US3673194A - DERIVATIVES OF 1,4,4a,9b-TETRAHYDRO-8,9b-DIMETHYL-2-PHENYL-1,4-ETHANOBENZOFURO {8 3,2-C{9 PYRIDINE-3(2H), 10-DIONE - Google Patents

Abstract

This disclosure describes derivatives of 1,4,4a,9b-tetrahydro8,9b-dimethyl-2-phenyl-1,4-ethanobenzofuro(3,2-c) -pyridine-3(2H), 10-dione useful as antidepressant, anti-inflammatory, or analgetic agents.

Description

United States Patent Morlock et al.

[ 1 June 27, 1972 Donald Albright; Leon Goldman, both of Nanuet, all of NY.

[73] Assignee: American Cyanamid Company, Stamford,

Conn.

[22] Filed: May 4, 1970 211 AppLNo 34,614

[52] US. Cl ..260/293.55, 260/3265 CA, 424/267 [51 Int. Cl. ..C07d 99/04 [58] Field of Search ..260/293.55

[56] References Cited OTHER PUBLICATIONS Plieninger et al., Ber. 97(3), 667 and 6 73 (1964) Primary Examiner-Hem R. J iles Assistant ExaminerG. Thomas Todd Attorney'Edward A. Conroy, Jr.

57 ABSTRACT This disclosure describes derivatives of l,4,4a,9b-tet rah ydro- 8 ,9b-dimethyl-2-phenyl-l ,4-ethanobenzofuro[ 3 ,2-c pyridine-3(2H),lO-dione useful as antidepressant, anti-inflammatory, or analgetic agents.

9 Claims, No Drawings DlMETHYL-Z-PHENYL-l ,4-ETIMNOBENZOFURO [3,2-

CIPYRIDINE-SQH), lO-DIONE BRIEF SUMMARY OF THE INVENTION This invention relates to novel derivatives of '1,4,4a,-9b.-

I tetrahydro-S ,Qb-dimethyl-Z-phenyll ,4-ethanobenzofuro[ 3,2-

c]-pyridine-3(2I-I),l0-dione and to methods of preparing these compounds. The novel compounds of the present invention may be represented by the following general formulae:

o A -NH-R,

wherein R is phenyl or p-bromophenyl, and R and R are the same and are phenyl or p-bromophenyl. Also included within the purview of the present invention are the 3-pyrr0lidine enamines of the carboxanilides (II) which are useful as intermediates in the preparation of the carboxanilides (II).

DETAILED DESCRIPTION OF THE INVENTION Certain of the novel compounds of the present invention are active analgetics when measured by the writhing syndrome test for analgetic activity as described by Siegmund et al., Proc. Soc. Exptl. Biol. Med, Vol. 9, p. 729 (1957), with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection of l mg./kg. of body weight of phenyl-p-quinone in male Swiss Albino mice weighing 15-25 grams per mouse. This syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs beginning 3 to 5 minutes after injection of the phenyl-pquinone. The test compound is administered orally to groups of two mice each 30 minutes before injection of the phenyl-pquinone. The total number of writhes exhibited by each group of mice is recorded fora 3 minute period commencing minutes after injection of the phenyl-pquinone. A compound is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per air to a value of 18 or less. In a representative operation, the following compounds of the present invention showed analgetic activity when tested by this procedure at the oral doses indicated in the following table:

4a,9b-hexahydro-8 ,9b-climethyl-3 l 0- -dioxol ,4-ethanobenzofuro[3,2-c]- pyridine-l l-carboxanilide 4',4"-dibromo-2-(p-bromophenyl -1,2,3,4,4a,9b-hexahydro-8,9b-dimethyI-B-oxo- I 0-( l-pyrrolidinyl l ,4-ethenobenzofuro[ 3 ,2-c lpyridine- 4,1 l-dicarboxanilide The antidepressant properties of l,4,4a,9b-tetrahydro-8,9bdimethyl-2-phenyll ,4-ethanobenzofuro[3,2-c]pyridine-3 (2H),-l0-dione are evident by measuring its ability to comteract a depression induced in animals by the administration of tetrabenazine hexamate. Graded doses of the compound are administered by intraperitoneal injection to groups of mice, and this is followed by administering intraperitoneally a dose of tetrabenazine which is known to markedly depressthe exploratory behavior of normal mice. The antidepressant treated groups show normal exploratory behavior, while the control groups, and groups treated with an inefiective antidepressant agent, do not show this normal exploratory behavior, but show the well known profound depression induced by tetrabenazine. Theresults from several dose levels are used to establish effective dose ranges. The antidepressant compound of this invention shows its desirable properties by this procedure at dose levels which produce little or no untoward reactions such as ataxia or reduced spontaneous motor activity. In a representative operation, l,4,4a,9b-tetrahydro- 8,9b-dimethyl-2-phenyll ,4-ethanobenzofuro[ 3 ,2-c]pyridine- 3(2I-I), lO-dione showed antidepressant activity when tested by this procedure at a dose of 25 mg./kg. of body weight.

