CA1145758A - 2,3-dihydro-2-benzofurancarboxamide derivatives - Google Patents

Abstract

ABSTRACT
This invetation relates to 2,3-dihydro-2-benzofurancarboxamide derivatives. There are provided 2,3-dihydro-2-benzofurancarboxamide derivatives of formula

Description

il~S'7S8 K.3216 III CAN

2,3-DI~DRO-2-BENZOFU~ANCAR~OXAMIDE DERIVATIVES

Thi6 invention relates to 2,3-dihydro-2-benzofuran-carboxamide derivatives.
According to the invention there are provided 2,3-dihydro-2-benzofurancarboxamide derivatives of formula:-o R ~ C - NH ~ CH2 ~ CH = CH2 wherein R is a sub6tituent at the 5-position on the 2,3-dihydro-benzofuran ring system and is a thienyl group, or a phenyl, phenoxy, benzyl or benzoyl group substituted by an alkoxy group of 1 to 6 carbon atoms, a l-hydroxyethyl group or an acetamido group, or is a substituent at the 4-position on the 2,3-dihydro-benzof~ran ring system and is a phenoxy group optionally substituted by alkyl or alkoxy of 1 to 6 carbon atoms, acetamido, l-hydroxyethyl or nitro.
When R is a substituted 5-phenyl, phenoxy, benzyl or benzoyl group, the alkoxy, l-hydroxyethyl or acetamido group is preferably attached at the 4-position thereof. An alkoxy moiety may be of straight-chain or branched-chain configuration.
Methoxy i6 a preferred alkoxy group. When R is a thienyl group it is preferably a (2-thienyl) group.
Particularly preferred compounds of the invention are those wherein R is a 5-(4-(1-hydroxyethyl)phenyl), 5-(4-acetamidophenyl) or 4-phenoxy group, the first and last of these groups being ~4S758 most preferred.
~ Irther in accordance with the invention there is provided a process for preparing the compounds of formula I which process comprises reacting a 2,3~dihydro-2-benzofurancarboxylic acid ester derivative of formula:-o R ~ C - 0 _ Rl (II) wherein R is as defined above and R is an alkyl group of from 1 to 6 carbon atoms, with 2-propenylamine.
Conveniently the process of the invention is effected in the presence of an alkanol of one to four carbon atoms a6 solvent, and R is an alkyl group of from 1 to 4 carbon atoms. In a preferred process, R is ethyl and the process is effected using ethanol as solvent. The reaction will go forward at room temperature; however, higher temperatures - for example, the mixture can be refluxed - may be employed to reduce the reaction time. Preferably, about a four-to-six fold excess of the 2-propenamine is used. The desired product can be recovered by evaporating the solvent and excess amine, then employing conventional techniques such as selective extraction, recrystallization and/or dry column chromatography, to isolate the desired product.
In general, the precursor esters of formula II can be prepared as follows:-(a) The ethyl ester of the appropriate benæofurancarboxylic acid is prepared by condensation of the appropriate R-substituted salicylaldehyde with diethyl bromomalonate in the presence of potassium carbonate, according to the method of Kurkudar and Rao, Indian Acad. Sci., Section A, 58, 336 (1963). (b) Hydrolysis of the ester to the corresponding acid, alsoas shown in Kurkudar and Rao.

