WO1994003425A2

WO1994003425A2 - Carbostyril derivatives for the treatment of arrhythmia

Info

Publication number: WO1994003425A2
Application number: PCT/US1993/007050
Authority: WO
Inventors: Dominique Blondet; Jean-Claude Pascal
Original assignee: Syntex (U.S.A.) Inc.
Priority date: 1992-07-31
Filing date: 1993-07-30
Publication date: 1994-02-17
Also published as: AU4787593A; MX9304626A; WO1994003425A3; IL106549A0

Abstract

Compounds of formula (I), wherein m is 0, 1 or 2; n is 0, 1 or 2; R1 is hydrogen, lower alkyl, or phenyl lower alkyl; R2 is hydrogen, lower alkyl, trifluoromethyl, lower alkoxy, or phenyl lower alkoxy; R3 is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy; R4 is hydrogen, lower alkyl, or hydroxy, provided that when R4 is hydroxy both m and n are 1; R5 is hydrogen or lower alkyl; R6 is lower alkyl; W and Y are independently -SO¿2?- or -C(O)-; X is oxygen, -S(O)p-, -CH2-, or a single bond; wherein p is 0, 1 or 2; and Z is -CH=CH- or -(CH2)q-, wherein q is 1 or 2; or a pharmaceutically acceptable acid addition salt, ester or N-oxide thereof, are useful in the treatment of cardiovascular diseases, particularly arrhythmias.

Description

HETEROCYCLIC DERIVATIVES USEFUL IN THE TREATMENT OF

CARDIOVASCULAR DISEASES

BACKGROUND OF THE INVENTION

Field of the Invention

This invention is concerned with heterocyclic derivatives useful in treating cardiovascular diseases, particularly in treating arrhythmias. Background to the Invention

Aryl and heterocyclic derivatives are disclosed in the patent literature as having cardiotonic, anti-arrhythmic, α- and β-adrenoceptor blocking activities, and as being calcium antagonist, antihistaminic and local anesthetic agents. See, for example, U.S. Patents Nos. 4,081,447, 4,210,753, 4,256,890, 4,482,560, 4,642,309, and 5,082,847; European Patent Applications 245,997 and 355,583; and Japanese Kokai Tokyo Koho Sho

57-018,674, 59-164,786, 55-002,631, and 53-028,179.

SUMMARY OF THE INVENTION

A first aspect of this invention comprises compounds of the formula:

wherein:

m is 0, 1 or 2;

n is 0, 1 or 2;

R¹ is hydrogen, lower alkyl, or phenyl lower alkyl;

R² is hydrogen, lower alkyl, trifluoromethyl, lower alkoxy, or phenyl lower alkoxy;

R³ is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy;

R⁴ is hydrogen, lower alkyl, or hydroxy, provided that when R⁴ is hydroxy both m and n are 1;

R⁵ is hydrogen or lower alkyl;

R⁶ is lower alkyl;

W and Y are independently -SO₂- or -C(O)-;

X is oxygen, -S(O)_p-, -CH₂-, or a single bond; wherein p is 0, 1 or 2; and

Z is -CH=CH- or - (CH₂)_q- , wherein q is 1 or 2;

or a pharmaceutically acceptable acid addition salt, ester or N-oxide thereof.

A second aspect of this invention comprises pharmaceutical

compositions containing at least one compound of Formula I and one or more pharmaceutically acceptable excipients.

A third aspect of this invention comprises methods for treating cardiovascular disease in a mammal by administering an effective amount of a compound of Formula I, or a composition containing it, to the mammal. In a preferred embodiment, the cardiovascular disease treated is a cardiac arrhythmia.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein:

"Alkyl" means a branched or unbranched saturated hydrocarbon chain containing 1 to 8 carbon atoms, such as methyl, ethyl, propyl, tert-butyl, n-hexyl, n-octyl and the like.

"Lower alkyl" means a branched or unbranched saturated hydrocarbon chain containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, n-hexyl and the like, unless otherwise indicated.

"Lower alkoxy" means the group -O-R wherein R is lower alkyl is as defined above.

"Phenyl" encompasses all possible isomeric phenyl radicals optionally monosubstituted or disubstituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, trifluoromethyl and halo.

"Phenyl lower alkyl" denotes phenyl as defined above attached to a lower alkyl group as defined above, for example phenylmethyl (benzyl), 1-phenylethyl, and the like.

"Benzyl" denotes phenylmethyl.

"Halo" denotes fluoro, chloro, bromo, or iodo, unless otherwise indicated.

"N-oxide" refers to the stable amine oxide formed at the heterocyclic nitrogen atom.

The term "leaving group" means a group capable of being displaced by a nucleophile in a chemical reaction, for example chloro, bromo, iodo, methanesulfonate, toluenesulfonate, and the like.

The terms "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform ("CHCl₃"), methylene chloride (or dichloromethane or "CH₂Cl₂"), diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like]. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

"Pharmaceutically acceptable ester" as used herein refers to those non-toxic esters of a compound of Formula I where R⁴ is hydroxy, and are formed by reaction of such compounds with an appropriate carboxylic acid or carboxylic acid derivative. Typical esters are those derived from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, hexanoic acid, optionally substituted benzoic acid, optionally substituted phenylacetic acid, and the like. The esters are prepared by methods well known in the art, for example by reacting the compound of Formula I with the appropriate acid in the presence of an acid catalyst, for example sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and the like.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally followed by converting the free base to the acid addition salt" means that said conversion may or may not be carried out in order for the process described to fall within the invention, and the invention' includes those processes wherein the free base is converted to the acid addition salt and those processes in which it is not.

It should be understood that Formula I where R⁴ is other than hydrogen represents the racemic form of compounds of Formula I as well as the individual enantiomers and non-racemic mixtures thereof. The scope of the invention as described and claimed encompasses the racemic forms of the compounds of Formula I as well as the individual enantiomers and non-racemic mixtures thereof.

The term "treatment" as used herein covers any treatment of a disease in a mammal, particularly a human, and includes:

(i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it;

(ii) inhibiting the disease, i.e. arresting its development; or (iii) relieving the disease, i.e. causing regression of the disease.

The term "a disease-state that is characterized by cardiac

arrhythmia" as used herein is intended to cover all disease states which are generally acknowledged in the art to be usefully treated with anti-arrhythmia compounds in general, and those disease states which have specifically been found to be usefully treated by the specific compounds of our invention, the compounds of Formula I. Such disease states include, but are not limited to, supraventricular premature beat, heart block (first degree block, second degree block and complete degree block), atrial fibrillation, atrial flutter, atrial tachyarrhythmia of other etiology, atrioventricular nodal or atrioventricular junctional arrhythmias, ventricular premature beats (unifocal ventricular premature beats and multifocal ventricular premature beats), torsades de pointes, ventricular tachyarrhythmia, ventricular fibrillation, sudden death after myocardial infarction or in congestive heart failure, supraventricular arrhythmia, ventricular tachycardia, and junctional re-entry arrhythmia.

The numbering of the compounds of Formula I varies according to the definitions. For example, a compound of Formula I where both n and m are 1 and Z is -(CH₂)₂- is numbered as illustrated below:

Alternatively, a compound of Formula I where m is 1, n is 0 and Z is -CH₂- is numbered as illustrated below:

Following are examples of how representative compounds of Formula I are named: A compound of Formula I wherein m and n are 1, R¹ and R³ are hydrogen, R² is methyl, R⁴ is hydroxy, R⁵ and R⁶ are methyl, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is -(CH₂)₂- is named:

3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methane-sulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril.

A compound of Formula I wherein m is 1, n is 0, R¹, R³, R⁴ are hydrogen, ^R2 is methoxy, R³ and R⁶ are methyl, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is -(CH₂)₂- is named:

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril.

A compound of Formula I wherein m is 1, n is 0, R¹ and R⁴ are hydrogen, R² is methoxy, R³ is 7-trifluoromethyl, R³ and R⁶ are methyl, W is -C(O)-, X is oxygen, Y is -SO₂-, and Z is -(CH₂)₂- is named:

3,4-dihydro-8-methoxy-7-trifluoromethyl-5-{2-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]ethoxy}-1H-2,1-benzothiazine-2,2-dioxide.

Preferred Embodiments

Among the family of compounds of the present invention, one preferred category includes the compounds where Y is -C(O)-, Within this category a preferred group includes the compounds where R⁴ is hydrogen and R³ is lower alkyl, especially where m is 1 and n is 0. One preferred subgroup within this group includes compounds in which W is -SO₂- and R³ and R⁶ are methyl, especially where R¹ and R³ are hydrogen, and R² is lower alkyl or lower alkoxy. One preferred class within this subgroup includes compounds where X is a single bond or oxygen, Z is - (CH₂)₂-, and R² is methyl or methoxy.

Another preferred group of this category includes those compounds where R⁴ is hydroxy, and m and n are both 1. One preferred subgroup within this group includes compounds in which W is -SO₂- and R³ and R⁶ are methyl, especially where R¹ and R³ are hydrogen, and R² is lower alkyl or lower alkoxy. One preferred class within this subgroup includes compounds where X is a single bond, Z is -(CH₂)₂-, and R² is methyl or methoxy.

Another preferred category includes the compounds where Y is -SO₂-. Within this category a preferred group includes the compounds where R⁴ is hydrogen and R³ is lower alkyl, especially where m is 1 and n is 0. One preferred subgroup within this group includes compounds in which W is -SO₂- and R³ and R⁶ are methyl, especially where R¹ and R³ are hydrogen, and R² is lower alkyl or lower alkoxy. One preferred class within this subgroup includes compounds where X is a single bond or oxygen, Z is -(CH₂)₂-, and R² is methyl or methoxy.

Another preferred group within this third category includes those compounds where R⁴ is hydroxy, and m and n are both 1. One preferred subgroup within this group includes compounds in which W is -SO₂- and R⁵ and R⁶ are methyl, especially where R¹ and R³ are hydrogen, and R² is lower alkyl or lower alkoxy. One preferred class within this subgroup includes compounds where X is oxygen or a single bond, Z is -(CH₂)₂-, and R² is methyl or methoxy.

At present the most preferred compounds are:

3,4-dihydro-8-methoxy-5{2-[N-(2-(4-methanesulfonamido¬phenyl)ethyl)methylaminolethoxy}carbostyril; and

3,4-dihydro-8-methyl-5{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril.

PREPARATION OF INTERMEDIATES OF FORMULA (1)

A common intermediate for the preparation of compounds of Formula I has the following structure:

wherein R¹, R², R³, Y and Z are as defined in the Summary of the Invention. Compounds of Formula (1) may be prepared by methods well known in the art, and by the procedures set forth below.

(A) Preparation of Carbostyril Derivatives

(i) The compounds of Formula (1) where Y is -C(O)- and Z is -(CH₂)₂- or -CH=CH- are carbostyril derivatives, illustrated below as formula (1a):

where the broken line represents an optional bond.

Compounds of Formula (1a) may be prepared, for example, by procedures disclosed in U.S. Patent No. 5,082,847, the complete disclosure of which is hereby incorporated by reference. (ii) Compound of Formula (la) where R¹ and R³ are hydrogen and R² is trifluoromethyl (la¹)

Compounds of Formula (1a) where R¹ and R³ are hydrogen and R² is trifluoromethyl (shown below as Formula (1a¹)) are preferably prepared as shown below in Reaction Scheme IA:

i.e. (1a¹) is a compound of Formula (1a) where R¹ and R³ are hydrogen, R² is trifluoromethyl, and Z is -(CH₂)₂-. The synthesis of such compounds is shown in more detail in Preparation 1, infra.

Compounds of Formula (1a) where R¹ and R³ are hydrogen, R² is trifluoromethyl, and Z is -CH=CH- are made similarly, except the step of hydrogenating the compound of Formula (6) to (7) is eliminated. (B) Preparation of Oxindole Derivatives

The compounds of Formula (1) where Y is -C(O)- and Z is - (CH₂) - are oxindole derivatives, illustrated below as formula (1b):

The compounds of Formula (lb) may be prepared, for example, by procedures according to Beckett et al., Tetrahedron, Vol. 24, pp 6093-6109 (1968).

(C) Preparation of 3,4-dihydro-1H-2,1-benzothiazine-2,2-dioxide

Derivatives

The compounds of Formula (1) where Y is -SO₂- and Z is - {CH₂) ₂- are 3,4-dihydro-1H-2,1-benzothiazine-2,2-dioxide derivatives, illustrated below as formula (1c):

Compounds of Formula (lc) where R¹ is benzyl and R² and R³ are hydrogen (shown below as (1c¹)), may be prepared, for example, by the procedure shown in Reaction Scheme IB below.