The novel compound 2-(p-bromophenyl)-l,4,4a,9btetrahydro-8,9b-dimethyll ,4-ethanobenzofuro[ 3,2- I c]pyridine-3(2H),l0-dione possesses anti-inflammatory properties as determined by the carrageenin-induced rat paw edema test as follows. In this test weanling Sherman strain rats ranging in weight from 50-55 grants are used and fed standard laboratory diet ad libitum. Thetest compound is administered to the rats by gavage (250 milligrams per kilogram in a volume of 1.7 milliliters of bufi'ered aqueous starch) 1 hour prior to challenge with carrageenin. The challenge agent, carrageenin, is obtained from Marine Colloids, 2 Edison Place, Springfield, New Jersey and prepared as a sterile 1 percent suspension in 0.09 percent aqueous sodium chloride. A volume of 0.05 milliliter is injected using a 26 gauge needle into the plantar tissue of the right hind paw of treated and untreated rats. Measurements of the volumes of the carrageenin inflamed right (challenged) paw and left (unchallenged) paw are determined 4 hours subsequent to the carrageenin challenge. The method of determining paw volumes is carried out essentially as described by C. A. Winter, et al., in Proc. Soc. Exptl. Biol. Med. 1 11: 544-547 (1962) using mercury immersion. The differences in volume of the two paws of each rat is considered to be the volume of the carrageenin induced edema. The mean edema volume of eight control rats divided by the mean edema volume of two treated rats is calculated and designated the C/T efficacy ratio. A compound is considered active in this test if the mean Cfl efficacy ratio of 2 consecutive tests is equal to or greater than 1.43. In a representative operation, the mean Cfl efficacy ratio (four rats) of 2-(p-bromophenyl)- l ,4,4a,9btetrahydro-8,9b-dimethyl-2-phenyl- 1 ,4- ethanobenzofuro[ 3,2 ]-pyridine-3( 2H), 1 O-dione above-described test was 3.48.

When mixed with suitable excipients or diluents, the compounds of this invention can be prepared as pills, capsules, tablets, powders, solutions, suspensions, and the like for unit dosage and to simplify administration.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 Preparation of 1-(4a,9b-dihydro-8,Qb-dimethyl-3- dibenzofuranyl)-pyrrolidine To a suspension of 2.00 g. of 4a, 9b-dihydro-8,9b-dimethyldibenzofuran-3(4I- I)-one in 50 ml. of methanol was added 3.4

in the ml. (2.9 g.) of pyrrolidine and the mixture was heated on a steam bath for 10 minutes. The resulting clear yellow solution was allowed to stand at room temperature for 1 hour. The solvents were removed by evaporation under reduced pressure to yield a yellow syrupy residue which was redissolved in benzene and evaporated to dryness under reduced pressure to yield l-( 4a,9b-dihydro-8 ,9b-dirnethyl-3-dibenzofuranyl )pyrrolidine as a yellow syrup;

CHCI:

max.

6.05 and 6.14 ,i.

EXAMPLE 2 Preparation of l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxo- 2 phcnyll l-pyrrolidinyl)- l ,4-ethenobenzofuro[ 3,2-c

lpyridinel l-carboxanilide and l,4,4a,9btetrahydro-8,9b-dimethyl-2- phenyll ,4-ethanobenzofuro[ 3 ,2-c]pyridine-3( 2H, 1 O-dione To 0.0221 mole of l-(4a,9-dihydro-8,9b-dimethyl-3- dibenzofuranyl)pyrrolidine, prepared as in Example 1, in 100 ml. of dry benzene was added 2.40 ml. of phenyl isocyanate and the solution was allowed to stand at room temperature for 20 hours. The precipitate of 4a,9b-dihydro-8,9b-dimethyl-3- l-pyrrolidinyl)-4-dibenzofurancarboxanilide which had separated was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to yield a yellow gum as residue. The gum was crystallized from ether to give 0.530 g. of crude product which was triturated with benzene and filtered to yield 0.378 g. of l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxo-2-phenyl-10-( l-pyrrolidinyl)- l ,4-ethenobenzofuro[ 3 ,2-c]pyridine-l l-carboxanilide colorless crystals, m.p. 2072 1 5 C.;

5.90, 5.98, 6.08 and 6.27 g. The ethereal mother liquor from above was evaporated to dryness under reduced pressure to yield an orange gum. This was chromatographed on 100 g, of neutral alumina (Activity Ill). Elution with 180 ml. of benzene and evaporation of the eluate yielded 0.890 g. of crude product, m.p. 1'8 3-l90 C. Crystallization from absolute ethanol gave 0.788 g. of 1,4,4a,-9b-tetrahydro-8,Qb-dimethyl- 2-phenyll ,4-ethanobenzofuro[ 3 ,2-c]-pyridine-3( 2H), l 0 dione as colorless crystals, m.p. l92-l94 C.;

5.74 and 5.93 p.