:li457S8 (c) Reduction of the acid to the 2~3-dihydrobenzofurancarboxylic acid, by use of sodium/mercury amalgam, according to the method of Fredga, Acta Chem. Scand., 9, 719 (1955).
(d) Fisher-Speier esterification of the acid with the appropriate alkanol, e.g. ethanol. i.e. treating the acid with the alkanol in a solvent such as toluene,in the presence of a catalytic amount of an acid such as sulfuric acid, hydrochloric acid, or para-toluene-sulfonic acid.
The precursor R-substituted salicylaldehydes can be prepared by treating the appropriate phenol with chloroform under strongly basic conditions, according to the Reimer-Tiemann Reaction. (References cited in The Merck Index, 9th Edition, page ONR-74; also, Russel, A. and Lockhar, L.B., Organic Synthesis, 22, 63 (1942)).
Many of the precursor phenols are known compounds; others can be prepared by conventional procedures. For example, alpha-(4-hydroxyphenyl)thio-phene, the precursor phenol for the compound of formula I wherein R is a 5-(2-thienyl~ group, can be prepared by either or both of the methods disclosed by M. A. Al'perovich, et al, Zh. Obschch. Khim., 34, 645-50 (1964); Chem.
Abst., 60, 14639d (1964)), and Y. Ahmad, et al, Canadian Journal of Chemistry, 45, 1539-42 (1967).
Compounds of formula I have exhibited lipogenesis inhibiting activity in animals intended for human consumption after slaughter.
Chirality exists in the compounds of formula I, hence they can exist in two optical isomeric forms. None of the isomers has been separated, nor has the lipogenesis inhibiting activity of any of the individual isomers been deter-mined. The individual species that have been prepared inhibit lipogenesis.
Under the circumstances, the invention contemplates the active individual isomers, as well as the mixtures thereof. Compounds of formula I can be used to inhibit ~14S758 lipogenesis in animals such as livestock, sheep, swine, cattle and horses. The effect is obtained by administering an effective amount of one or a mixture of the inhibitors orally or parenterally to the animal. They may be administered as such, or as an active ingredient of a conventional pharmaceutical formulation.
They may be administered orally by any convenient means. Thus, they may be orally administered as a drench, by intubation, in the animal's food and water, in a food supplement or in a formulation expressly designed for administration of the drug. Suitable formulations include solutions, suspensions, dispersions, emulsions, tablets, boluses, powders, granules, capsules, syrups and elixirs.
For parenteral administration, they may be in the form of a solution, suspension, dispersion or emulsion. They can be administered in the form of an implant or other controlled sustained release formulation. Inert carriers, such as one or more of water, edible oil, gelatin, lactose, starch, magnesium stearate, talc or vegetable gum can be used. The dosage of the inhibitor needed to inhibit lipogenesis will depend upon the particular compound(s) used, and the particular animal being treated. However, in general, satisfactory results are obtained when the inhibitor is administered in a dosage of from about 1 to about 500 milligrams per kilogram of the animal's body weight. The inhibitor can be admin-instered in a single dose or in a series of doses in the same day, or over a period of days. For any particular animal, a specified dosage regimen should be adjusted according to the individual need, the particular inhibitor used, and the professional judgement of the person administering or supervising the admin-istration of the inhibitor.
Lipogenesis inhibiting compositions comprise a derivative of formula I in assocation with a pharmaceutically or veterinarily acceptable carrier therefor. Such compositions are made by bringing the derivative of formula I
into association with the carrier.

~ - 4 -~145758 The invention will be further understood from the following examples, in each of which the identities of the products, and the intermediates involved, were confirmed by appropriate elemental and spectral analyses.
Example 1 2,3-Dihydro-4-phenoxy-N-(2-propenyl)-2-benzofurancarboxamide 145.0 g of meta-phenoxyphenol was dissolved in 700 ml of 95% ethanol. 468 g of sodium hydroxide was then added rapidly.
The resulting suspension was heated to 70-80 C. Then 558.7 g of chloroform was added, at such a rate that gentle reflux was was maintained (the addition resuired 10 hours). The ~ixture then was stirred for 2 hours at 75-80 C, held at room temperature overnight and then was filtered. The solid product was dissolved in 1000 ml of water. The solution was acidified to pH = 2 with concentrated hydrochloric acid, then was extracted with ether. The ether layer was dried (MgS04) and concentrated. The residue was extracted ~ith hot petroleum ether. The extract was dried (Na2S04) and concentrated to give an oil, which was wet column chromatographed over silica gel, using a 9/1 v/v mixture of petroleum ether and ether as eluent, then using a 4/1 v/v mixture of petroleum ether and ether as eluent. The fourth fraction obtained was identified as 2-hydroxy-6-phenoxybenzaldehyde (lA).
A mixture of 1.07 g of lA, 0.96 g of diethyl bromomalonate and 1.25 g of anhydrous potassium carbonate in 20 ml of 2-butanone, was refluxed for 10 hours. The solvent was evaporated under reduced pressure. The residue was cooled, poured into 100 ml of water and extracted with ether. The extract was washed with cold 5~ sodium hydroxide solution and water and

