 100 + 200 4/60.52 + 0.17 Cpd. 3 25 + 50 3/60.02 + 0.014 Cpd. 3 50 + 100 6/61.43 + 0.43 Cpd. 3 100 + 200 6/66.82 + 1.40 Table 6 Dose (mg/kg, p.o.) Incidence Lesion index (mm ) . _ . . . _ _ . . .
Cpd. 2 100 + 200 0/6 0 Cpd. 2-Ca salt100 + 200 2/60.12 + 0.10 Cpd. 3 100 + 200 6/67.70 + 3.23 .. ... . . . .
The following examples are illustrative of the present invention and are not intended in any way to limit the invelttion, the scope of which is defined by the appended claims.
Example 1 A mixture of 8.3 g of 2-tosyltropone, 4.5 g of p-aminophenylacetic acid and 9 ml of triethylamine in 200 ml of tert-butylalcohol was refluxed for 24 hours. The mixture was concentrated and acidified with 2 N hydro-chloric acid, followed by extraction with dichloromethane. The dichloro-methane solution was extracted with a saturated sodium bicarbonate aqueous solution. The aqueous layer was acidified and extracted with dichloromethane.

,: ~ :-~2~

The dichloromethane solution was washed with water and dried over anhydrous magnesium sulfate and evaporated to give a yellow crystalline solid, which was recrystallized from ethanol to yield 4.6 g of p-(2-troponylaJnino) phenylacetic acid; m.p. 175 - 176C; Analysis -- Calculated for C15H13N03:
C 70.5~ %, H 5.13 %, N 5.49 %; Found: C 70.34 %, H 5.30 %, N 5.55 %.
Example 2 A mixture of 2.8 g of 2-chlorotropone, 3.3 g of 2-(p-aminophenyl) propionic acid, 4.9 g of sodium acetate, and 0.20 g of sodium iodide in 100 ml of N,N-dimethylformamide was stirred at 80 - 90 C for 8 hours. The mixture was cooled and acidified with 2 N hydrochloric acid, followed by extraction with dichloromethane. The dichloromethane solution was extracted with a saturated aqueous sodium bicarbonate solution. The aqueous layer was acidified and extracted with dichloromethane. The dichloromethane solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to give a yellow crystalline solid, which was recrystallized from ethanol to yield 3.8 g of 2-[p-(2-troponylamino)phenyl] propionic acid; m.p. 185 - 186 C, Analysis --- Calculated for C16H15NO3: C 71.36 %, H 5.61 %, N 5.20 %, Found: C 71.20 %, H 5.60 %, N 5.27 %.
Example 3 A mixture of 2.8 g of 2-chlorotropone, 3.3 g of 2-(m-aminophenyl) acetic acid, 4.9 8 Of sodium acetate and 0.20 ~ of potassium iodide in 50 mQ
of N,N-dimethylformamide was stirred at 80 - 90 C for 8 hours. The mixture was concentrated and acidified with 6 N hydrochloric acid, followed by extraction with dichloromethane. The dichloromethane solution was extracted with a saturated aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH 4 - 5 with 6 N hydrochloric acid and extracted with dichloro-methane. The extract was washed with water, dried over anhydrous magnesium ~Z~53 sulfate and evaporated to give a yellow oil, which was chromatographed on silicagel with chloroform and crystallize from benzene to give 3.0 g of m-(2-troponyl-amino)phenylacetic acid; m.p. 97 - 98 &; Analysis --- Calculated for C15H13NO3:
C 70.58 %, H 5.13 %, N 5.49 %, Found: C 70.36 %, H 5.20 %, N 5.54 %.
Example 4 To a mixture of 4.6 g of 2-(4-chloro-3-nitrophenyl)propionic acid and 250 mg of 10 ~ palladiumron-charcoal in 50 ml of ethanol, was added dropwise 2.5 g of hydrazine hydrate under a stream of nitrogen. After the completion of the addition, the mLxture was stirred at room te~lperature for one hour and thenrefluxed for 6 hours. The resulting mixture was cooled to room temperature, mixed with 250 mg of 10 % palladium-on-charcoal and 2.5 g of hydrazine hydrate, and refluxed for 6 hours. After filtration, the filtrate was evaporated and dis-solved in 20 ml of water. The aqueous solution was adjusted to pH 5 - 6 with 6 N hydrochloric acid and then concentrated to a volume of 20 ml. On standing ove might at room temperature, 3.0 g of 2-(mraminophenyl)propionic acid was ob-tained; m.p. 98 - loo&; Analysis - - Calculated for CgHllNO2: C 65.43 %, H 6.71 %, N 8.48 %; Found: C 65.41 %, H 6.72 %, N 8.48 %.
A mixture of 7.03 g of 2-chlorotropone, 8.3 g of 2-(m-aminophenyl) propionic acid, 12.3 g of sodium acetate and 0.83 g of sodium iodide in 150 ml of N,N-dimethylformamide was stirred at 90 - 100 C for 6 hours, follcwed by the procedure exemplified in Example 3 to give 8.7 g of 2-[m-(2-troponylamino) phenyl]-propionic acid as a yellow oil; Analysis --- Calculated for C16H15N03:
C 71.36 ~, H 5.61 %, N 5.20 %; Found: C 71.27 %, H 5.60 %, N 5.26 %.
To a solution of 10.0 g of 2-[m-(2-troponylamino)phenyl]-propionic acid in 30 ml of dichloromethane, was added 30 ml of water. The mixture was -~ , ` .