REACTION SCHEME IB

i .e . (1c¹) is a compound of Formula (1c) where R¹ is benzyl and R² and R³ are hydrogen .

The preparation of the compound of Formula (1c¹) is set forth in more detail in the Preparations . Similarly, other compounds of Formula (1c) , varying R¹ , R² and R³, may be prepared by similar methods .

METHODS OF PREPARATION OF COMPOUNDS OF FORMULA I

A. COMPOUNDS OF FORMULA I WHERE R⁴ IS HYDROXY AND n AND m ARE l

Those compounds of Formula I where R⁴ is hydroxy and n and m are 1 may be prepared as follows: where R⁵ is lower alkyl, by reacting together the intermediates of Formula (16) and (22); and where R⁵ is hydrogen, by reacting together the intermediates of Formula (16) and (21b), followed by debenzylation. The preparation of intermediate (16) is shown in Reaction Scheme II, intermediate (21b) in Reaction Scheme IIIB, and intermediate (22) in Reaction Schemes III and IIIA.

Preparation of Intermediates of Formula (16)

The preparation of a compound of Formula (16) starts from the compound of Formula (1) , as shown in Reaction Scheme II below. REACTION SCHEME II

where Halo is chloro or bromo, and R¹, R², R³, Y and Z are as defined in the Summary of the Invention.

The hydroxy heterocycle of Formula (1) is reacted with about 1-2 molar equivalents, preferably about 1.1 molar equivalents, of a suitable base, preferably an alkali hydroxide (such as sodium hydroxide), in an appropriate inert solvent (e.g., lower alkanol, dioxane or water, or mixtures thereof). To this mixture is added about 1-20 molar equivalents, preferably about 10 molar equivalents, of an epihalohydrin (commercially available from, i.a. Aldrich). The reaction is carried out at a

temperature of about from 10-100°C, preferably at about 20°C, for about 4 to 48 hours, preferably about 20 hours. The reaction product, a (2,3-epoxypropoxy)-heterocycle compound of Formula (16), is purified by conventional means, e.g., extraction by an organic solvent, fractional recrystallizations, column chromatography methods, or the like.

Alternatively, the preparation of a compound of Formula (16) may be conducted according to the procedures described in U.S. Patent No.

4,482,560 (where the starting material is 5-hydroxy-3,4-dihydrocarbostyril), or in Swiss Patent No. 547,800 (where the starting material is 4-hydroxyoxindole), or in JP Patent No. 59,164,786 A2 (where the starting' material is 5-hydroxy-3,4-dihydro-1H-2,1-benzothiazine-2,2-dioxide). Preparation of Intermediates of Formula (22)

The preparation of a compound of Formula (22), where R⁵ is lower alkyl, is shown in Reaction Scheme III below. REACTION SCHEME III

where Bn is benzyl, Halo is chloro, bromo or iodo, R⁵ is lower alkyl, and R⁶, W and X are as defined in the Summary of the Invention.

Preparation of Intermediates of Formula (19)

Intermediates of Formula (19) (where R⁵ is lower alkyl) may be prepared starting from compounds of Formula (17). For example, the intermediate of Formula (19) wherein X is a single bond can be prepared starting from 4-nitrophenethyl bromide (17), (available e.g. from Aldrich).

The derivative of Formula (17) is contacted with a phenylmethylamine of the Formula (18), where R⁵ is lower alkyl, (available e.g. from Aldrich) to form the amine of Formula (19). Reaction conditions are well known to those skilled in the art, e.g. as described in U.S. Patent No. 3,139,456.

Intermediates of Formula (19) wherein X is -(CH₂)- can be prepared starting from the appropriate 4-nitrophenylalkyl halide (17), for example 3-(4-nitrophenyl)propyl bromide, which may be prepared as shown in J. Med. Chem. , Vol. 20, No. 8, p1023 (1977).

Intermediates of Formula (19) wherein X is oxygen can be prepared starting from 3-(4-nitrophenoxy)ethyl halide (17), which may be prepared as shown in EPO Patent 0 245 997 or Chemical Abstracts, Vol. 54, 11046a.

Intermediates of Formula (19) wherein X is -S(O)_p- can be prepared starting from the appropriate 4-nitrothiophenoxyethyl halide (17), for example 4-nitrothiophenoxyethyl bromide, which may be prepared as shown in J. Am. Chem. Soc , Vol. 45, p2405. Preparation of Intermediates of Formula (20)

Reduction of the nitro compound of Formula (19) to the amine of Formula (20) (where R⁵ is lower alkyl) is readily accomplished by

conventional methods, e.g. by hydrogenating (19) under hydrogen at atmospheric pressure in the presence of a metal catalyst, preferably platinum (IV) oxide. The reaction is conducted in an inert solvent, preferably a lower alkanol, most preferably methanol, at a temperature of about from 10-40°C, preferably at about 20°C, for about 2 to 10 hours, preferably about 3 hours. The reaction product, an N-benzylalkylamine derivative of Formula (20), may be purified by conventional means, or preferably used directly in the next reaction without further purification.

Preparation of Intermediates of Formula (21)

The compound of Formula (21) (where R⁵ is lower alkyl) is prepared by conventional reaction of the intermediate of Formula (20) with a compound of the formula R⁶WHalo, where Halo is chloro or bromo and R⁶ and W are as defined in the Summary of the Invention, for example as described in EPO Pat. Appl. No. 0245,997, or alternatively with an anhydride of the formula (R⁶W)₂O.

Preparation of Intermediates of Formula (22)

The benzyl group of the compound of Formula (21) is removed to give (22) (where R⁵ is lower alkyl) by conventional hydrogenation, at a hydrogen pressure of about 1-5 atmospheres, preferably about 1 atmosphere, in the presence of a metal catalyst, preferably palladium hydroxide. The reaction is conducted in an inert solvent, preferably a lower alkanol, most preferably ethanol, at a temperature of about from 10-40°C, preferably at about 20°C, for about 2 to 12 hours, preferably about 6 hours. The reaction product, an alkylamine derivative of Formula (22), may be purified by conventional means.

Alternatively, intermediates of Formula (22) wherein X is a single bond can be prepared from 4-aminophenethyl alcohol (available e.g. from Aldrich) according to the method disclosed in EPO Pat. Appl. No. 0245,997. Preparation of Compounds of Formula (22) where R⁵ is lower alkyl, R⁶ is methyl, X is -CH₂-, and W is -SO₂- A convenient and highly efficient method of preparing compounds of Formula (22) where R⁵ is lower alkyl, R⁶ is methyl, X is -CH₂-, and W is -SO₂- is shown in Reaction Scheme IIIA below: REACTION SCHEME IIIA

where R³ is lower alkyl. Compounds of Formulae (21a) and (22a) are embodiments of compounds of Formulae (21) and (22) (disclosed in Reaction Scheme III above) where R⁵ is lower alkyl, R⁶ is methyl, X is -CH₂-, and W is -SO₂-. The compound of Formula (25a) is an embodiment of a compound of Formula (25) (disclosed in Reaction Scheme IVA below) where R⁶ is methyl, X is -CH₂-, and W is -SO₂-.

The compound of Formula (23) is prepared according to the procedure in J. Med. Chem. , Vol. 20, 1023 (1970). Its conversion to the compound of Formula (22a) is described in detail in Preparation 4C infra.

Preparation of Intermediates of Formula (21b) The preparation of a compound of Formula (21b), which is an embodiment of a compound of (21) where R⁵ is hydrogen, is shown in Reaction Scheme IIIB below.

REACTION SCHEME IIIB

Intermediates of Formula (21b) may be prepared starting from compounds of Formula (25). The compound of Formula (25) is reacted with a large excess of benzylamine (as a solvent), in the presence of about 1-2 molar equivalents, preferably about 1.1 molar equivalents, of a suitable base, preferably an organic base, more preferably a tertiary amine, most preferably triethylamine. The reaction is carried out at a temperature of about from 80-120°C, preferably at about 80°C, for about 4 to 48 hours, preferably about 24 hours. When the reaction is substantially complete, the reaction product, an amine of Formula (21b), which is a compound of Formula (21) where R⁵ is hydrogen, is separated and purified by

conventional means, preferably recrystallization. Preparation of Compounds of Formula I where R⁴ is hydroxy and n and m are 1

A. Preparation of I where R⁵ is lower alkyl

The compounds of Formula I where R⁴ is hydroxy, R⁵ is lower alkyl, and n and m are 1 are made by reaction of the intermediates of Formula (16) and (22) where R⁵ is lower alkyl, as shown in Reaction Scheme IV.

REACTION SCHEME IV

where R⁴ is hydroxy, R³ is lower alkyl, and m and n are 1, and R¹, R², R³, R⁶, W, X, Y and Z are as defined in the Summary of the Invention.

The compound of Formula (16) is reacted with about 1-2 molar equivalents, preferably about 1.1 molar equivalents, of an amine of Formula (22) (where R⁵ is lower alkyl) in an inert solvent capable of dissolving both reactants, for example, a lower alkanol, preferably isopropanol. The reaction is carried out at a temperature of about from 60-120°C, preferably at about the reflux temperature of the solvent used, for about 4 to 48 hours, preferably about 20 hours.

Note that the compound where R¹ is benzyl can be hydrogenated to the compound where R¹ is hydrogen at this stage by addition of a hydrogenation catalyst, preferably palladium hydroxide, and stirring under hydrogen, in the same manner as shown above for the preparation of (22).

The reaction product, a compound of Formula I where m and n are 1, R⁴ is hydroxy, and R⁵ is lower alkyl, is then purified by conventional means, e.g. column chromatography followed by formation of an acid addition salt.

Alternatively, the reaction may be carried out using a compound of Formula (16) where R¹ is hydrogen, Y is -C(O)- and Z is -(CH₂)₂- as

disclosed in U.S. Patent Nos. 4,482,560 and 5,082,847.

Alternatively, the reaction may be carried out using a compound of Formula (16) where R¹ is hydrogen, Y is -C (O) - and Z is - (CH₂) - as disclosed in Swiss Patents CH 548,391 and CH 571,490.

Alternatively, the reaction may be carried out using a compound of Formula (16) where R¹ is hydrogen, Y is -SO₂- and Z is -(CH₂)₂- as described in the Japanese Patent No. JP 59,164,786.

B. Preparation of I where R⁵ is hydrogen

The compounds of Formula I where R⁴ is hydroxy, R⁵ is hydrogen, and n and m are 1, are made by reaction of the intermediates of Formula (16) and (21b), followed by debenzylation, as shown in Reaction Scheme IVA. REACTION SCHEME IVA

where Bn is benzyl, R⁴ is hydroxy, and m and n are 1, and R¹, R², R³, R⁶, W, X, Y and Z are as defined in the Summary of the Invention.

The compound of Formula (16) is reacted with about 1-2 molar equivalents, preferably about 1.1 molar equivalents, of an amine of Formula (21b) in an inert solvent capable of dissolving both reactants, for example, a lower alkanol, preferably isopropanol. The reaction is carried out at a temperature of about from 60-120°C, preferably at about the reflux temperature of the solvent used, for about 4 to 48 hours, preferably about 20 hours. The reaction product, a compound of Formula (26), is then isolated by conventional means, and debenzylated by means well known in the art, for example as shown above in Reaction Scheme III, for the preparation of compounds of Formula (22), to give a compound of Formula I where m and n are 1, R⁴ is hydroxy, and R⁵ is hydrogen, which is then separated and purified by conventional means, e.g. column chromatography followed by formation of an acid addition salt.

B. COMPOUNDS OF FORMULA I WHERE R⁴ IS HYDROGEN OR LOWER ALKYL

The compounds of Formula I where R⁴ is hydrogen or lower alkyl may be prepared as follows: where R⁵ is lower alkyl, from the intermediates of Formula (31) or (33), the preparation of which is shown below in Reaction Schemes V and VII; where R⁵ is hydrogen, from the intermediate of Formula (34), the preparation of which is shown below in Reaction Scheme VIII.

Preparation of Intermediates of Formula (31) The preparation of a compound of Formula (31) where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl is shown in Reaction Scheme V.

REACTION SCHEME V

where R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and R¹, R², R³, m, n, X, Y and Z are as defined in the Summary of the Invention.