3 then concentrated under reduced pressure. The residue was recrystallized from ethanol to give ethyl 4-phenoxyben7ofuran-2-carboxylate (lB), as a liquid.
A mixture of 1.4 g of Compound lB and 50 ml of 10% alcoholic potassium hydroxide was refluxed for 4 hours. The solvent was ~14575B

evaporated under reduced pressure and the residue was washed with ether and dissolved in water. The basic solution was acidified with dilute hydrochloric acid and extracted with ether. The ether layer was extracted with dilute sodium bicarbonate solution. The aqueous solution was re-acidified with dilute hydrochloric acid and extracted with ether.
The ether extract was dried (Na2S04) and concentrated under reduced pressure. The residue was crystallized from ethanol to give 4-phenoxy-2-benzofurancarboxylic acid (lC)1 m.p.:
10 215-217C.
5.3 g of lC was mixed with 90 ml of 10% sodium hydroxide solution. Sodium amalgam (prepared from 1.5 g of sodium and 50 g of mercury) was added to the stirred mixture over a period of one hour. The mixture was then stirred for 24 hours and allowed to stand at room temperature for an additional 24 hours. The mercury was separated, the solution was neutralized with dilute hydrochloric acid and extracted with ether. The extract was dried (Na2S04) and concentrated under reduced pre6sure. The residue was recrystallized from ethanol to give 2,3-dihydro-4-phenoxy-2-benzofurancarboxylic acid (lD), m.p.:
123-125C.
A mixture of 2.7 g of lD, 60 ml of ethanol, 20 ml of dry benzene and 2 ml of concentrated sulfuric acid was refluxed for seven hours, with removal of water as it formed. The resulting mixture was concentrated, and the residue dissolved in ether.
The solution was washed with saturated sodium bicarbonate solution and water. The aqueous portion was extracted with ether. The combined organic layers were dried (Na2S04) and the solvent was evaporated under reduced pressure. ~he residue was 3 distilled to give ethyl 2,3-dihydro-4-phenoxybenzofuran-2-carboxylate (lE), m.p.: 56-58C.
An ethanol solution of lE and an excess of 2-propenamine was refluxed for 2.5 days. The excess amine and the solvent were evaporated under reduced pressure. The resulting gum was 35 recrystallized from methylene chloride/hexane to give 1, m~p.: 55-57C.
~", 114S'75 Example 2 2,3-Dihydro-5-(4-(1-hydroxyethyl)phenyl-N-(2-prope~
2-benzofurancarboxamide 12.2 g of acetyl chloride was added to a mixture of 10.3 g of ethyl-5-phenylbenzofuran-2-carboxylate, and 120 ml of carbond disulfide, then 21.8 g of anhydrous aluminum chloride was added in portions to the stirred mixture. The mixture then was stirred at room temperature for 2.5 hours, the temperature rising to 32 C. The mixture was poured into 1 liter of ice water, the mixture was stirred for 30 minutes, and the solution was extracted with ether. The extract was dried (MgS04) and concentrated. The residue was washed with ether and dried. It was dissolved in 100 ml of chloroform, the solution was treated with a dec310rizing agent, and 100 ml of hexane was added. The resulting solution was concentrated to about 100 ml and cooled to give ethyl 5-(4-acetylphenyl)benzofuran-2-carboxylate (2A), m.p.: 105-107C.
1.2 g of sodium borohydride was added in one portion to a stirred mixture of 15.0 g of 2A, 200 ml of ether and 40 ml of ethanol. ~he mixture was stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure. 1.6 liters of water was added to the residue and the mixture was extracted with chloroform. The extract was dried (MgS04), filtered and the solvent was evaporated under reduced pressure.
The residue was dissolved in 150 ml of chloroform. The solution was filtered through charcoal. 400 ml of hexane was added. The solid which formed was collected, recrystallized from a 3/50 v/v mixture of chloroform and hexane and dried in a vacuum oven to give ethyl 5-t4-(1-hydroxyethyl)phenyl)-2-benzofurancarboxylate (2B), m.p.: 108-109C.
3 75 ml of ethanol was added to a solution of 23.9 g of 6B in 300 ml of tetrahydrofuran, then 195.7 g of 2.5% sodium/mercury amalgam was added in portions, at room temperature. The mixture was stirred at room temperature overnight. The mercury was separated, the solid was collected and d~ssolved in 300 ml of water. The solution was acidi~ied to pH = 1 with concentrated hydrochloric acid. The solid was collected, wached with water and dried (P205; reduced pressure, 45C). The product was dissolved in tetrahydrofuran, the solution was filtered and its S ~olume reduced to 30 ml by evapora~ing the solvent under reduced pressure. The resulting solution was triturated with ether. The solid was collected and dried in a vacuum oven over P205 to give 2,3-dihydro-5-(4-(1-hytroxyethyl)phenyl)-2-benzofurancarboxylic acid (2C), mp: 155-157C.