EXAMPLE 3 syrup as residue. Trituration of the syrup with anhydrous ether yielded a tan percipitate which on filtration gave 2.30 g. of crude product. Trituration of the solid with hot benzene and filtration yielded 0.524 g. of 4-bromo-2-(p-bromophenyl)- l ,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxol 0-( l-pyrrolidinyl)- l ,4-ethenobenzofuro[ 3,2-c]pyridine-l l-carboxanilide as colorless crystals, m.p. 224-229 G; A333;

5.92, 6.08, and 6.28 pt. The ethereal mother liquor from above was evaporated to dryness under reduced pressure to yield a dark red syrup as residue. The residue was chromatographed on 100 g. of neutral alumina (Activity Ill). Elution with benzene yielded, on evaporation under reduced pressure of the 150-320 ml. cut of the eluate, a colorless syrup which solidified on trituration with anhydrous ether. Filtration gave 0.365 g. of 2-(p-bromophenyl)-l,4,4a,9b-tetrahydro-8,9b-

dimethyl-l ,4-ethanobenzofuro[ 3,2-c]pyridine-3( 2H), 1 0- dione'as colorless crystals, m.p. l98204 C.;

use:

5.72 and 5.91

EXAMPLE 4.

Preparation of 4',4' '-dibromo-2-(p-bromophenyl)- l,2,3,4,4a,9b-

hexahydro-S,9b-dimethyl-3-oxol 0-( l-pyrrolidinyl)- l ,4- ethanoa benzofuro[3 ,2-c]pyridine-4,l l-dicarboxanilide To 0.0221 mole of l-(4a,9b-dihydro-8,9b-dimethyl-3- dibenzofuranyl)pyrrolidine, prepared as in Example 1, in 100 ml. of dry benzene was added 9.20 g. of p-bromophenyl isocyanate and allowed to stand at room temperature for 18 hours. The resulting suspension was filtered to remove 6.56 g. of crude 4'-bromo-4a,9b-dihydro-8,9b-dimethyl-B-(l-pyrrolidinyl)-4-dibenzofurancarboxanilide. The filtrate was evaporated under reduced pressure to yield a residual yellow syrup. This was tn'turated with ether and filtered to remove 1.71 g. of 1,3,5-tris(p-bromophenyl)-s-triazine-2,4,6(l H,3H,5H)-trione, formed by self-condensation of the pbromophenyl isocyanate. The ethereal filtrate was evaporated to dryness under reduced pressure to yield a red syrup which was chromatographed on 100 g. of neutral alumina (Activity III). Elution with 80 ml. of benzene yielded 0.560 g. of crude product. Trituration with hot ethanol .and filtration yielded 0.482 g. of 4,4"-dibromo-2-(p-bromophenyl)- l,2,3,4,4a,9bhexahydro-8,9b-dimethyl-3-oxo l 0-( l-pyrrolidinyl)- l ,4- ethenobenzofuro[ 3 ,2 ]pyridine-4,1 l-dicarboxanilide colorless crystals, m.p. 224-225 C.;

KB Max.

5.90 and 6.00 p..

EXAMPLE 5 Preparation of l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3,10- dioxo- 2-phenyll ,4-ethanolbenzofuro[ 3 ,2-c ]pyridine-l l-carboxanilide A solution of 0.500 g. of l,2,3,4,4a,9b-hexahydro-8,9bdimethyl-3oxo-2-phenyll 0-( l-pyrrolidinyl )-l ,4- ethenobenzofuro[ 3,2-c]pyridine-l l-carboxanilide in 50 ml. of methanol and 3 m1. of 1N hydrochloric acid was heated at reflux for 7 hours. The solvents were removed by evaporation under reduced pressure to yield a semi-solid residue. Trituration with water yielded a solid which was collected by filtration to yield 0.424 g. of crude product. Recrystallization from ethanol yielded 0.230 g. of l,2,3,4,4a,9b-hexahydro-8,9bdimethyl-3 l 0-dioxo-2-phenyll ,4ethanobenzofuro[ 3 ,2-c] pyridine-l l-carboxanilide as colorless crystals, m.p. l82l 85 KB mi.