Preparation of Compounds of Formula (28)

An ethyl halide derivative of Formula (17), where X is as defined above, is reacted with an appropriately substituted amine of Formula (27) (i.e. where R⁵ is lower alkyl) to give the ethylamino derivative (28). The reaction is conducted in presence of an excess of amine (27) in an appropriate inert solvent (e.g. a lower alkanol, dimethylformamide or the like) at atmospheric pressure, or alternatively (preferably for lower boiling amines) the reaction is carried out in a sealed vessel, reacting with about 2-20 molar equivalents, preferably about 10 molar equivalents, of amine (27) where R⁵ is lower alkyl. The reaction is conducted at a temperature ranging from 60 to 120° C, preferably 70 to 90°C, for 12 to 48 hours, preferably for 18 to 24 hours. The reaction product of Formula (28) is purified by conventional means, e.g., extractions by an organic solvent, fractional recrystallizations, column chromatography methods, or the like.

Alternatively, preparation of the compound of Formula (28) can be conducted according to the procedure described in e.g., J. Org. Chem. 21, 45 (1956).

Preparation of Compounds of Formula (30)

The ω-chloroalkoxy heterocycle of Formula (29) where R⁴ is hydrogen or lower alkyl is then reacted with about 1-2 molar equivalents, preferably about 1.1 molar equivalents, of the amine of Formula (28) where R⁵ is lower alkyl, in the presence of about 1-2 molar equivalents, preferably about 1.1 molar equivalents, of an agent able to neutralize hydrochloric acid (e.g., potassium or sodium carbonate or bicarbonate and the like, preferably potassium carbonate) and the reaction can.be optionally catalyzed by addition of one molar equivalent of a metal halide (e.g. lithium bromide and the like) . The reaction is conducted in an inert solvent, (for example tetrahydrofuran, dioxane, toluene, lower alkanol, acetonitrile,

dimethylformamide or the like, preferably dimethylformamide, acetonitrile or lower alkanol, most preferably acetonitrile), at a temperature of about 40-150°C, preferably at about the reflux temperature of the solvent employed, for about 10 to 50 hours, preferably about 36 hours. The reaction product, a heterocyclic nitrophenyl derivative of Formula (30) where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl, may be purified by conventional means.

Alternatively, the ω-chloroalkoxyheterocycles of Formula (29) and the amine of Formula (28) may be condensed using conventional methods such as those described in EP. Appl. 0245,997, or U.S. Patents 4,482,560 and 5,082,847.

Preparation of Compounds of Formula (31)

The nitro derivative of Formula (30) where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl is then hydrogenated conventionally, at a hydrogen pressure of about 1-5 atmospheres, preferably about 1 atmosphere, in the presence of a hydrogenation catalyst, preferably platinum (IV) oxide. The reaction is conducted in an inert solvent, preferably a lower alkanol, most preferably methanol, at a temperature of about from 10-40°C, preferably at about 20°C, for about 6 to 30 hours, preferably about 12-16 hours. When the reaction is substantially complete, the reaction product, a heterocyclic aminophenyl derivative of Formula (31) where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl, may be isolated and purified by conventional means.

Preparation of the Intermediate of Formula (29) An essential reactant in Reaction Scheme V, step 2, is a compound of

Formula (29) where R⁴ is hydrogen or lower alkyl, the preparation of which is shown in Reaction Scheme VI below.

REACTION SCHEME VI

where R⁴ is hydrogen or lower alkyl and R¹, R², R³, m, n, Y and Z are as defined in the Summary of the Invention.

The compound of Formula (1) (obtained as described above) is reacted with about 1 to 50 molar equivalents, preferably about 20-30 molar equivalents, of a ω-dihaloalkane of Formula (32) where R⁴ is hydrogen or lower alkyl. The reaction is carried out in the presence of about 1 to 2 molar equivalents, preferably about 1.1 molar equivalents, of a base, for example aqueous alkali hydroxide (e.g sodium hydroxide), or preferably aqueous alkali carbonate, most preferably aqueous potassium carbonate, in the presence of a phase transfer catalyst, for example "Aliquat 335". The reaction is conducted at about 50-100°C, preferably about 100°C, for 2 to 12 hours, preferably about 4 hours. Isolation and purification of the resulting haloalkoxy-heterocycle of Formula (29) where R⁴ is hydrogen or lower alkyl, if required, is achieved by conventional methods, such as extraction, crystallization or column chromatography.

The compounds of Formula (29) wherein R¹ is hydrogen, Y is -C(O)-, and Z is - (CH₂) ₂- can also be obtained using known procedures, e.g., as described in JP. 5, 1133.274, in U.S. Patent No. 4,482,560 and U.S. Patent No. 5,082,847.

Alternatively, compounds of Formula (29) can be prepared by contacting a hydroxy-heterocycle of Formula (1) with an ω-chloro- or a ω-bromo-alkyl-p-toluene sulfonate according, for example, to the method described in EPO Pat. Appl. No. 0245,997.

Preparation of the Intermediate of Formula (33)

The compounds of Formula (29), the preparation of which is shown in

Reaction Scheme VI above, are also useful for the preparation of the intermediates of Formula (33), as shown below in Reaction Scheme VII.

REACTION SCHEME VII

where R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and R¹, R², R³, m, n, Y and Z are as defined in the Summary of the Invention.

Preparation of Compounds of Formula (33)

In a manner similar to the method described in the preparation of the compound of Formula (28) above (Reaction Scheme V) , an alkylamine of Formula (27) (i.e. (27) where R⁵ is lower alkyl) is contacted with an ω-chloro-alkoxy-heterocycle of Formula (29) where R⁴ is hydrogen or lower alkyl to produce the desired secondary amino derivative of Formula (33) where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl.

Preparation of Intermediates of Formula (34)

The preparation of a compound of Formula (34) where R⁴ is hydrogen or lower alkyl is shown below in Reaction Scheme VIII.

REACTION SCHEME VIII

In a manner similar to the method described in the preparation of the compound of Formula (30) above (Reaction Scheme V), an benzylamine of Formula (21b) (i.e. (21) where R⁵ is hydrogen) is contacted with an ω-chloro-alkoxy-heterocycle of Formula (29) where R⁴ is hydrogen or lower alkyl to produce the desired secondary amino derivative of Formula (34) where R⁴ is hydrogen or lower alkyl.

Preparation of Compounds of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl a) From the Intermediate of Formula (31)

One method of preparing compounds of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl is from the intermediate of Formula (31), as shown in Reaction Scheme IX below.

REACTION SCHEME IX

where R⁴ is hydrogen or lower alkyl, R³ is lower alkyl, and R¹, R², R³, m, n, Y and Z are as defined in the Summary of the Invention.

The phenylamino derivative of Formula (31) is reacted with about 1 to 1.2 molar equivalents, preferably about 1.1 molar equivalents, of a compound of Formula R⁶WHalo, where Halo is chloro or bromo and R⁶ and W are as defined above, or alternatively with an anhydride of the formula (R⁶W) ₂O, in an inert solvent, preferably methylene chloride, in the presence of about 1 to 3 molar equivalents, preferably about 1.2 molar equivalents, of an inorganic or organic base, preferably a tertiary amine, most preferably triethylamine. The reaction is carried out for about 30 minutes to 6 hours, preferably about 1 hour, at a temperature of about 0-70°C,

preferably at about 30-50°C, followed by stirring overnight at room temperature. When the reaction is substantially complete the compound of Formula I is isolated and purified by conventional means, preferably chromatography followed by formation of an acid addition salt, preferably a monohydrochloride salt.

Alternatively, the reaction may be carried out as described in E.P. Appl. 0245,997. b) From the Intermediate of Formula (33)

Compounds of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl may also be prepared from the intermediate of Formula (33), as shown in Reaction Scheme X below.

REACTION SCHEME X

The amine of Formula (33) is reacted with about 1 to 1.4 molar equivalents, preferably about 1.1 molar equivalents, of a compound of Formula (25) (prepared, for example, according to EPO Pat. Appl. No.

0245,997) to give a compound of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl. The reaction is conducted in the presence of about 1 equivalent of a base, preferably a tertiary base, most preferably pyridine, in an inert polar solvent, preferably acetonitrile, for about 6 to 30 hours, preferably about 16 hours, at a temperature of about 20-100, preferably at the reflux temperature of the solvent employed. When the reaction is substantially complete the compound of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is lower alkyl is isolated and purified by conventional means, preferably chromatography followed by formation of an acid addition salt, preferably a monohydrochloride salt.

Preparation of Compounds of Formula I where R⁴ is hydrogen or lower alkyl and R^s is hydrogen

One method of preparing compounds of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is hydrogen is from the intermediate of Formula (34), as shown in Reaction Scheme XI below. REACTION SCHEME XI

To prepare compounds of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is hydrogen, the benzyl group of the compound of Formula (34) is removed by conventional hydrogenation, at a hydrogen pressure of about 1-5 atmospheres, preferably about 1 atmosphere, in the presence of a metal catalyst, preferably palladium hydroxide. The reaction is conducted in an inert solvent, preferably a lower alkanol, most preferably methanol, at a temperature of about from 10-40°C, preferably at about 20°C, for about 6 to 48 hours, preferably about 20 hours. The reaction product, a compound of Formula I where R⁴ is hydrogen or lower alkyl and R⁵ is hydrogen, is purified by conventional means, preferably by recrystallization of an acid addition salt, preferably a monohydrochloride salt.

Preparation of Compounds of Formula I where R⁴ is an Acyloxy Group

Esterification of compounds of Formula I where R⁴ is hydroxy can be carried out according to known methods. See, for example, "Protecting Groups in Organic Synthesis," Theodora W. Greene, John Wiley and Sons, 1981.

Esterification is generally accomplished by heating the compound of Formula I where R⁴ is hydroxy with an equivalent or an excess of the appropriate carboxylic acid anhydride, chloride or bromide in a suitable solvent in the presence of a tertiary amine. Temperature is kept at

10-90°C for 4-24 hours, preferably at 15-30°C for 6-8 hours. The desired ester is then recovered by ςonventional extraction and purification methods. Examples can be found in U.S. Patent, No. 4,374,835 and the appropriate sections of Morrison and Boyd, supra and Fieser and Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, published in 1967. Suitable esters which are prepared include acetates, propionates, butanoates, hexanoates, octanoates, dodecanoates and the like. Preparation of Compounds of Formula I as Pure Enantiomers

A. From a Racemic Mixture of Formula I

Products of Formula I wherein R⁴ is not a hydrogen atom exist in two different enantiomeric forms which can be resolved using conventional methods . One such method consists of contacting a racemic compound of Formula I with a suitable optically active acid e.g. preferably L-pyroglutamic acid in a ratio which may vary from 0.8:1 to 1.4:1, preferably 1:1, in a lower alkanol solvent, at a temperature within approximately 10°C of the reflux temperature of the solvent, and then allowing the resulting insoluble optically active acid salt of Product I to crystallize from the solution.

The crystalline insoluble optically active acid salt of Product I is then cleaved with a suitable base, preferably with sodium or potassium hydroxide, to produce one enantiomer of a compound of Formula I.

The opposite enantiomer of Formula I can be prepared starting from the remaining mother liquors of the crystallized optically active acid salt of Formula I obtained above.

The mother liquors are concentrated under reduced pressure and the residue is treated with aqueous potassium or sodium hydroxide. The aqueous phase is extracted with a suitable organic solvent (preferably methylene chloride or chloroform) which is then worked up by conventional means to recover the crude opposite enantiomer of Product I. Purification is achieved by contacting this crude enantiomer with D-pyroglutamic acid following the method described above.

From Optically Active Intermediates

Enantiomers of compounds of Formula I wherein R⁴ is hydroxy can also be prepared by reacting first a compound of Formula (1) with a chiral epihalohydrin according to general conditions described under Reaction Scheme II for the preparation of (16), then condensing the resulting chiral compound as before with an amine of Formula (22), following the reaction conditions given under Reaction Scheme IV.

Chiral epihalohydrins are commercially available, e.g. (2R) and (2S)-epichlorohydrins may be obtained from DAISO Co. Ltd. (Japan).

Alternatively, in Reaction Scheme II epihalohydrins can be replaced by chiral glycidyltosylates which are readily available, e.g. (2R)- and (2S)-glycidyltosylates can be obtained from Aldrich Chemical Co.

(Wisconsin). Preparation of Products of Formula I as acid addition salts

The compounds of Formula I in free base form may be converted to the acid addition salts by treatment with the appropriate organic or inorganic acid, such as, for example, phosphoric, pyruvic, hydrochloric or sulfuric acid and the like. Typically, the free base is dissolved in a polar organic solvent such as ethanol or methanol, and the acid added thereto. The temperature is maintained between about 0°C and about 100°C. The resulting acid addition salt precipitates spontaneously or may be brought out of solution with a less polar solvent.