23.3 g of methyl iodide and 7.6 g of potassium carbonate were added to a mixture of 7.8 g of 2~, 200 ml of acetone and 50 ml of dimethylsulfoxide. The resulting suspension was heated under reflux for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was stirred with 400 ml of water, the water was decanted, and the residue was dissolved in tetrahydro-f~ran. The solution was filtered and the filtrate was concentrated.
The residue was mixed with 50 g of silica gel and purified by dry column chromatography, a 9/1 v/v chloroform/tetrahydrofuran mixture being used as eluent. The band containing product was extracted with tetrahydro-furan, the solvent was evaporated from the extract under reduced pressure and the residue was dried in a vacuum oven. The residue was stirred with ether and the solid was collected and dried to give methyl 2,3-dihydro-5-(4-(1-hydroxye~hyl)phenyl)-2-benzofurancarboxylate (2D), mp: 98-100C.
15 ~1 of 2-proper.ylamine was added to a mixture of S.0 g of 6D
and 100 ml of methanol. The solution was stirred at room temperature o~ernight. The volatile ~aterials were evaporated under reduced pressure. The residue was stirred with 5C ml of ether, the solid was co'lected and dried in a vacuum oven to give 2, mp: 122-124C.
Exa~ple~ 5-(4-(Acetylamino)phenyl)-273-dihydro-N-(2-propenyl)-2-benzo-furancarboxamide ~
A mixture of 6.2 g of 2~, 100 ml of ethanol and 200 ml of tetrahydrofuran was heated to 60-70C. A solution of 1.;3 g of hydroxyl-amine hydrochloride and 1.16 g of sod~um carbonate in 20 ml of water was added. The mixture was heated for 3 hours at 60-70C. 1.53 g of ~ydroxyl-amine hydrochloride and 1.16 g of sodium carbonate in 20 ml of water was added and the mixture was heated at 60-70C for 4 hours. 1.53 g of 5'7S8 hydro~ylamine and 1.16 g of sodium carbonate in 20 ml of water was added and the mixture heated at 60-70C for 4 hours. The solid was collected, washed with water, then ethanol, and extracted with methylene chloride.
The solvent was evaporated from the e~tract under reduced pressure to give ethyl 5-(4-(l-(hydroxyimino)ethyl)phenyl-2-benzofurancarboxylate (3A), mp: 220-222C.
56.5 g of phosphorus pentachloride was added in portions to a sQlution of 55.0 g of ~A in l liter of chloro~orm, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pres ure. The residue was suspended in 4 liters of water, the mixt~re was stirred vigorously for 30 minutes and filtered. The solid was extracted with chloroform. The extract was washed, successively, with water, saturated sodium bicarbonate solution, and water, then was filtared through celite (to break do~n the emulsion). The filtrate was lS dried (MgS04) and the solvent was evaporated under reduced pressure.
The residue was triturated wlth ether and separated. The filtrate was concentrated to about half its volume under reduced pressure and allowed to stand over a weekend. The solid which formed was collected and dissolved in 400 ml of chloroform. The solution was filtered over charcoal, and diluted with 400 ml of hexane. The solid was collected, and dry column chromatographed over silica gel, using a 1/9 v/v mixture of tetrahydrofuran and chloroform as eluent. The appropriate fractions were combined and extracted with tetrahydrofuran. The solvent was evaporated under reduced pressure and the residue was triturated with ether. The solid was collected and dried under reduced pressure to give ethyl 5-(4-acetylamino)phenyl)-2-benzofurancarboxylate (3B), mp: 174~176C.
25 ml of ethanol was added to a mixture of 2.3 g of ~ in 8~ ml o, tetrahydrofuran. Then 18.8 g of 2.5,~' sodium a~algam was added in portions, and the mixtu.e was stirred for 20 hours. The mercury was separated and the solvent was evaporated under reduced pressure. The residue was dissolved in 350 ml of water~ the solution W2S filtered, and concentrated hydrochloric acid was added until the solution had a pH of 2. The solid was collected, washed with water and dried under reduced pressure. The residue was stirred witn 30 ml of acetone. The solid was collected and refluxed with acetone. The solution was filtered and the filtrate was concentrated to a small volume under reduced pressure. The solid was collected and dried, to oive 5-(4-(acetylamino)phenyl)-2,3-dihydro-2-benzofurancarboxylic acid (3C), mp: 274-276C.
~ .

