The invention relates to compounds having pharmacological activity and more particularly relates to novel pharmacologically active 3-subs tituted 2-alkyl benzo(b) thiophene derivatives, and methods for their 5 preparation.

Compounds in accordance with the invention are represented by the general formula:

and pharmaceutically acceptable addition salts thereof wherein X represents a substituted or unsubstituted alkylene 15 chain containing 1 to 4 carbon atoms, wherein Re. is a lower alkyl group, wherein Rg is either hydrogen or methyl, wherein Am is a group selected from the class consisting of. amino, lower mono and dialkylamino, piperidino, piperazino, N-lower alkyl piperazino, pyrrolidino, and morpholino groups, wherein 20 Y^ and Y2 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 aliphatic hydrocarbon chain of between 1 and 4 carbon atoms with or without one or more substituents. Substituents are limited ^to those which do not diminish the pharmacological activity o ^f t ^h e com ^p ounds below a useful level and include branche _d or stra ^igh t-ch ^a in alkyl or cycloalkyl groups, aryl groups,

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 methylamino, 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 an t iarry thmic agents. Preferred for this purpose are compounds of Formula I above

? ¹ wherein X represents the Formula -C- above wherein RT and/or i -~

R ₂

R ₂ are hydrogen, lower alkyl groups, groups with the Formula -OR with R3 being a lower alkyl group, or groups with the

O II Formula -0-C-R4 with ₄ being hydrogen or a lower alkyl group, R5 is a lower alkyl group containing 1-4 carbon atoms,

Rg is hydrogen, Am is as defined above for Formula I, ^ 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 _l

R ₂ is hydrogen, or -OR3 with R3 being a lower alkyl group, or R _j

0 11 is -0-C-R4 with R ₄ being hydrogen or a lower alkyl group, R ₅ is butyl, Rg is hydrogen, Am is amino ^" or lower mono and dialkyl amino, Y-^ and Y are identical and are hydrogen, bromine, iodine, or methyl and n is an integer in the range

of 1-3. Most preferably, X is -C- wherein R ₂ is hydrogen and

R

R _] _ is hydrogen or -OR ₃ with R ₃ being a lower alkyl group

0

II containing between 1 and 4 carbon atoms, or R _χ 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, R ₆ is hydrogen. Am is amino, ethylamino or diethylamino, ι 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 ₂ are both hydrogen are particularly desirable. Compounds of Formula I in which R is hydrogen are prepared by first condensing an alkali metal salt of a compound represented by Formula II below in which X, R ₅ , _] _ and Y ₂ have the same meanings as in Formula I with a dibro oal ane represented by Formula III in which R ₆ is hydrogen and n is 1-5 in an inert organic medium such as dimethyl formamide.

The resulting bromoalkoxy-substituted compounds of Formula IV are condensed with an amine of the Formula V in which _A m has t ^h e same meaning as in Formula I in an inert so _l vent suc _h as ^b enzene 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

Z-CH-(CH ) _n -Am I ~ ^{~~ R} 6

The compounds represented by Formula II can be 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 R ₅ , Y _1# and Y ₂ are as defined in Formula I.

When A is a single, direct bond, Formula VII ketones generally are known intermediates and are disclosed in U.S. Patent No. 4,007,204 which is 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-Craf ts acylation of a 2, 6-subst ituted anisole of Formula IX with an acid chloride of Formula VIII wherein m represents an integer of 0-3 and R ₇ 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 oan be prepared from 3- carboxy-2-alkyl benzothiophenes of Formula X by reaction in the presence of CdCl ₂ with an alkene Grignard reagent of Formula XI wherein o is 0-2 and R _? and R ₈ are defined as in Formula VIII to result in the formation of the secondary alcohols of Formula XII.

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 benzothiophene 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.

XIV

The particularly preferred compounds of Formula I

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

R'

0 II hydrogen or 0- R ₃ with R ₃ being a lower alkyl group or o-C-R ₄ with R ₄ 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:

with R ₄ , Re,, Rg, _j _ and Y ₂ , and n as defined for Formula I. Formula XIV ketones wherein Y and Y ₂ are methyl, Rg is hydrogen and n is 2-5 are known and procedures for their synthesis are described in U.S. Patent No. 4,007,204, the disclosure of which is 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 XV 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 tetrahydrofuran-methanol mixture (10:1 v/v) at approximately 0°C produces high yields of the alcohol represented by Formula XVI:

To prepare compounds of the invention wherein Y^ and Y 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 XVII. Alternately, to produce the compounds where Y^ and Y ₂ a ^re both hydrogen, reduction of Formula XV compounds wherein ^ 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 XV 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.

Compounds of Formula I wherein X is C and R ₁ (and

R ₂ ) is hydrogen are produced from the intermediates of Formulas XVI and XVII by further reduction at the alcohol group. Compounds of Formula XVI (Y _j and Y are both halogens, methyl or ethyl) or XVII (Y _χ and _{2 a} r _{e b} ot _h hydrogen), when reacted in a suitable solvent at 0° _{C w} it _h sodium borohydride in trif luoroacetic acid produce c _o mp _ou n _ds of Formulas XVIII and XIX, respectively.

-9-

XVIII

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

C and R ₂ is hydrogen and R^ is -OR3 and R3 is a lower alkyl.

A Williamson synthesis whereby the alcohols or Formula XVI or XVII are converted to the corresponding alkoxide and reacted with an alkyl halide of the Formula R ₃ X is used to produce the ethers represented by Formulas XX (Y and Y ₂ are both halogens, methyl or ethyl) and XXI ( ^ and Y ₂ are both hydrogen) .

To produce the compounds of Formula I wherein X is

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

Formulas XV and XVI are esterified. Acyl halides of the 0

II formula R -C-X can be reacted with the alcohols of Formulas XV or XVI, respectively, preferably in the presence of a solvent capable of acting as an acid scavenger, e.g., pryridine, to produce compounds of Formulas XXII ( ^ and ₂ are both halogen, methyl or ethyl) or XXIII (Y^ and Y ₂ are both hydrogen), respectively:

XXIII

The compounds of Formula I react to _f orm aci _d a ^dd it ⁱ on salts with pharmaceutically accepta _bl e _a ci _d s, _f or

example, with inorganic acids, such as hydroαhloric acid, hydrobromic acid, sulphuriα acid and phosphoric acid and with organic acids such as acetic acid, tartaric acid, maleic acid, citric acid and toluenesulfoniσ aαid. 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 pharmaσeutiσal 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 pharmaαeutiσal 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 pharmaαeutiαal dosage forms.