adjusted to pll 7.0 with 0.01 N sodium hydroxide solution. The aqueous layer which separated was collected, and 2.22 g of calcium chloride in 10 ml of water was added dropwise with stirring to form a yellow precipitate. The precipitate was collected on a filter, washed with cold water and dried ~o give 10.2 g of calcium 2-[m-(2-troponylamino)-phenyl]propionate.
Recrystallization from aqueous ethanol gave a yellow powder which decomposed at 240 - 242 C.

_g_ . ;
'

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the preparation of anilinotropone compounds of formula I, and their pharmaceutically acceptable salt I

wherein R represents hydrogen or a methyl group, which process comprises reacting a tropone derivative of formula II

II

wherein X represents halogen, a sulfonyloxy group or an alkoxy group, with a substituted aniline of formula III

III

wherein R is as defined above and Y represents a carboxyl group or a group that can be converted into a carboxyl group by hydrolysis, in the presence of a base, and, if desired converting the thus obtained compound into a pharma-ceutically acceptable salt.

2. Compounds of anilinotropone derivatives of formula 1, as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. Process according to claim 1 wherein the group -CHRCO2H and the -NH-group are in a meta or para positional relationship.

4. Process according to claim 1 wherein X is chosen from the group comprising chlorine, fluorine, bromine, a sulfonyloxy group, and an alkoxy group.

5. Process according to claim 1 wherein Y is chosen from the group comprising a carboxyl group, an esterified carboxyl group, and a nitrile group.

6. Process for the preparation of p-(2-troponylamino)-phenylacetic acid which comprises reacting together 2-tosyltropone and p-iminophenylacetic acid in the presence of triethylamine.

7. p-(2-Troponylamino)-phenylacetic acid whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

8. Process for the preparation of 2-[p-(2-troponylamino)phenyl]-prop-ionic acid which comprises reacting together 2-chlorotropone and 2-(p-amino-phenyl)-propionic acid in the presence of sodium acetate and sodium iodide.

9. 2-[p-(2-Troponylamino)-phenyl]propionic acid, whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

10. Process for the preparation of 2-[m-(2-troponylamino)phenyl]prop-ionic acid, or the calcium salt thereof, which comprises reacting 2-chloro-tropone and 2-(m-aminophenyl)propionic acid in the presence of sodium acetate and sodium iodide, and, if desired, converting the thus obtained acid into its calcium salt by reaction with calcium chloride.

11. 2-[m-(2-Troponylamino)phenyl] propionic acid or the calcium salt thereof whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.