li45758 .,~

S drops of concentrated sulfuric acid was added to a mixture of 3.2 g of 3C and 150 ml of ethanol. The mixture was heated under reflux, using a Soxhlet extractor filled with molecular sieve (3A). After 4 hours, the solvent was evaporated under reduced pressure, and the residue was dissolved in chloro-form. The solution was washed with saturated sodium bicarbonate solution, dried ~MgS04) and the solvent was evaporated under reduced pressure. The residue was dry column chromatographed over silica gel, using chloroform as eluent. The product was extracted with tetrahydrofuran and the solvent was evaporated under reduced pressure. The residue was stirred in ether. The solid was collected and refluxed in ether. The solid was collected and dried under reduced pressure to give ethyl 5-~4-~acetylamino)phenyl)-2,3-dihydro-2-benzofurancarboxylate (3D), mp: 164-166C.
20 ml of ethanol was added to a mixture of 1.6 g of 3D and 20 ml of 2-propenylamine. The mixture was stirred for 3 hours at room temperature. The solid which formed was collected, washed with ethanol, then ether and dried under reduced pressure to give 3, mp: 244-247~C.
Compounds 1 - 3 have been found to inhibit lipogenesis in tissues of animals intended for human consumption after slaughter. The manner in which they cause this effect is not known with certainty; it is believed that they interfere with the synthesis of fatty acids in the tissues. Their effectiveness for this purpose has been ascertained by immersing samples of swine adipose tissue in a liquid medium containing radioactive glucose and the test chemical for a period of time, then isolating the lipid from the treated tissue and determining the up-take of the radioactive carbon by means of scintillation counting techniques.
These tests were conducted in swine adipose tissue because in swine, the primary site of lipogenesis -- i.e., fatty acid synthesis -- appears to be adipose tissue.
Described in more detail, the tests were conducted according to the following general procedure:

o ,,~ ~ 1 0 -.