The acid addition salts of the compounds of Formula I may be decomposed to the corresponding free base by treatment with a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent, and at a temperature of between about 0°C and 100°C. The free base form is isolated by conventional means, such as extraction with an organic solvent .

Salts of the compounds of Formula I may be interchanged by taking advantage of differential solubilities and volatilities, or by treatment with a suitably loaded ion exchange resin. This conversion is carried out at a temperature between about 0°C and the boiling point of the solvent being used as the medium for the procedure.

Preferred Processes

In summary, compounds of Formula I are prepared according to the following last steps:

1. A process for preparing compounds of Formula I, wherein:

m and n are 1;

R¹ is hydrogen, lower alkyl, or phenyl lower alkyl;

R³ is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy;

R⁴ is hydroxy;

R⁵ is lower alkyl;

R⁶ is lower alkyl;

W and Y are independently -SO₂- or -C(O)-;

X is oxygen, -S(O)_p-, -CH₂-, or a single bond;

wherein p is 0, 1 or 2; and

Z is -CH=CH- or -(CH₂)_q-, wherein q is 1 or 2;

comprises:

reacting a compound of the formula:

where R¹, R², R³, Y and Z are as defined above, with a compound of the formula:

where R³ is lower alkyl and R⁶, W and X are as defined above.

2. Alternatively, a process for preparing compounds of Formula I where R⁴ is hydrogen or lower alkyl, R³ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the Summary of the Invention,

comprises:

reacting a compound of the formula:

where R⁴ is hydrogen or lower alkyl , R³ is lower alkyl , and m, n, R¹ , R²

R⁶ W, X, Y and Z are as defined in the Summary of the Invention;

with a compound of Formula R⁶WHalo, in which Halo is chloro or bromo and R⁶ and W are as defined above, or alternatively with an anhydride of the formula (R⁶W)₂O.

3. Alternatively, a process for preparing compounds of Formula I where R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the Summary of the Invention, comprises reacting a compound of the formula:

where R⁴ is hydrogen or lower alkyl , R³ is lower alkyl , and m, n, R¹ , R², R³, R⁶, W, X, Y and Z are as defined in the Summary of the Invention;

with a compound of the formula:

where R⁶, W and X are as defined above .

4. Alternatively, a process for preparing compounds of Formula I where R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the Summary of the Invention, comprises reacting a compound of the formula:

wherein R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the Summary of the Invention;

with a compound of the formula:

where R³ is lower alkyl , and R⁶, W and X are as defined above .

5. Alternatively, a process for preparing compounds of Formula I where m, n, R¹, R², R³, R⁴, R⁵, R⁶, W, X, Y and Z are as defined in the Summary of the Invention, comprises reacting a compound of the formula:

where L is a leaving group, and m, n, R⁴, R⁵, R⁶, W and X are as defined above.

6. Alternatively, a process for preparing compounds of Formula I where R⁵ is hydrogen, and m, n, R¹, R², R³, R⁴, R⁶, W, X, Y and Z are as defined in the Summary of the Invention, comprises reacting a compound of the formula:

where Bn is benzyl, and m, n, R¹, R², R³, R⁴, R⁶, W, X, Y and Z are as defined in the Summary of the Invention;

with hydrogen.

7. Alternatively, a process for preparing compounds of Formula I where m, n, R¹, R², R³, R⁴, R⁵, R⁶, W, X, Y and Z are as defined in the

Summary of the Invention, comprises:

(a) reacting the free base of a compound of Formula I with an acid to give a pharmaceutically acceptable acid addition salt; or

(b) reacting an acid addition salt of a compound of Formula I with a base to give the corresponding free base; or

(c) converting an acid addition salt of a compound of Formula I to another pharmaceutically acceptable acid addition salt of Formula I.

Utility and Administration

General utility

The compounds of this invention and the pharmaceutically acceptable salts, esters and N-oxides thereof are useful for the treatment of cardiovascular diseases in mammals, particularly humans, including a wide variety of arrhythmias, including supraventricular premature beat, heart block (first and second degree and complete), atrial fibrillation, atrial flutter, atrial tachyarrhythmia of other etiology, atrioventricular nodal or atrioventricular junctional arrhythmias, ventricular premature beats (unifocal and multifocal), torsades de pointes, ventricular

tachyarrhythmia, ventricular fibrillation, and to prevent sudden death, particularly after myocardial infarction or in congestive heart failure. In particular, the compounds of the present invention are useful for the treatment of supraventricular arrhythmia, ventricular tachycardia, and junctional re-entry arrhythmia.

Testing

The utility of a compound for treating arrhythmia can be assessed in vitro by measuring the ability of the compound to prolong the effective refractory period in guinea-pig papillary muscle as described by Bruckner, Schmitz & Scholz (Naunyn - Schmiedeberg's Arch. Pharmacol. (1985) 329, 86-93) using the preparation described by Dumez, Patmore, Ferrandon, Allely & Armstrong (J. Cardiovascular Pharmacol . , 1989, 14 , 184-193). The in vivo antiarrhythmic activity of a compound may be determined by measuring its ability to prolong the VERP (ventricular effective refractory period) and the QTc-interval of the ECG in an anesthetized guinea-pig (see, e.g., Poizot, J.Pharmacol . (Paris) 17 (1986) 712-719).

Formulation and Administration

A second aspect of this invention comprises pharmaceutical

compositions useful in the treatment of arrhythmia in mammals . Such compositions contain a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt or N-σxide thereof, in admixture with one or more pharmaceutically acceptable excipient(s).

The level of the drug in the formulation can vary from about 0.1 percent weight (%w) to about 95%w of the drug based on the total

formulation and about 99.9%w to 5%w excipient. Preferably the drug is present at a level of about 0.1%w to about 80%w.

Useful pharmaceutical excipients for the preparation of the

pharmaceutical compositions hereof can be solids or liquids. Thus, the compositions can take the form of tablets, capsules, powders, sustained release formulations, solutions, suspensions, aerosols, and the like.

Liquid excipients can be selected from various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soyabean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions.

Suitable solid excipients include starch, cellulose, microcrystalline cellulose, talc, glucose, lactose, sucrose, gelatin, povidone,

crosscarmellose sodium, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, and the like.

Other suitable pharmaceutical excipients and their formulations are described in "Remington's Pharmaceutical Sciences" 16th Edit. (1980), by E.W. Martin.

A third aspect of this invention comprises methods for treating disease-states that are characterized by cardiac arrhythmia in mammals (particularly humans) which comprise administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically

acceptable acid addition salt or N-oxide thereof, or a composition containing it, to the mammalian subject.

In the practice of this method, a therapeutically effective amount of the compound of Formula I or a pharmaceutical composition containing it is administered in any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention or other pharmaceutical agents. These compounds or compositions can thus be administered orally, systemically

(e.g., transdermally, intranasally or by suppository) or parenterally (e.g. intramuscularly, subcutaneously and intravenously), and can be administered either in the form of solid or liquid dosages including tablets, solutions, suspensions, aerosols, and the like, as discussed in more detail above. It is preferred to administer compounds of Formula I orally and parenterally.

The formulation can be administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.

In view of the foregoing, as well as in consideration of the degree of severity of the condition being treated, age of subject and so forth, all of which factors are routinely determinable by one skilled in the art, the effective dosage in accordance herewith can vary over a wide range. Generally a therapeutically effective amount ranges from about 0.001 to about 25mg/kg body weight per day and preferably about 0.005 to about 20mg/kg body weight per day. In alternative terms, for an average 70kg adult human subject, a therapeutically effective amount in accordance herewith would be, in preferred embodiments from about 0.07mg to about 1750mg per day per subject, and preferably from about 0.35mg to 1400mg per day per subject.

The following Preparations and Examples are intended to illustrate the invention, but are not intended to limit its scope.

PREPARATION 1

Preparation of 3,4-dihydro-5-hydroxy-8- trifluoromethylcarbostyril, the Compound of Formula (1a¹)

A. Preparation of 3-nitro-4-trifluoromethylanisole (3)

A suspension of 3-nitro-4-bromoanisole (36 g), potassium

trifluoroacetate (41.2 g) and copper (I) iodide (56.3 g) in toluene (250 ml) was heated, distilling off about 150 ml of the solvent. Dry

dimethylformamide (300 ml) was then added and the mixture distilled until the temperature of the reaction mixture reached 150°C. Heating was maintained at this temperature for 3 hours. After cooling, the reaction medium was filtered and the filtrate evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel, eluting with heptane/ethyl acetate (95/5), to yield 3-nitro-4-trifluoromethylanisole, the compound of Formula (3), as a yellow solid (12 g). m.p. 40-42°C.

B. Preparation of 3-amino-4-trifluoromethylanisole (4)

A solution of 3-nitro-4-trifluoromethylanisole (13 g), the compound of Formula (3), in ethanol (150 ml) was stirred at room temperature in the presence of platinum (IV) oxide (1.5 g) under one atmosphere of hydrogen for 48 hours. After filtration the filtrate was evaporated and the residue chromatographed on silica gel, eluting with methylene chloride/heptane (40/60), to give 3-amino-4-trifluoromethyl-anisole, the compound of Formula (4), as a pale yellow oil (9.1 g). C. Preparation of 3-[3,3-(diethoxy)propionamido]-4-trifluoromethylanisole (5)

A solution of 3-amino-4-trifluoromethylanisole (7 g), the compound of Formula (4), and 3,3-(diethoxy)propionic acid (7.7 g) in chloroform (100 ml) was added dropwise to a solution of dicyclohexylcarbodiimide (11.7 g) in chloroform (100 ml). After addition was complete, the reaction medium was heated under reflux for 48 hours. After cooling the solvent was evaporated and the residue chromatographed on silica gel, eluting with methylene chloride/methanol (99/1), giving 3-[3,3-(diethoxy)propionamido]-4-trifluoromethyl-anisole, the compound of Formula (5), as an amorphous white solid (6 g). m.p. 52-53°C.

D. Preparation of 5-methoxy-8-trifluoromethylcarbostyril (6)

3-[3,3-(diethoxy)propionamido]-4-trifluoromethyl-anisole (5.8 g), the compound of Formula (5), was added portionwise to cold 12N hydrochloric acid (50 ml), and the resulting solution was stirred at 0°C for 2 hours. Addition of crushed ice (100 g) to the reaction medium precipitated the desired compound, which was isolated by filtration. Washing with water and drying gave 3.1 g of 5-methoxy-8-trifluoromethylcarbostyril, the compound of Formula (6), m.p. 170-171°C.

E. Preparation of 3,4-dihydro-5-methoxy-8-trifluoromethyl-carbostyril (7)

A solution of 5-methoxy-8-trifluoromethylcarbostyril (0.5 g), the compound of Formula (6), in methanol (50 ml) was stirred at 50°C under one atmosphere of hydrogen in the presence of 10% palladium on carbon (0.13 g) for 72 hours. After cooling the catalyst was removed by filtration, and the filtrate evaporated to dryness to give 3,4-dihydro-5-methoxy-8-trifluoromethylcarbostyril (0.45 g), the compound of Formula (7), as an off-white solid, m.p. 107°C.

F. Preparation of 3,4-dihydro-5-hydroxy-8-trifluoromethyl-carbostyril (1a¹)

A solution of 3,4-dihydro-5-methoxy-8-trifluoromethyl-carbostyril (0.4 g), the compound of Formula (7), in 48% hydrobromic acid (5 ml) was stirred and refluxed for 90 minutes. After cooling, cold water (10 ml) was added and an off-white solid was isolated by filtration and washed with cold water. After drying under vacuum 3,4-dihydro-5-hydroxy-8-trifluoromethylcarbostyril (0.3 g), the compound of Formula (1a¹), was obtained, m.p. over 260°C. Similarly, starting with 3-nitro-4-bromoanisole substituted in the 5- or 6- position with an appropriate R³ group, and following the procedures of Preparation 1A to 1F above, other compounds of Formula (la) substituted at the 8-position by trifluoromethyl are prepared. PREPARATION 2

Preparation of 3,4-dihydro-5-hydroxy-1-(phenylmethyl)-1H-2,1- benzothiazine-2,2-dioxide, the Compound of Formula (1c¹) A. Preparation of 3-amino-2-methylanisolβ (9)

A solution of 10 g of 2-methyl-3-nitroanisole (2) in 200 ml of methanol was hydrogenated at atmospheric pressure under hydrogen in the presence of a small amount of platinum oxide on carbon as a catalyst. The reaction was carried out at room temperature and was complete in 3 hours. The catalyst was removed by filtration and the desired 3-amino-2-methylanisole of Formula (9) was recovered by evaporation of the solvent. The yield was quantitative (8.2 g), and the 3-amino-2-methylanisole was used in the next step without further purification. B. Preparation of 2-methyl-3-methylsulfonylaminoanisole (10)

A solution of 5.8 ml of methanesulfonyl chloride was added to a solution of 8.2 g of the crude 3-amino-2-methylanisole (9), in 150 ml chloroform and 6.5 ml pyridine at 0° C. The reaction was complete after stirring at room temperature for 20 hours. The reaction medium was poured into 500 ml water and the desired material was recovered by extraction with methylene chloride, washing the organic phase first with dilute

hydrochloric acid, then with water, drying over sodium sulfate and evaporation of the solvent. The residue, 13.5 g of 2-methyl-3-methylsulfonylaminoanisole, the compound of Formula (10), m.p. 97°C, was used in the next step without further purification.

