INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PC

(51) International Patent Classification 4 (11) International Publication Number : WO 89/ 0 C07D 307/18, 05/10, 407/10 Al

(43) International Publication Date : 6 April 1989 (06.

(21) International Application Number: PCT/US88/03347 (74) Agents: HODGES, Paul, E. et al.; Luedeka, Hod Neely, 1030 First American Center, Knoxvill

(22) International Filing Date: 28 September 1988 (28.09.88) 37902 (US).

(31) Priority Application Number: 103,484 (81) Designated States: AT (European patent), AU, B ropean patent), CH (European patent), DE (

(32) Priority Date: 30 September 1987 (30.09.87) pean patent), FR (European patent), GB (Eur patent), IT (European patent), JP, LU (Europea

(33) Priority Country: US tent), NL (European patent), SE (European pat

(71) Applicant: THE UNIVERSITY OF TENNESSEE RE¬ Published

SEARCH CORPORATION [US/US]; Suite 415, With international search report. Communications Building, Knoxville, TN 37996 Before the expiration of the time limit for amendi (US). claims and to be republished in the event of the r of amendments.

(72) Inventors: KENNEDY, Thomas, P. ; 1624 Clanlo

Drive, Memphis, TN 38104 (US). KABALKA, George, W. ; 7124 Cresthill Drive, Knoxville, TN 37919 (US).

(54) Title: CERTAIN 3-SUBSTITUTED 2-ALKYL BENZOFURAN DERIVATIVES

(57) Abstract

The disclosure relates to compounds of formula (I) and pharmaceutically acceptable addition salts thereof whe X represents a single, direct bond or a substituted or unsubstituted alkylene chain containing 1 to 4 carbon atoms, whe R ₅ is a lower alkyl group, wherein Rg is either hydrogen or methyl, wherein Am is selected from the class consisting of a no, lower mono and dialkylamino, piperidino, piperazino, N-lower alkyl piperazino, pyrrrolidino, and morpholino gro wherein Y[ and Y ₂ are identical and are hydrogen, a halogen, methyl or ethyl and n is an integer in the range of 1-5. T are useful in treating arrhythmic conditions and conditions for which treatment with a vasodilator is indicated.

CERTAIN 3-SUBSTITUTED 2-ALKYL BENZOFURAN DERIVATIVES

The invention relates to compounds hav ing pharmacological activity and more particularly relates to novel pharmacologically active 3-subs t i tu ted 2-alkyl benzofuran derivatives, and methods for their preparation. Compounds in accordance with the invention are represented by the general formula:

and pharmaceutically acceptable addition salts thereof wherein X represents a single, direct bond or a substituted or unsubstituted alkylene chain containing 1 to 4 carbon atoms, wherein Rς is a lower alkyl group, wherein R ₆ is either hydrogen or methyl, wherein Am is a group selected f £" o m the class consisting of amino, lower mono and dialkylamino, piperidino, piperizino, N-lower alkyl piperizino, pyrrolidino, and morpholino groups, wherein Y-^ and ₂ are identical and are hydrogen, halogen, methyl or ethyl, and n is an integer in the range of 1-5. The term "unsubstituted or substituted alkylene chain containing 1 to 4 carbon atoms" is intended, unless further defined, to designate a saturated aliphati hydrocarbon chain of between 1 and 4 carbon atoms with or without one or more substituentβ. Substituents are limited to those which do not diminish the pharmacological activity of the compounds below a useful level and include branched or straight-chain alkyl or cycloalkyl groups, aryl groups,

alkoxy groups, and ester substituents. "Lower alkyl" is intended to designate straight-chain, branched, or cyclic saturated aliphatic hydrocarbon groups containing 1-6 carbon atoms. "Lower mono and dialkylamino" refers to amino groups with one or two straight-chain, branched or cyclic saturated aliphatic hydrocarbon groups containing 1-6 carbon atoms.

When two groups are present, they may be the same or different. Examples are ethylamino, dimethy 1 amino , ethylamino, diethylamino, n-propylamino, isopropylamino, and the like. Halogen, unless further defined, is intended to refer to fluorine, chlorine, bromine, and iodine.

Compounds in accordance with the invention are useful as vasodilators and as ant iarrythmic agents.