4S7St~

150 milligrams of slices of swine adipose tissue were incubated at37C for 2 hours with shaking in 3 milliliters of Krebs-Ringer bicarbonate sol-ution containing one-half of the normal calcium ion concentration, 60 micromoles of glucose, 0.5 micro-Curie of glucose-U14C, and 300 microunits of insulin, and 5% dimethyl sulfoxide ~DMS0). The test compound was added as a solution or sus-pension in DMSO and was present as a concentration of 100 micrograms per milli-liter of incubation mixture.
The incubation was terminated by addition of 0.25 ~illiliter of 1 N
sulfuric acid. The resulting mixture was extracted with a total of 25 milliliters of chloroform: methanol (2:1, v/v). The extracts were washed according to Folch et al. (J. Biol. Chem., 226, 497-509, (1957)), air dried, and counted in a liquid scintillation counter with 15 milliliters of counting fluid (two parts toluene containing 0.4% w/v New England Nuclear Omnifluor: 1 part Triton X-100*).
The tests were conducted in triplicate and were accompanied by control tests in which all ingredients, proportions and conditions were the same except that no test compound was included. From the data obtained were calculated the percent inhibition of lipid synthesis by the test compound. The data obtained are report-ed as the p0rcent inhibition of lipogenesis compared to the results obtained in the control tests wherein only the test compound was omitted. The results are 20summarized in Table I.

Table I
Compound Percent Inhi6ition * a trade mark.

.. ,~ . .

Claims (7)

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

1. A 2,3-dihydro-2-benzofurancarboxamide derivative of formula (I) wherein R is a substituent at the 5-position on the 2,3-dihydrobenzofuran ring system and is a thienyl group, or a phenyl, phenoxy, benzyl or benzoyl group substituted by an alkoxy group of 1 to 6 carbon atoms, a 1-hydroxyethyl group or an acetamido group, or is a substituent at the 4-position on the 2,3-dihydrobenzofuran ring system and is a phenoxy group optionally sub-stituted by alkyl or alkoxy of 1 to 6 carbon atoms, acetamido, 1-hydroxy-ethyl or nitro.

2. A derivative according to claim 1 wherein when R is a substituted 5-phenyl, phenoxy, benzyl or benzoyl group, the alkoxy, 1-hydroxyethyl or acetamido group is attached at the 4-position thereof.

3. A derivative according to claim 1 wherein R is a 5-(4-(1-hydroxy-ethyl)phenyl), 5-(4-acetamido phenyl) or 4-phenoxy group.

4. A process for preparing a 2,3-dihydro-2-benzofurancarboxamide derivative of formula (I) wherein R is a substituent at the 5-position on the 2,3-dihydrobenzofuran ring system and is a thienyl group, or a phenyl, phenoxy, benzyl or benzoyl group substituted by an alkoxy group of 1 to 6 carbon atoms, a 1-hydroxyethyl group or an acetamido group, or is a substituent at the 4-position on the 2,3-dihydrobenzofuran ring system and is a phenoxy group optionally substituted by alkyl or alkoxy of 1 to 6 carbon atoms, acetamido, 1-hydroxyethyl or nitro, which process comprises reacting a 2,3-dihydro-2-benzofurancarboxylic acid ester derivative of formula (II) wherein R is as defined above and R1 is an alkyl group of from 1 to 6 carbon atoms with 2-propenylamine.

5. A process according to claim 4 wherein when R is a substituted 5-phenyl, phenoxy, benzyl or benzoyl group, the alkoxy, 1-hydroxyethyl or acetamido group is attached at the 4-position thereof.

6. A process according to claim 4 wherein R is a 5-(4-(1-hydroxyethyl) phenyl)-, 5-(4-acetamidophenyl)- or 4-phenoxy-group.

7, A process according to any one of claims 4 to 6 wherein R1 is ethyl and the process is effected using ethanol as solvent.