C. Preparation of N-benzyl-2-methyl-3-methylsulfonylamino- anisole (11)

To a solution of 14.3 g of the methylsulfonylamino compound (10) in 200 ml dimethylformamide was added 1.84 g of sodium hydride (80%) in portions; stirring at room temperature was maintained for 1 hour. Benzyl bromide (7 ml) was then added; the reaction medium was heated to 70° C for 1 hour and then allowed to return to room temperature overnight.

Dimethylformamide was removed by evaporation under reduced pressure, and the residue was dissolved in chloroform. The organic phase was washed twice with water, dried over sodium sulfate, and the solvent removed under reduced pressure. The desired compound was recovered by flash

chromatography using methylene chloride as eluent, giving 19 g of N-benzyl-2-methyl-3-methylsulfonylamino anisole, the compound of Formula (11), m.p. 93-94°C.

D. Preparation of N-benzyl-2-acetoxymethyl-3-methylsulfonyl-amino anisole (12)

60 g of eerie ammonium nitrate was added to a solution of 15 g of N-benzyl-2-methyl-3-methylsulfonylamino anisole (11) in 350 ml acetic acid, and the reaction mixture heated to reflux until full decolorization occurred (red to yellow in about 1 hour). Acetic acid was removed by evaporation under reduced pressure, and the residue was partitioned between a mixture of water-methylene chloride. The organic phase was separated, washed and dried over sodium sulfate, and the solvent removed under reduced pressure. The desired compound was isolated by flash chromatography

(methylene chloride/methanol 99/1), giving 11 g of N-benzyl-2-acetoxymethyl-3-methylsulfonylamino anisole, the compound of Formula (12), as a pale yellow oil. E. Preparation of N-benzyl-2-hydroxymethyl-3-methylsulfonyl-aminoanisole (13)

A solution of 10.2 g of N-benzyl-2-acetoxymethyl-3-methylsulfonylamino anisole (12) in 200 ml methanol, 50 ml of water and 5 ml of 35% aqueous sodium hydroxide was stirred for 3 hours at room temperature. Methanol was removed by evaporation under reduced pressure, and the resulting aqueous medium extracted with methylene chloride. After separation, the organic phase was washed and dried over sodium sulfate. Evaporation of the solvent left 8.6 g of N-benzyl-2-hydroxymethyl-3-methylsulfonylamino anisole, the compound of Formula (13), which was used in the next step without further purification.

F. Preparation of N-benzyl-2-chloromethyl-3-methyl-sulfonylaminoanisole (14)

2.1 ml of thionyl chloride was added dropwise over 15 minutes to a stirred cold solution of 8.2 g of N-benzyl-2-hydroxymethyl-3-methylsulfonylamino anisole (13) in 50 ml chloroform. The reaction mixture was stirred at room temperature overnight, then washed twice with 30 ml cold water. The organic phase was dried over sodium sulfate. Evaporation of the solvent left 8.5 g of N-benzyl-2-chloromethyl-3-methylsulfonylamino anisole, the compound of Formula (14), which was used without further purification in the following step.

G. Preparation of 3,4-dihydro-5-methoxy-1-benzyl-1H-2,1-benzothiazine-2,2-dioxide (15)

A solution of 8.5 g of N-benzyl-2-chloromethyl-3-methylsulfonylamino anisole (14) in 50 ml dimethylformamide was added over 30 minutes to a cold solution of 1.9 g sodium hydride in 30 ml of dimethylformamide. The reaction mixture was stirred for 10 hours at room temperature, then heated to 60° C for 4 hours, and finally allowed to return to room temperature. Dilute hydrochloric acid was added until the pH rose to 6.

Dimethylformamide was removed by evaporation under reduced pressure, and the residue dissolved in methylene chloride. The organic phase was washed with water, dried over sodium sulfate, and the solvent evaporated under reduced pressure. The residue was flash chromatographed (ethyl

acetate/heptane 1:3), to yield 3,4-dihydro-5-methoxy-1-benzyl-1H-2,1- benzothiazine-2,2-dioxide, the compound of Formula (15).

H. Preparation of N-benzyl-3,4-dihydro-5-hydroxy-1H-2,1-benzothiazine-2,2-dioxide (1c¹)

To a cold solution of 1.7 g of 3,4-dihydro-5-methoxy-1-benzyl-1H-2,1-benzothiazine-2,2-dioxide (15) in methylene chloride (30 ml) was added a solution of boron tribromide in methylene chloride (6 ml of a commercial IM solution). The mixture was stirred at room temperature for 3 hours . Cold water was added, and precipitated boron salts were removed by filtration. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered and the filtrate evaporated. Trituration of the residue in 30 ml isopropyl ether afforded 1 g of N-benzyl-3,4-dihydro-5-hydroxy-1H-2,l-benzothiazine-2,2-dioxide, m.p. 176° C, the compound of Formula (1c¹). Similarly, starting with 2-methyl-3-nitroanisole substituted in the

4- , 5- or 6- position with an appropriate R² and/or an R³ group, and following the procedures of Preparation 2A to 2H above, other compounds of Formula (1c) are prepared. PREPARATION 3

Preparation of Compounds of Formula (16)

A. Preparation of (16) where R¹ is benzyl, R² and R³ are hydrogen, Y is -SO₂-, and Z is - (CH₂) ₂- To a 1/1 water/dioxane mixture (20 ml), made basic by addition of sodium hydroxide (120 mg) , was added 850 mg of 3,4-dihydro-1-benzyl-5-hydroxy-1H-2,1-benzothiazine-2,2-dioxide, a compound of Formula (1c), prepared for example as shown in Preparation 2. Epichlorohydrin (2 ml) was added dropwise to the reaction mixture, which was stirred at room

temperature for 20 hours. After dilution with water (50 ml), the solution was extracted twice with chloroform (20 ml). The organic portions were combined, washed, dried over sodium sulfate, filtered and the solvent evaporated to give 3,4-dihydro-1-benzyl-5-(2,3-epoxy)propoxy-1H-2,1-benzothiazine-2,2-dioxide (16) (555 mg) as a pale yellow oil.

B. Preparation of (16) where R¹ and R³ are hydrogen, varying R², Y and Z Similarly, replacing 3,4-dihydro-1-benzyl-5-hydroxy-1H-2,1-benzothiazine-2,2-dioxide with other compounds of Formula (1), prepared for example as shown in Preparations 1 and 2, and following the procedures of Preparation 3A above, the following compounds of Formula (16) were prepared:

3,4-dihydro-5-(2,3-epoxy)propoxy-8-trifluoromethyl-carbostyril, m.p. 121°C.

4-(2,3-epoxy)propoxyindolin-2-one, m.p. 210°C; 3,4-dihydro-5-(2,3-epoxy)propoxy-8-methylcarbostyril, m.p. 180°C;

3,4-dihydro-5-(2,3-epoxy)propoxy-8-methoxycarbostyril, m.p. 196-198°C; and

5-(2,3-epoxy)propoxy-8-methoxycarbostyril, m.p. 182°C.

C. Preparation of (16), varying R¹, R², R³, Y and Z

Similarly, replacing 3,4-dihydro-1-benzyl-5-hydroxy-1H-2,1-benzothiazine-2,2-dioxide with other compounds of Formula (1), prepared for example as shown in Preparations 1 and 2, and following the procedures of Preparation 3A above, the following exemplary compounds of Formula (16) are prepared:

3,4-dihydro-1-benzyl-5-(2,3-epoxy)propoxy-8-trifluoromethyl-1H-2,1-benzothiazine-2,2-dioxide;

3,4-dihydro-1-benzyl-5-(2,3-epoxy)propoxy-8-methyl-1H-2,1-benzothiazine-2,2-dioxide;

3,4-dihydro-1-benzyl-5-(2,3-epoxy)propoxy-8-methoxy-1H-2,1-benzothiazine-2,2-dioxide;

5-(2,3-epoxy)propoxy-8-trifluoromethylcarbostyril;

5-(2,3-epoxy)propoxy-8-methylcarbostyril;

5-(2,3-epoxy)propoxy-8-methoxycarbostyril; and

7-trifluoromethyl-4-(2,3-epoxy)propoxyindolin-2-one.

PREPARATION 4

Preparation of Compounds of Formula (22)

A. Preparation of (22) where R⁵ and R⁶ are both methyl, W is -SO₂-, and X is a single bond

(i) Preparation of (19) where Bn is benzyl, R⁵ is methyl and X is a single bond

A mixture of 4-nitrophenethyl bromide (10 g), N-benzylmethylamine (5.2 g), potassium carbonate (6 g) and lithium bromide (3.8 g) were heated to 80°C in dimethylformamide (100 ml) for 12 hours. The solvent was then evaporated under reduced pressure, the residue taken up in methylene chloride and washed three times with water. The organic phase was dried

(Na₂SO₄), filtered and evaporated. The residue was flash-chromatographed on silica gel, eluting with methylene chloride containing methanol (91/2), to yield 7.5 g of N-methyl-N-benzyl-2-(4-nitrophenyl)ethylamine, a compound of Formula (19), in.p. 117-119ºC.

(ii) Preparation of (20) where Bn is benzyl, R⁵ is methyl and X is a single bond

A mixture of N-methyl-N-benzyl-2-(4-nitrophenyl)-ethylamine (15 g), prepared as shown in 4A(i) above, in methanol (300 ml), and platinum IV oxide (0.8 g) was stirred under hydrogen at atmospheric pressure for 3 hours. The reaction mixture was filtered and the solvent evaporated to give N-methyl-N-benzyl-2-(4-aminophenyl)ethylamine, a compound of Formula (20), as an oil (14 g), which was used directly without further

purification.

(iii) Preparation of (21) where Bn is benzyl, R⁵ and R⁶ are methyl, W is - SO₂-, and X is a single bond

Methanesulfonyl chloride (4.95 ml) dissolved in dry methylene chloride (15 ml) was added in 30 min. to a cold (5°C) solution of N-methyl- N-benzyl-2-(4-aminophenyl)-ethylamine (14 g), prepared as shown in 4A(ii) above, and triethylamine (7.1 ml) in dry methylene chloride (200 ml). The reaction mixture was allowed to return to room temperature and was further stirred for 48 hours. Aqueous sodium hydroxide (2.5 g) in 50 ml water) was added and the organic phase separated, washed and dried (Na₂SO₄).

Evaporation of the solvent left a residue which was purified by

chromatography on silica gel, eluting with methylene chloride containing methanol (98/2), to give N-methyl-N-benzyl-2-(4-methanesulfonamidophenyl)ethylamine, a compound of Formula (21), as an oil

(12 g), which was used directly in the next step.

(iv) Preparation of (22) where R⁵ and R⁶ are methyl, W is

-SO₂-, and X is a single bond

A solution of 12 g of N-methyl-N-benzyl-2-(4-methanesulfonamidophenyl)ethylamine, prepared as shown in 4A(iii) above, in ethanol (500 ml) containing 20% palladium hydroxide on carbon (1 g) was stirred under hydrogen at atmospheric pressure for 6 hours. The reaction mixture was filtered and the solvent evaporated to give 7.7 g of N-methyl- 2-(4-methanesulfonamidophenyl)ethylamine, a compound of Formula (22), m.p.

131-133°C.

B. Preparation of (22) where R⁵ and R⁶ are methyl, W is -SO₂-, and X is oxygen

Similarly, following the procedures of Preparations 4A(i), 4A(ii), 4A(iii) and 4A(iv) above, but replacing 4-nitrophenethyl bromide with 4-nitrophenoxyethyl chloride, the following intermediates (19), (20), (21) and (22) were prepared:

N-methyl-N-benzyl-2-(4-nitrophenoxy)ethylamine, a compound of Formula

(19) where X is oxygen and R⁵ is methyl, yield 52% of a yellow powder.