Preferred for this purpose are compounds of Formula I above R, i -~ wherein X represents the Formula -C- above wherein Ri and/or l ~

^{" R} 2 R2 are hydrogen, lower alkyl groups, groups with the Formula

-OR3 with R3 being a lower alkyl group, or groups with the 0

11

Formula -0- C-R4 with R4 being hydrogen or a lower alkyl group, R- is a lower alkyl group containing 1-4 carbon atoms, R ₆ is hydrogen, Am is as defined above for Formula I, Y- _j and Y ₂ are identical and are hydrogen, bromine, iodine, or methyl, and n is in the range of 1-3. Particularly preferred

are compounds wherein X is -C- wherein R ₂ is hydrogen and R- _j _

R ₂ is hydrogen, or -OR3 with R3 being a lower alkyl group, or R-_ 0 11 is -O-C-R^ with R4 being hydrogen or a lower alkyl group, R5 is butyl, Rg is hydrogen, Am is amino or lower mono and dialkyl amino, Y-^ and Y ₂ are identical and are hydrogen, bromine, iodine, or methyl and n is an integer in the range R. of 1-3. Most preferably, X is -C- wherein R _. is hydrogen and

1

^R 2

Rτ_ is hydrogen or -OR3 with R3 being a lower alkyl group

0

II containing between 1 and 4 carbon atoms, or R___ is -0-C-R4 with R ₄ being hydrogen or a lower alkyl group containing 1 to 4 carbon atoms, R ₅ is n-butyl, Rg is hydrogen, Am is amino, ethylamino or diethylamino, Y and Y ₂ are either both hydrogen, both iodine, or both methyl, and n is 1. Of the most preferred compounds, compounds where R-^ and R are both hydrogen are particularly desirable. Compounds of Formula I in which Rg is hydrogen are prepared by first condensing an alkali metal salt of a compound represented by Formula II below in which X, Rς , Y _j _ and Y ₂ have the same meanings as in Formula I with a dibroirioalkane represented by Formula III in which Rg is hydrogen and n is 1-5 in an inert organic medium such as dimethyl formamide.

The resulting bro oalkoxy-substi-tuted compounds of Formula IV are condensed with an amine of the Formula V in which Am has the same meaning as in Formula I in an inert solvent such as benzene to produce the Formula I compounds.

H-Am

Alternately, when Am does not represent a secondary amine and Rg is either hydrogen or methyl, an alkali metal salt of a compound of Formula II can be condensed with an amine represented by Formula VI in which Z is a halogen atom to produce of Formula I compounds.

VI

The compounds represented by Formula II can DΘ synthesized by a number of reaction routes. As will become more apparent hereinafter, many of such compounds can be prepared by reduction of or reduction and subsequent reaction of a ketone intermediate represented by Formula VII wherein A is a single direct bond or a substituted or unsubstituted alkalene chain containing 1-3 carbon atoms in the chain and Rς, Y _] _, and Y ₂ are as defined in Formula I.

When A is a single, direct bond. Formula VII ketones are known intermediates and are disclosed in U.S. Patent Nos. 3,248,401 and 3,920,707, which are incorporated herein by reference. When A represents a substituted or unsubstituted alkalene chain containing 0-3 carbon atoms, the ketone intermediates represented by Formula VII can be prepared by Friedel-Crafts acylation of a 2, 6-substituted anisole of Formula IX with an acid chloride of Formula VIII wherein represents an integer of 0-3 and Rη and Rg represent the same entities as R^ and R ₂ or precursors thereof followed by demethylation of the anisole with pyridine hydrochloride.

The acid chlorides of Formula VIII can be prepared from 3- carboxy-2-alkyl benzofurans of the Formula X by reaction with an alkene Grignard reagent of Formula XI wherein o is 0-2 and R ₇ and R _g are defined as in Formula VIII in the presence of

CdCl ₂ to result in the formation of the secondary alcohols of Formula XII.

Formula XII alcohols can be dehydrated to the corresponding alkenes of Formula XIII below by reaction with sulfonyl chloride in pyridine followed by reaction with lithium tri- ethyl borohydride. Formula XIII alkene substituted benzofuran compounds are converted to acid chlorides of Formula VIII by ozination in the presence of zinc and oxidation of the resulting aldehyde of Formula XIV to the carboxylic acid employing potassium permanganate (cold) followed by reaction with sulfonyl chloride.

When X is a single direct bond, compounds of

Formula I are prepared by first reacting a compound of Formula XV with ^ and Y ₂ as defined in Formula I with ethyl bromoacetate in acetone in the presence of K C03 to form a compound of Formula XVI. Formula XVI compounds are converted to the compounds of Formula XVII by Perkin condensation in the presence of acetic anhydride and sodium acetate followed by the conversion of the ester group to R5 groups. Demethy 1 ation of the substituted anisole moiety yields compounds of Formula II wherein X is a single, direct bond which can be employed as previously discussed to prepare Formula I compounds.

Compounds of Formula XV can be prepared by Friedel- Crafts acylation of the substituted anisoles of Formula IX with salicyloyl chloride.