hexa- -hydrob-hexa hydro-8 ,9b-dimethyl-3 l Odioxo-l ,4-ethanobenzofuro[ 3 ,2-c ]pyridine-l l-carboxanilide A suspension of 0.813 g. of 4'-bromo-2-(p-bromophenyl)- l ,2,3,4,4u,9b-hexahydro-8,9b-dimethyl-3-oxol-( l -pyrrolidinyl l ,4-ethenobenzofurol 3,2-c1pyridine-l l-carboxani lide in 70 ml. of methanol and 4 ml. of 1N hydrochloric acid was refluxed for 4% hours. The solvents were removed by evaporation under reduced pressure to yield a semi-solid as residue. The solid was collected by filtration and recrystallized from chloroform-heptane to give 0.525 g. of 4'-bromo-2-(pbromophenylyl ,2,3,-4,4a,9b-hexahydro-8,9b-dimethyl-3,10- dioxol ,4-ethanobenzofuro-[ 3 ,2-c]pyridine-l l-carboxanilide as colorless crystals, m.p. 123-129 C.;

5.74 and 5.90

We claim:

1. A compound of the formula:

wherein R is selected from the group consisting of phenyl and p-bromophenyl.

2. The compound according to claim 1 wherein R is phenyl; l ,4,4a,9b-tetrahydro-8,9b-dimethyl-2-phenyl-l ,4- ethanobenzofuro[ 3 ,2-c ]pyridine-3( 2H l O-dione.

3. The compound according to claim 1 wherein R is pbromophenyl; 2-(p-bromophenyl)-l ,4,4a,9b-tetrahydro-8,9bdimethyll ,4-ethanobenzofuro[3,2-c]pyridine-3( 2H, 1 0- dione.

4. A compound of the formula:

wherein R and R are the same and are each selected from the group consisting of phenyl and pbromophenyl.

5. The compound according to claim 4 wherein R and R are both phenyl; 1,2,3,4,4a,9bhexahydro-8,9b-dimethyl- 3,10-dioxo-2-phenyl-l ,4-ethanobenzofuro[ 3 ,2-c]pyridinel l carboxanilide.

6. The compound according to claim 4 wherein R and R are both p-bromophenyl; 4'-bromo-2-(p-bromophenyl)- 1,2,3,4,-4a, 9b-hexahydro-8,9b-dimethyl-3 l O-dioxol ,4- ethanobenzofuro-[ 3,2-c]pyridine-1 l-carboxanilide.

7. A compound of the formula:

0 CH3 /W l wm wherein R 5561 are the same and are each selected from the group consisting of phenyl and p-bromophenyl.

8. The compound according to claim 7 wherein R and R are both phenyl; l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3- oxo-2-phenyll 0-( 1-pyrrolidinyl)-1,4-ethenobenzofuro[3,2-

c pyridine-1 l-carboxanilide.

9. The compound according to claim 7 wherein R, and R are both p-bromophenyl; 4'-bromo-2-(p-bromophenyl)- 1,2,3,4,-4a,9b-hexahydro-8,9b-dimethyl-3-oxol 0-( l-pyrrolidinyl l ,4-ethenobenzofuro[3,2-c1pyridinel l-carboxanilide.

Claims (8)

1. 2. The compound according to claim 1 wherein R is phenyl; 1,4, 4a,9b-tetrahydro-8,9b-dimethyl-2-phenyl-1,4-ethanobenzofuro(3,2-c)pyridine -3(2H),10-dione.
2. 3. The compound according to claim 1 wherein R is p-bromophenyl; 2-(p-bromophenyl)-1,4,4a,9b-tetrahydro-8,9b-dimethyl-1,4-ethanobenzofuro(3,2-c)pyridine-3(2H,10-dione.
3. 4. A compound of the formula:
4. 5. The compound according to claim 4 wherein R1 and R2 are both phenyl; 1,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3,10-dioxo-2-phenyl-1,4 -ethanobenzofuro(3,2-c)pyridine-11-carboxanilide.
5. 6. The compound according to claim 4 wherein R1 and R2 are both p-bromophenyl; 4''-bromo-2-(p-bromophenyl)-1,2,3,4,-4a, 9b-hexahydro-8,9b-dimethyl-3,10-dioxo-1,4-ethanobenzofuro-(3,2-c)pyridine-11-carboxanilide.
6. 7. A compound of the formula:
7. 8. The compound according to claim 7 wherein R1 and R2 are both phenyl; 1,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxo-2-phenyl-10-(1-pyrrolidinyl)-1,4-ethenobenzofuro(3,2-c)pyridine-11-carboxanilide.
8. 9. The compound according to claim 7 wherein R1 and R2 are both p-bromophenyl; 4''-bromo-2-(p-bromophenyl)-1,2,3,4,-4a,9b-hexahydro-8,9b-dimethyl-3-oxo-10 -(1-pyrrolidinyl)-1,4-ethenobenzofuro(3,2-c)pyridine-11-carboxanilide.