N-methyl-N-benzyl-2-(4-aminophenoxy)ethylamine, a compound of Formula

(20) where X is oxygen and R⁵ is methyl, yield 68% of a pale yellow oily product.

N-methyl-N-benzyl-2-(4-methanesulfonamidophenoxy)-ethylamine, a compound of Formula (21) where W is -SO₂-, X is oxygen and R⁵ and R⁶ are methyl, yield 71% of a white powder characterized by NMR.

N-methyl-2-(4-methanesulfonamidophenoxy)ethylamine, a compound of Formula (22) where W is -SO₂-, X is oxygen and R⁵ and R⁶ are methyl, yield 96% of a product characterized by NMR.

C. Preparation of (22) where R⁵ and R⁶ are methyl, W is -SO₂-, and X is - CH₂- (represented as (22a) in Reaction Scheme IIIA) (i) Preparation of (24)

A solution of 3.6 g of 3-(4-nitrophenyl)propan-1-ol in 150 ml of ethanol was stirred under hydrogen in the presence of 150 mg of platinum oxide at room temperature for 48 hours. The mixture was filtered, solvent removed from the filtrate under reduced pressure, and the residue was flash chromatographed, eluting with 2% methanol/methylene chloride, to yield 1.9 g of 3-(4-aminophenyl)propan-1-ol, the compound of Formula (24).

(ii) Preparation of (25a)

A solution of 1.9 g of 3- (4-aminophenyl)propan-1-ol and 3.23 ml of pyridine in 50 ml of methylene chloride was cooled to 0°C. A solution of 2.5 ml of methanesulfonyl chloride in 20 ml of methylene chloride was slowly added, and the mixture stirred for 48 hours at room temperature. The reaction was washed successively with water, IN hydrochloric acid, and water, then dried over magnesium sulfate and the solvent removed under reduced pressure. The product, 3-(4-methanesulfonamidophenyl)-1-(methanesulfonyloxy)propane, the compound of Formula (25a) , was used without further purification.

(iii) Preparation of (21a) where R⁵ is methyl

A solution of 4 g of 3-(4-methanesulfonamidophenyl)-1-(methanesulfonyloxy)propane, 1.8 ml of benzylmethylamine, and 2.1 ml of triethylamine in 50 ml of tetrahydrofuran was refluxed for 24 hours. The solvent was then removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried over magnesium sulfate, and evaporated. The residue was flash chromatographed, eluting with ethyl acetate, giving

N-methyl-N-benzyl-3-(4-methanesulfonamidophenyl)-propylamine, a compound of

Formula (21a).

(iv) Preparation of (22a) where R⁵ is methyl

A mixture of 0.9 g of N-methyl-N-benzyl-3-(4-methanesulfonamidophenyl)propylamine and 100 mg of palladium hydroxide was stirred in 50 ml of methanol under hydrogen for 48 hours at room

temperature. The catalyst was removed by filtration, and solvent removed from the filtrate under reduced pressure to give N-methyl-3-(4-methanesulfonamido-phenyl)propylamine, a compound of Formula (22a).

D. Preparation of (22) where R⁵ and R⁶ are methyl, W is -C(O)-, and X is a bond

Similarly, following the procedures of Preparations 4A(i), 4A(ii), 4A(iii) and 4A(iv) above, but replacing methanesulfonyl chloride in 4A(iii) with acetyl chloride, the following intermediate of Formula (22) was prepared:

N-Methyl-2-(4-acetamidophenyl)ethylamine. E. Preparation of (22), varying R⁵, R⁶, W and X

Similarly, following the procedures of Preparations 4A(i), 4A(ii), 4A(iii) and 4A(iv) above, but in step (i) optionally replacing 4-nitrophenethyl bromide with other compounds of Formula (17), and in step (iii) optionally replacing methanesulfonyl chloride with other compounds of formula R⁶WHalo, where Halo is chloro or bromo and R⁶ and W are as defined in the Summary of the Invention, or alternatively following the procedures of Preparations 4C(i), 4C(ii), 4C(iii) and 4C(iv) above, the following exemplary intermediates of Formula (22) are prepared:

N-methyl-2-(4-methanesulfonamidothiophenyl)ethylamine;

N-methyl-3-(4-methanesulfonamidophenyl)propylamine;

N-ethyl-2-(4-methanesulfonamidophenyl)ethylamine;

N-ethyl-2-(4-methanesulfonamidophenoxy)ethylamine;

N-methyl-2-(4-ethanesulfonamidophenyl)ethylamine; and

N-methyl-2-(4-propanamidophenyl)ethylamine.

PREPARATION 5

Preparation of Compounds of Formula (21b)

A. Preparation of (21b) where R⁶ is methyl, W is -SO₂-, and X is a single bond

A solution of 26 g of 4-[2-methanesulfonyloxy)ethyl]-methanesulfonanilide (a compound of Formula (25)) and triethylamine (13.7 g) in benzylamine (125 ml) was stirred at 100°C for 23 hours. After cooling, the solvents were removed under reduced pressure. The residue was dissolved in water and the resultant solution basified by addition of sodium hydroxide (5.5 g) in water (50 ml). Evaporation gave an off-white solid which was crystallized from propanol to give 4-[2-(benzylamino)ethyl]methanesulfonanilide, a compound of Formula (21b), (16 g, m.p. 244-245°C).

B . Preparation of (21b) varying R⁶, W and X

Similarly, following the procedures of Preparation 5A above, but replacing 4- [2-methanesulfonyloxy) ethyl] -methanesulfonanilide with other compounds of Formula (25), the following exemplary intermediates of Formula (21b) are prepared:

4-[2-(benzylamino)ethyl]ethanesulfonanilide;

4- [2-(benzylamino)ethoxy]methanesulfonanilide;

4-[2-(benzylamino)ethylthio]methanesulfonanilide; and

4-[3-(benzylamino)ethyl]propanesulfonanilide. 1REPARATION 6

Preparation of Compounds of Formula (28)

A. Preparation of (28) where R⁵ is methyl and X is a single bond

A solution of 53 g of 4-nitrophenethyl bromide (a compound of Formula

(17)) and methylamine (200 ml of a 40% wt/vol. solution in ethanol) in ethanol (400 ml) was heated overnight at 80°C in an autoclave. Solvent was removed under reduced pressure, and the residue was stirred with

dichloromethane for 30 minutes. The desired compound was filtered off and dried under vacuum, giving 44 g of N-methyl-2-(4-nitrophenyl)ethylamine, a compound of Formula (28), m.p. 165°C.

B. Preparation of (28) varying R⁵ and X

Similarly, following the procedures of Preparation 6A above, but optionally replacing 4-nitrophenethyl bromide with other compounds of

Formula (17), and optionally replacing methylamine with other amines of Formula (27), the following exemplary intermediates of Formula (28) are prepared:

N-ethyl-2-(4-nitrophenyl)ethylamine;

N-methyl-3-(4-nitrophenyl)propylamine;

N-methyl-2-(4-nitrophenoxy)ethylamine; and

N-methyl-2-(4-nitrophenylthio)ethylamine.

PREPARATION 7

Preparation of Compounds of Formula (29)

A. Preparation of (29) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² is methoxy, Y is -C(O)- and Z is - (CH₂)₂-

A mixture of 81 g of 3,4-dihydro-8-methoxy-5-hydroxycarbostyril (a compound of Formula (1a)), 1-bromo-2-chloroethane (1000 ml), water (660 ml), potassium carbonate (116 g) and phase transfer catalyst "Aliquat 336" (5 g) was stirred and heated to reflux for 4 hours. The organic phase was separated, washed with water until neutral, and approximately 800 ml of the l-bromo-2-chloroethane was removed by distillation under reduced pressure. The remaining organic portion was diluted with cold (10 to 15°C)

isopropanol (280 ml), and the desired compound recovered by filtration. Washing with cold isopropanol and drying under vacuum overnight gave 3,4-dihydro-8-methoxy-5-(2-chloroethoxy)-carbostyril, a compound of Formula (29), as a white powder (92 g, m.p. 125°C).

B. Preparation of (29) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² is methyl, Y is -C(O)- and Z is -(CH₂)₂-

Similarly, following the procedures of Preparation 7A above, but replacing 3,4-dihydro-8-methoxy-5-hydroxy-carbostyril with 3 ,4-dihydro-8- methyl-5-hydroxycarbostyril, the following compound of Formula (29) was prepared:

3,4-dihydro-8-methyl-5- (2-chloroethoxy) carbostyril, m.p. 191-192°C. C. Preparation of (29), varying m, n, R¹, R², R³, R⁴, Y and Z

Similarly, following the procedures of Preparation 7A above, but optionally replacing 3,4-dihydro-8-methoxy-5-hydroxycarbostyril with other compounds of Formula (1), and optionally replacing 1-bromo-2-chloroethane with other compounds of Formula (32), the following exemplary intermediates of Formula (29) are prepared:

3,4-dihydro-8-methoxy-5-(3-chloropropoxy)carbostyril;

3,4-dihydro-8-methyl-5-(3-chloropropoxy)carbostyril;

3,4-dihydro-6,8-dimethyl-5-(2-chloroethoxy)carbostyril;

3,4-dihydro-5-(2-chloroethoxy)carbostyril;

3,4-dihydro-8-trifluoromethyl-5-(2-chloroethoxy)-carbostyril;

8-methoxy-5-(2-chloroethoxy)carbostyril;

8-methyl-5-(2-chloroethoxy)carbostyril;

3,4-dihydro-5-(2-chloroethoxy)-1H-2,1-benzothiazine-2,2-dioxide; and 4-(2-chloroethoxy)indolin-2-one.

PREPARATION 8

Preparation of Compounds of Formula (30)

A. Preparation of (30) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² is methoxy, R⁵ is methyl, X is a single bond, Y is -C(O)- and Z is -(CH₂)₂-

To a solution of 9 g of 3,4-dihydro-8-methoxy-5-(2-chloroethoxy)carbostyril (a compound of Formula (29)), and 7 g of N-methyl-4-nitrophenethylamine (7 g) (a compound of Formula (28), prepared as shown in J.O.C. 21, 45 (1956)) in acetonitrile (200 ml) was added potassium carbonate (5.2 g) and lithium bromide (3.3 g), and the suspension was stirred at reflux for 36 hours. The insoluble material was removed by filtration and the solution was evaporated to dryness. The oily residue was chromatographed on silica gel, eluting with ethylacetate/methanol (98/2), to give 3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-nitrophenyl)ethyl)methylamino]ethoxy}carbostyril

(5 g), a compound of Formula (30), as a pale yellow oil, which was used in the next step (Preparation 9) without further purification. B. Preparation of (30) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R^s is methyl, Y is -C(O)- and Z is -(CHj)₂-, varying R², and X

Similarly, following the procedures of Preparation 8A, above, but optionally replacing 3,4-dihydro-8-methoxy-5-(2-chloroethoxy)carbostyril with other compounds of Formula (29) , and optionally replacing N-methyl-4- nitrophenethylamine with other compounds of Formula (28) , the following intermediates of Formula (30) were prepared:

3,4-dihydro-5-{2-[N-(2-(4-nitrophenyl)ethyl)-methylamino]ethoxy}carbostyril (oil);

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-nitrophenyl)ethyl)-methylamino]ethoxy}carbostyril (oil);

3,4-dihydro-6,8-dimethyl-5-{2-[N-(2-(4-nitrophenyl)-ethyl)methylamino]ethoxy}carbostyril (oil);

3,4-dihydro-5-{2-[N-(2-(4-nitrophenoxy)ethyl)-methylamino]ethoxy}carbostyril; and

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-nitrophenoxy)ethyl)-methylamino]ethoxy}carbostynil.

C. Preparation of (30), varying m, n, R¹, R², R³, R⁴, R⁵, X, Y and Z

Similarly, following the procedures of Preparation 8A, above, but optionally replacing 3, 4 -dihydro-8-methoxy-5- (2-chloroethoxy) carbostyril with other compounds of Formula (29) , and optionally replacing N-methyl-4-nitrophenethylamine with other compounds of Foirmula (28), the following exemplary intermediates of Formula (30) are prepared:

3,4-dihydro-8-trifluoromethyl-5-{2-[N-(2-(4-nitrophenyl)-ethyl)methylamino]ethoxy}carbostyril;

8-methoxy-5-{2-[N-(2-(4-nitrophenyl)ethyl)methylamino]-ethoxy}carbostyril;

8-methyl-5-{2-[N-(2-(4-nitrophenyl)ethyl)methylamino]-ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(3-(4-nitrophenyl)propyl)-methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(3-(4-nitrophenyl)propyl)-methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-nitrophenyl)ethyl)-ethylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-S-{2-[N-(2-(4-nitrophenyl)ethyl)-ethylamino]ethoxy}carbostyril;

3,4-dihydro-5-{2-[N-(2-(4-nitrophenyl)ethyl)-methylamino]ethoxy}-1H-2,1-benzothiazine-2,2-dioxide; and

4-{2-[N-(2-(4-nitrophenyl)ethyl)methylamino]ethoxy}-indolin-2-one.