The particularly preferred compounds of Formula I

described above wherein X is -C- and R ₂ is hydrogen and R ₂ is

R-

hydrogen or -OR ₃ with R ₃ being a lower alkyl group or -0-C-R4 with R4 being hydrogen or a lower alkyl group are advantageously prepared by way of an alcohol intermediate which is produced by reducing a ketone of the formula:

XVIII

with R ₄ , R ₅ , R , Y-^ and Y ₂ , and n as defined for Formula I. Formula XVII ketones are known and procedures for their synthesis are described in U.S. Patent Nos. 3,248,401 and 3,920,707, the disclosures of which are incorporated herein by reference. To produce compounds according to Formula I wherein Y^ and Y ₂ are identical halogens, reduction of the compounds of Formula XVIII with Y^ and Y ₂ being halogens is performed under conditions which reduce the ketone group to the alcohol without otherwise affecting the molecule. A reducing system employing sodium borohydride in a t e t r ahyd of u ran-me thano 1 mixture (10:1 v/v ) at approximately 0°C produces high yields of the alcohol represented by Formula XIX:

To prepare compounds of the invention wherein Y^ and Y ₂ are both hydrogen, both methyl, or both ethyl, the ketones of the Formula XIV wherein Y and Y ₂ are both hydrogen, both methyl or both ethyl are similarly reduced to produce the alcohol intermediate shown in Formula XX. Alternately, to produce the compounds where Y _j and Y ₂ are both hydrogen, reduction of Formula XVIII compounds wherein Y _} and Y ₂ are both halogens can be performed employing a reduction system which reduces the ketone group to the alcohol while also dehalogenating the benzene ring to produce Formula XX alcohols. Sodium borohydride in ethanol in the presence of a PdCl ₂ catalyst at 20°C is a preferred reduction

system to achieve both reduction and dehalogenation.

i -- Compounds of Formula I wherein X is -C- and R^ (and R ₂

R ₂ ) is hydrogen are produced from the intermedia es of Formulas XIX and XX by further reduction at the alcohol group. Compounds of Formula XXI (Y^ and Y ₂ are both halogens, methyl or ethyl) or XXII (Y-__ and Y ₂ are both hydrogen), when reacted in a suitable solvent at 0°C with sodium borohydride in trif luoroacetic acid produce compounds of Formulas XXI and XXII, respectively.

The alcohols of Formulas XIX and XX are also employed as intermediates to produce compounds wherein X is

. ^'

C and R ₂ is hydrogen and R^ is -OR3 with R3 being a lower R ₂ alkyl group. A Williamson synthesis whereby the alcohols or Formula XIX or XVII are converted to the corresponding alkoxide and reacted with an alkyl halide of the Formula R3X is used to produce the ethers represented by Formulas XXIII (Y _j and Y ₂ are both halogens, methyl or ethyl) and XXIV (Y _χ and Y are both hydrogen).

XXIII

To produce the compounds of Formula I wherein X is R-, 0

I II

-C- and R _j is -0-C-R ₄ (R ₂ is hydrogen), the alcohols of

R ₂ Formulas XIX and XX are esterified. Acyl halides of the

0 11 formula R4-C-X can be reacted with the alcohols of Formulas

XIX or XX, respectively, preferably in the presence of a solvent capable of acting as an acid scavenger, e.g., pryridine, to produce compounds of Formulas XXV (halogenated) (Y-L and Y ₂ are both halogen, methyl or ethyl) or XXVI ( - and ₂ are both hydrogen), respectively:

0

The compounds of Formula I react to form acid addition salts with pharmaceutically acceptable acids, for example, with inorganic acids, such as hydrochloric acid, hydrobro ic acid, sulphuric acid and phosphoric acid and with

organic acids such as acetic acid, tartaric acid, maleic acid, citric acid and toluenesulfonic acid.

The compounds of the Formula I above and the salts thereof are useful in treating arrhythmic conditions and conditions for which treatment with a vasodilator is indicated. The novel pharmaceutically active agents provided by the present invention can be administered in pharmaceutical dosage forms, internally, for example, parenterally or enterally with dosage adjusted to fit the exigencies of the therapeutic situation. The pharmaceutical dosage forms are prepared by incorporating the active ingredient in conventional liquid or solid vehicles to thereby provide emulsions, suspensions, tablets, capsules, powders and the like according to acceptable pharmaceutical practices. A wide variety of carriers or diluents as well as emulsifying agents, dispersing agents and other pharmaceutically acceptable adjuvants can be incorporated in the pharmaceutical dosage forms.

The following examples are offered to illustrate the invention and are not intended to be limiting.

EXAMPLE I Preparation of ( 2-n-buty 1-3-benzof urany 1 ) 4-[2- (diethylamino)ethoxyl] -3 , 5-diiodophenyl methanol .

One 1 mmole (645 mg ) of the ketone ( 2-n-buty 1-3- benzofuranyl) 4- [ 2-(diethy lamino)ethoxyl ] -3,5-diiodopheny 1 - methanone is dissolved in 30 ml of THF:MeOH (10:1 v/v). Sodium borohydride (1.2 mmole, 45.42 mg ) is added to the solution and the mixture is stirred and maintained at a temperature of 0°C until the starting material is consumed ( 15 minutes). Excess borohydride is destroyed by the dropwise addition of water (0.5 ml). Volatile components are removed under reduced pressure (roto-evaporator). Water is added to the residue ( 10 ml) followed by the addition of methylene chloride ( 10 ml). The methylene chloride layer is separated from the aqueous phase and is dried over anydrous sodium sulfate. The methylene chloride solvent is removed

under reduced pressure and the product is purified by column chromatography (silica gel support using methylene chloride) and is recovered by reduced pressure evaporation of the methylene chloride. The yield of the product, .p. 106- 107 ^β C, is >50% of theoretical. (The m.p. of the hydrochloride salt is 143-145°C.)

EXAMPLE II

Preparation of ( 2-n-butyl-3-benzof uranyl) 4- [2-

(diethylamino) ethoxyll -phenyl methanol .

One mmole (645 mg) of the ketone, ( 2-n-buty 1-3- benzofuranyl) 4- [2-(diethylamino)ethoxyl]-3,5-diiodophenyl methanone is dissolved in 10 ml of methanol. Palladium dichloride (2 mmole, 354 mg) is added and the mixture is agitated to suspend the palladium dichloride. The temperature of the mixture is adjusted to 20°C. Sodium borohydride (10 mmole, 379 mg ) is added and stirring is continued until reaction is complete ( 1 hour). The palladium dichloride is removed by filtration and water is added to the filtrate. An ether extraction is performed and the product is removed from the ether phase by evaporation under reduced pressure. The produce is purified by chromatography (silica gel using methylene chloride) and results in >50% yield of the product, m.p. 203°C

(decomposes ) .

EXAMPLE III

Preparation of ( 2-n-butyl-3-benzof uranyl ) 4- [2-

(diethylamino) ethoxyl] -3 ,5-diiodophenyl methane. One mmole (647 mg) of the alcohol as prepared in

EXAMPLE I is dissolved in methylene chloride (5 ml). Sodium borohydride (38 mg , 10 mmole) added to 10 ml of trif luoroacetic acid and the mixture is cooled to 0°C. The methylene chloride solution is added slowly to the trif luoacetic acid solution and the mixture stirred for 30 minutes at 0°C. Excess borohydride is destroyed by the

dropwise addition of water (0.5 ml). Volatile components are removed under reduced pressure (roto-evaporator). Water is added to the residue (25 ml) followed by the addition of methylene chloride (25 ml). The methylene chloride layer is separated, washed twice with 25 ml of 5% aqueous sodium hydroxide and 25 ml of water. The methylene chloride solution is dried over sodium sulphate and then passed through a short ( 5 cm) basic alumina column. Evaporation of the solvent yields the product, m.p. 80-81°C, in >70% yield. (The m.p. of the hydrochloride salt is 119-121°C.)

EXAMPLE IV Preparation of methoxy ( 2-n-butyl-3-benzofuranyl) 4- [2-(diethylamino)ethoxyl] -3,5-diiodophenyl methane.

One mmole (647 mg ) of the alcohol as prepared in EXAMPLE I is dissolved in 10 ml of THF. The solution is cooled to -78°C and lithium diisopropylamide in cyclohexane (1.1 mmole, 0.73 ml of a 1.5 M solution) is slowly added. Methyl iodide (1.2 mmole, 0.17 g) is added and the mixture permitted to warm to room temperature ( 30 minutes). The volatile components are removed under reduced pressure (roto- evaporator) and the residue is dissolved in methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate and is purified by passing the solution through silica gel column as in EXAMPLE I. The product, m.p. 96-98°C, is obtained upon evaporation of the solvent in a theoretical yield of >90%.

EXAMPLE V Preparation of ( 2-n-buty 1-3-benzof uranyl ) 4-[2- (diethylamino)ethoxyl] -3 ,5-diiodophenyl methyl pivalate.

One mmole (647 mg) of the alcohol as prepared in EXAMPLE I is dissolved in pyridine (4 ml). Excess pivaloyl chloride (5 mmole, 605 mg) is added to the pyridine solution and the mixture heated to 65°C until the starting alcohol is completely consumed (approximately 12 hours). Volatile materials are removed under reduced pressure (roto- evaporator). The residue is dissolved in methylene chloride

and the methylene chloride solution washed twice with 25 ml of 5% aqueous sodium hydroxide and once with 25 ml of water. The methylene chloride solution is dried over sodium sulfate and then passed through a short ( 5 cm) basic alumina column. Evaporation of the solvent yields the product in >90% yield. (The m.p. of the hydrochloride salt is 108-110°C.)