PREPARATION 9

Preparation of Compounds of Formula (31)

A. Preparation of (31) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² is methoxy, R⁵ is methyl, Y is -C(O)- and Z is -(CH₂)₂-

A solution of 5 g of 3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-nitrophenyl)ethyl)methylamino]ethoxy}carbostyril (a compound of Formula (30)), in methanol (200 ml) was stirred for 16 hours at room temperature under one atmosphere of hydrogen in the presence of 20% platinum oxide on carbon (0.5 g). The reac.ion mixture was filtered and evaporated to dryness to give 3,4-dihydro-6-methoxy-5-{2-[N-(2-(4-aminophenyl)ethyl)-methylamino]ethoxy}carbostyril (4.6 g), a compound of Formula (31), which was used directly in the next step (see Example 4).

B. Preparation of (31) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R^s is methyl, Y is -C(O)- and Z is -(CH₂)₂-, varying R² and X

Similarly, following the procedures of Preparation 9A, above, but replacing 3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-nitrophenyl)ethyl)methylamino]ethoxy}carbostyril with other compounds of Formula (30), the following intermediates of Formula (31) were prepared:

3,4-dihydro-5-{2-[N-(2-(4-aminophenyl)ethyl)-methylamino]ethoxy}carbostyril, (oil);

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-aminophenyl)ethyl)-N-methylamino]ethoxy}carbostyril, (oil);

3,4-dihydro-6,8-dimethyl-5-{2-[N-(2-(4-aminophenyl)ethyl)methylamino]ethoxy}carbostyril, (oil);

3,4-dihydro-5-{2-[N-(2-(4-aminophenoxy)ethyl)-methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-aminophenoxy)ethyl)-methylamino]ethoxy}carbostyril; and

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-aminophenoxy)ethyl)-methylamino]ethoxy}carbostyril.

C. Preparation of (31), varying m, n, R¹, R², R³, R⁴, R⁵, X, Y, and Z

Similarly, following the procedures of Preparation 9A, above, but replacing 3, 4-dihydro-8-methoxy-5- {2- [N- (2- (4- nitrophenyl) ethyl)methylamino] ethoxy}carbostyril with other compounds of Formula (30) , the following intermediates of Formula (31) are prepared:

3,4-dihydro-8-trifluofomethyl-5-{2-[N-(2-(4-aminophe-yl)-ethyl)methylamino]ethoxy}carbostyril;

8-methoxy-5-{2-[N-(2-(4-aminophenyl)ethyl)methylamino]-ethoxy}carbostyril;

8-methyl-5-{2-[N-(2-(4-aminophenyl)ethyl)methylamino]-ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(3-(4-aminophenyl)propyl)-methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(3-(4-aminophenyl)propyl)-methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-aminophenyl)ethyl)-ethylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-aminophenyl)ethyl)- ethylamino]ethoxy}carbostyril;

3,4-dihydro-5-{2- [N- (2- (4 -aminophenyl) ethyl) -methylamino] ethoxy} -1H- 2 , 1-benzothiazine-2,2-dioxide; and

4-{2- [N- (2- (4-aminophenyl) ethyl)methylamino] ethoxy} -indolin-2 -one.

PREPARATION 10

Preparation of Compounds of Formula (33)

A. Preparation of (33) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² and R⁵ are methyl, Y is -C(O)-, and Z is -(CH₂)₂-

A solution of 10 g of 3,4-dihydro-8-methyl-5-(2-chloroethoxy)carbostyril, a compound of Formula (29) prepared as shown in Preparation 7, in methylamine (110 ml) was heated in a sealed vessel at 80°C for about 12 hours. After cooling, methylamine was evaporated off and the residue was taken up in water (400 ml). The mixture was made basic by addition of aqueous sodium hydroxide, and then extracted twice with methylene chloride (200 ml). The combined organic phases were washed and dried over sodium sulfate, and the solvent evaporated off to give 3,4-dihydro-8-methyl-5-[2-(methylamino)ethoxy]carbostyril, (9.5 g, m.p. 155°C), a compound of Formula (33).

B. Preparation of (33) where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² is methoxy, R⁵ is methyl, Y is -C(O)-, and Z is -(CH₂)₂-

Similarly, following the procedures of Preparation 10A above, but replacing 3,4-dihydro-8-methyl-5-(2-chloroethoxy)-carbostyril with 3,4-dihydro-8-methoxy-5-(2-chloroethoxy)-carbostyril, the following

intermediate of Formula (33) was prepared:

3,4-dihydro-8-methoxy-5-[2-(methylamino)ethoxy]-carbostyril. C. Preparation of (33), varying m, n, R¹, R², R³, R⁴, R⁵, Y

and Z

Similarly, following the procedures of Preparation 10A above, but optionally replacing 3,4-dihydro-8-methyl-5-(2-chloroethoxy)carbostyril with other compounds of Formula (29), and optionally replacing methylamine with other compounds of Formula (27), the following exemplary intermediates of Formula (33) are prepared:

3,4-dihydro-8-methoxy-5-[2-(ethylamino)ethoxy]-carbostyril;

3,4-dihydro-8-methyl-5-[2-(ethylamino)ethoxy]-carbostyril;

3,4-dihydro-8-methoxy-5-[3-(methylarαiuo)propoxy]-carbostyril;

3,4-dihydro-8-methyl-5-[3-(methylamino)propoxy]-carbostyril;

3,4-dihydro-6,8-dimethyl-5-[2-(methylamino)ethoxy]-carbostyril;

3,4-dihydro-5-[2-(methylamino)ethoxy]carbostyril;

3,4-dihydro-8-trifluoromethyl-5-[2-(methylamino)ethoxy]-carbostyril;

8-methoxy-5-[2-(methylamino)ethoxy]-carbostyril; 8-methyl-5-[2-(methylamino)ethoxy]-carbostyril;

3,4-dihydro-5-[2-(methylamino)ethoxy]-1H-2,1-benzothiazine-2,2-dioxide; and

4 -[2-(methylamino)ethoxy]indolin-2-one.

EXAMPLE 1

Preparation of Compounds of Formula I where m and n are 1,

R⁴ is hydroxy, Y is -SO₂-, and Z is - (CH₂)₂-

(Reaction Scheme IV)

A. Preparation of I where m and n are 1, R¹, R² and R³ are hydrogen, R⁴ is hydroxy, R⁵ and R⁶ are methyl, W and Y are -SO₂-, X is a single bond, and Z is -(CH₂)₂-

A solution of 3,4-dihydro-1-benzyl-5-(2,3-epoxy)propoxy-1H-2,1-benzothiazine-2,2-dioxide (270 mg) (a compound of Formula (16), prepared as shown in Preparation 3), and N-methyl-2-(4-methanesulfonamidophenyl)ethylamine (180 mg) (a compound of Formula (22), prepared as shown in Preparation 4), in isopropanol (20 ml) was heated under reflux for 20 hours. After cooling, 20% palladium hydroxide on carbon (20 mg) was added to the medium which was stirred under a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was filtered and evaporated to dryness. The residue was chromatographed on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide

(1000/50/1), to give crude 3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-methane-sulfonamidophenyl)ethyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide as a yellow oil (200 mg). The hydrochloride salt was prepared by dissolving the oily base (200 mg) in 20 ml of ethanol saturated with hydrogen chloride and precipitating the salt by addition of diethylether. The off-white solid was collected by filtration, washed with diethylether and dried to give 3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide hydrochloride (165 mg, m.p. 160-162°C), a compound of

Formula I. B. Preparation of I where m and n are 1, R⁴ is hydroxy, R⁵ is lower alkyl, Y is -SO₂-, and Z is -(CH₂)₂-, varying R¹, R², R³, R⁴, R⁶, W and X

Similarly, following the procedures of Example 1A above, but optionally replacing 3,4-dihydro-1-benzyl-5-(2,3-epoxy)propoxy-1H-2,1-benzothiazine-2,2-dioxide with other compounds of Formula (16) where Y is -SO₂- and Z is -(CH₂)₂-, prepared as shown in Preparation 3, and optionally replacing N-methyl-2-(4-methanesulfonamidophenyl)ethylamine (180 mg) with other compounds of Formula (22), prepared as shown in Preparation 4, the following exemplary compounds of Formula I where m and n are 1 and R⁴ isi hydroxy are prepared as the free base or acid addition salts thereof: 3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-acetamidophenyl)-ethyl)methylamino]propoxy}-1H-2,l-benzothiazine-2,2-dioxide;

3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide;

3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide; and

3,4-dihydro-8-trifluoromethyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide.

3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide;

3,4-dihydro-5-{2-hydroxy-3-[N-(3-(4-methanesulfonamidophenyl)propyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide; and

3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)ethylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide.

EXAMPLE 2

Preparation of Compounds of Formula I where m and n are 1

R⁴ is hydroxy and Y is -C(O)- (Reaction Scheme IV)

A. Preparation of I where m and n are 1, R¹, R² and R³ are hydrogen, R⁴ is hydroxy, R⁵ and R⁶ are methyl, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is -(CH₂)-

A solution of 240 mg of 4-(2,3-epoxy)propoxyindolin-2-one, (a compound of Formula (16), prepared as shown in Preparation 3A), and 280 mg of N-methyl-2-(4-methane-sulfonamidophenyl)ethylamine (a compound of Formula (22), prepared as shown in Preparation 4), in isopropanol (20 ml) was heated to reflux for 20 hours. The solvent was removed under reduced pressure, and the residue chromatographed on silica gel, eluting with ethylacetate/methanol (92/8), to give 4-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)-methylamino]propoxy}indolin-2-one (380 mg), a compound of Formula I, as a yellow oil. The hydrochloride salt was formed as described in Example 1A, (350 mg, m.p. 190-192°C).

B. Preparation of I where m and n are 1, R⁴ is hydroxy, W is -SO₂-, Y is -C(O)-, and Z is -(CH₂)₂-, varying R¹, R², R³, R⁴, R⁵, R⁶, and X

Similarly, following the procedures of Example 2A above, but replacing 4- (2,3-epoxy)propoxyindolin-2-one with other compounds of Formula (16), prepared as shown in Preparation 3, and optionally replacing

N-methyl-2-(4-methanesulfonamido-phenyl)ethylamine with other compounds of Formula (22), prepared as shown in Preparation 4, the following compounds of Formula I where m and n are 1 and R⁴ is hydroxy were prepared:

3, 4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril hydrochloride, m.p. 180-182°C;

3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(3-(4-methanesulfonamidophenyl)propyl)methylamino]propoxy}carbostyril hydrochloride, m.p. 172-174°C;

3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril

hydrochloride, m.p. 120-122°C;

8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril, m.p. 120°C; m.p.

hydrochloride, m.p. 168°C;

3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]propoxy}carbostyril hydrochloride, m.p. 150- 152°C; and

3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]propoxy}carbostyril hydrochloride, m.p. 148-150°C.

C. Preparation of I where m and n are 1, R⁴ is hydroxy, varying R¹, R²

R³, R⁴, R⁵, R⁶, W, X, Y and Z

Similarly, following the procedures of Example 2A above, but optionally replacing 4-(2,3-epoxy)propoxyindolin-2-one with other compounds of Formula (16), and optionally replacing N-methyl-2-(4-methanesulfonamidophenyl)ethylamine with other compounds of Formula (22), the following compounds of Formula I where m and n are 1 and R⁴ is hydroxy are prepared:

3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(3-(4-methanesulfonamidophenyl)propyl)methylamino]propoxy}carbostyril;

3,4-dihydro-8-trifluoromethyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}-carbostyril;

3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-acetamidophenyl)-ethyl)methylamino]propoxy}carbostyril;

8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamido¬phenyl)ethyl)methylamino]propoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)ethylamino]propoxy}carbostyril; and

3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)ethylamino]propoxy}carbostyril. EXAMPLE 3

Preparation of Compounds of Formula I where R⁴ is Hydrogen or

Lower Alkyl From Intermediates of Formula (33)

(Reaction Scheme X)

A. Preparation of I where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R², R⁵ and R⁶ are methyl, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is -(CH₂)₂-

A solution of 15.5 g of 3,4-dihydro-8-methyl-5-(2-methylaminoethoxy)carbostyril (a compound of Formula (33)) and 20 g of

4-[2-(methanesulfonyloxy)ethyl]methanesulfonanilide (a compound of Formula (25)) in pyridine (2.3 ml) and acetonitrile (350 ml) was heated under reflux for 16 hours. After cooling, the solvent was removed under reduced pressure, and the residue chromatographed on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide (850/40/1), to give

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)-methylamino]ethoxy}carbostyril as a pale yellow oil (10 g).

Further purification of this compound was achieved by forming its monohydrochloride salt, by dissolving the crude base in ethanol (300 ml), heating to 60°C and adding ethanol saturated with hydrochloric acid (20 ml). On cooling the monochloride salt precipitated (7 g), m.p. 210-212°C.

B. Preparation of I where R⁴ is Hydrogen or Lower Alkyl, varying m, n, R¹, R², R³, R⁴, R⁵, R⁴, W, X, Y and Z

Similarly, following the procedures of Example 3A above, but optionally replacing 3,4-dihydro-8-methyl-5-(2-methylaminoethoxy)carbostyril with other compounds of Formula (33), prepared as shown in Preparation 10, and optionally replacing

4-[2-(methanesulfonyloxy)ethyl]methanesulfonanilide with other compounds of Formula (25), the following compounds of Formula I where R⁴ is hydrogen or lower alkyl are prepared:

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)ethylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)ethylamino]ethoxy}carbostyril;

8-methyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)-methylamino]ethoxy}carbostyril;

8-methoxy-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)-methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(3-(4-methanesulfonamido¬phenyl)propyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(3-(4-methanesulfonamido phenyl)propyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-6,8-dimethyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-trifluoromethyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril; and

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-acetamidophenyl)-ethyl)methylamino]ethoxy}carbostyril. EXAMPLE 4

Preparation of Compounds of Formula I where R⁴ is Hydrogen or

Lower Alkyl from Intermediates of Formula (31)

(Reaction Scheme IX)

A. Preparation of I where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² is methoxy, R⁵ and R⁶ are methyl, W is -SO₂-, X is a single bond, Y is - C(O)-, and Z is -(CH₂)₂-

To a solution of 4.6 g of 3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-aminophenyl)ethyl)methylamino]ethoxy}carbostyril (a compound of Formula (31), prepared as shown in Preparation 9A), and triethylamine (1.9 ml) in methylene chloride (100 ml), was added dropwise methanesulfonyl chloride

(1.1 ml). The mixture was stirred and refluxed for l hour. After cooling to room temperature the stirring was continued overnight. The reaction mixture was poured into water (200 ml), the organic phase separated, and the aqueous phase extracted twice with methylene chloride (100 ml) . The organic portions were combined, washed with cold water, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual off- white solid was chromatographed on silica gel, eluting with methylene chloride/methanol (97/3), to give 3,4-dihydro-8-methoxy-5-[2-[N-[2-(4-methanesulfonamidophenyl)-ethyl]methylamino]ethoxy]carbostyril as an oily solid. Crystallization from diisopropylether/ethanol mixture gave the desired compound of Formula I as a white solid (1.2 g, m.p. 135-136°C) . The hydrochloride salt was prepared by dissolving the solid base in ethanol, adding ethereal hydrogen chloride, filtering off the resultant precipitate and washing it with diethylether (1.1 g, m.p. 140-142°C).

B. Preparation of I where i is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R² is methyl, R⁵ and R⁶ are methyl, W is -CO-, X is a single bond, Y is -C(O)-, and Z is - (CH₂)₂-

To a solution of 4 g of 3,4-dihydro-8-methyl-5-{2-[N-(2-(4-aminophenyl)ethyl)methylamino]ethoxy}carbostyril (a compound of Formula (31) , prepared as shown in Preparation 9A) in chloroform (50 ml) , was added acetic anhydride (1.6 ml) . The mixture was stirred at room temperature for 15 hours, the solvent removed under reduced pressure, and the residue purified by precipitation from ethanol with diethyl ether. The precipitate was filtered off, and the hydrochloride salt prepared by dissolving the solid base in ethanol, adding ethereal hydrogen chloride, filtering off the resultant precipitate and washing it with diethylether, to yield

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-acetamidophenyl)ethyl)-methylamino]ethoxy}carbostyril hydrochloride, (1.7 g, m.p. 193-195°C).

C. Preparation of I where m is 1, n is 0, R¹, R³ and R⁴ are hydrogen, R⁵ and R⁶ are methyl, W is -SO₂-, Y is -C(O)-, and Z is -(CH₂)₂-, varying R² and X

Similarly, following the procedures of Example 4A above, but optionally replacing 3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-aminophenyl)ethyl)methylamino]ethoxy}carbostyril with other compounds of Formula (31), prepared as shown in Preparation 9, the following compounds of Formula I where R⁴ is hydrogen or lower alkyl were prepared:

3,4-dihydro-5-{2-[N-(2-(4-methanesulfonamidophenyl)-ethyl)methylamino]ethoxy}carbostyril hydrochloride, m.p. 175°C;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril hydrochloride, m.p. 210°C;

3,4-dihydro-6,8-dimethyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril, m.p. 80°C, hydrochloride salt m.p. 190-192°C;

3,4-dihydro-5-{2-[N-(2-(4-methanesulfonamidophenoxy)-ethyl)methylamino]ethoxy}carbostyril hydrochloride, m.p. 128-130°C;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]ethoxy}carbostyril hydrochloride, m.p. 175-177°C; and

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-methanesulfonamidophenoxy)ethyl)methylamino]ethoxy}carbostyril hydrochloride, m.p. 140-142°C.

D. Preparation of I where R⁴ is Hydrogen or Lower Alkyl, varying m, n, R¹, R², R³, R⁵, R⁶, W, X, Y and Z

Similarly, following the procedures of Example 4A or 4B above, but optionally replacing 3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-aminophenyl)ethyl)methylamino]ethoxy}carbostyril with other compounds of Formula (31), prepared as shown in Preparation a, and optionally replacing methanesulfonyl chloride or acetic anhydride with other acid halides of

Formula R⁶WHalo or anhydrides of Formula (R⁶W)₂O, the following compounds of Formula I where R⁴ is hydrogen or lower alkyl are prepared:

3,4-dihydro-8-trifluoromethyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril; 8-methoxy-5-{2-[N-2-(4-methanesulfonamidophenyl)-ethyl)methylamino]ethoxy}carbostyril;

8-methyl-5-{2-[N-(2-(4-methanesulfonamidophenyl)-ethyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(3-(4-methane-sulfonamidophenyl)propyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(3-(4-methane-sulfonamidophenyl)propyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-[N-(2-(4-methane-sulfonamidophenyl)ethyl)ethylamino]ethoxy}carbostyril;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-methane¬sulfonamidophenyl)ethyl)ethylamino]ethoxy}carbostyril;

3,4-dihydro-5-{2-[N-(2-(4-methanesulfonamidophenyl)-ethyl)methylamino]ethoxy}-1H-2,1-benzothiazine-2,2-dioxide;

4-{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)-methylamino]ethoxy}indolin-2-one;

3,4-dihydro-8-methyl-5-{2-[N-(2-(4-propanamidophenyl)-ethyl)methylamino]ethoxy}carbostyril;

3,4-dihydro-8-methoxy-5-[2-[N-[2-(4-ethane-sulfonamidophenyl)ethyl]methylamino]ethoxy]carbostyril; and

3,4-dihydro-8-methyl-5-[2-[N-[2-(4-propane-sulfonamidophenyl)ethyl]methylamino]ethoxy]carbostyril.

EXAMPLE 5

Preparation of pure enantiomers of Formula I where R⁴ is hydroxy from optically active intermediates of Formula (16)

A. Preparation of Chiral I where m and n are 1, R¹ and R³ are hydrogen, R² is methoxy, R⁴ is hydroxy, R⁵ and R⁶ are methyl, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is -(CH₂)₂-

Sodium hydroxide (1.07 g) was dissolved in water (100 ml) to which 5-hydroxy-8-methoxy-3,4-dihydrocarbostyril (5.2 g) was added portionwise. After solution was complete, (R)-epichlorohydrin (5 g) was added dropwise and the resulting mixture stirred at room temperature for 16 hours. The reaction medium was extracted twice with dichloromethane (50 ml) , the organic fractions combined, washed with water, dried over magnesium sulfate, filtered and evaporated to give a pale yellow oil. Chromatography on silica gel, eluting with dichloromethane/methanol (99.3/0.7), gave (2S)-(2,3-epoxy)-propoxy-8-methoxy-3,4-dihydrocarbostyril (4.1 g), an optical isomer of a compound of Formula (16), as an off-white solid (m.p. 196- 198°C).

Similarly, proceeding as above, but substituting (S) -epichlorohydrin for (R)-epichlorohydrin, (2R)-(2,3-epoxy)propoxy-8-methoxy-3,4-dihydrocarbostyril was prepared. (m.p. 195-197°C, yield 60%) . A solution of (2S) - (2, 3-epoxy)propoxy-8-methoxy-3,4 - dihydrocarbostyril (2.18 g), prepared as shown in 6A above, and N-methyl-2- (4-methanesulfonamidophenyl) ethylamine (2 g) , a compound of Formula (22) prepared as shown in Preparation 4A, in isopropanol (70 ml) was heated to reflux for 24 hours. After evaporation of the solvent, the residue was chromatographed on silica gel, eluting with ethylacetate/methanol (92/8), to give (2S)-3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril (3.2 g) as a white powder (m.p. 65-66°C). The hydrochloride was formed by adding 5 ml of 2N-ethanol/HCl to a solution of the base in 30 ml of ethanol followed by addition of diethylether until precipitation [2.7 g, m.p. 150-152°C, α_D = -15.7° (C = 2/MeOH)].

B. Preparation of Chiral I where m and n are 1, R¹ and R³ are hydrogen, R² is methoxy, R⁴ is hydroxy, R⁵ and R⁶ are methyl, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is -(CH₂)₂-

Similarly, proceeding as in part A above but substituting (2R)-(2,3-epoxy)propoxy-8-methoxy-3,4-dihydrocarbostyril for (2S)-(2,3-epoxy)propoxy-8-methoxy-3,4-dihydrocarbostyril, the following compound was prepared:

(2R)-3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril m.p. 88°C, hydrochloride (m.p. 174-176°C, α_D = +15.9° (C = 2/MeOH) .

C. Preparation of Chiral I where R⁴ is Hydroxy, varying m, n, R¹, R², R³, R⁴, R⁵, R⁶, W, X, Y and Z

Similarly, following the procedures of Example 5A and 5B above, but optionally replacing (2S)-(2,3-epoxy)propoxy-8-methoxy-3,4-dihydrocarbostyril with other optically active compounds of Formula (16), and optionally replacing N-methyl-2-(4-methanesulfonamidophenyl)ethylamine with other compounds of Formula (22) , any enantiomer of a compound of Formula I where R⁴ is hydroxy may be prepared.

EXAMPLE 6

Preparation of Compounds of Formula I where m and n are 1

R⁴ is hydroxy and R⁵ is hydrogen

(Reaction Scheme IVA)

A. Preparation of I where m and n are 1, R¹, R³ and R⁵ are hydrogen, R² and R⁶ are methyl, R⁴ is hydroxy, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is -(CH₂)₂-

A solution of 4-[2-(benzylamino)ethyl]methane-sulfonanilide (2 g), compound (21b) prepared as in Preparation 5A above, and 3, 4-dihydro-8-methyl-5-(2,3-epoxypropoxy)-carbostyril (1.5 g), compound (16) prepared as in Preparation 3 above, in isopropanol (50 ml) was heated to reflux overnight. After cooling, the solvent was evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate/methanol (98/2) made basic by addition of ammonium hydroxide (10 drops), to give 3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)benzyl-amino]propoxy}carbostyril, (0.7 g), a compound of Formula (26), as an off-white semi-solid.

A solution of 3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)benzylamino]propoxy}-carbostyril (0.7 g), compound (26) as prepared above, in methanol (10 ml) was stirred in the presence of 20% palladium hydroxide on carbon (0.1 g) for 20 hours at room temperature under one atmosphere of hydrogen. The reaction mixture was filtered and evaporated to dryness to give 3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)-ethyl)amino]propoxy}carbostyril, which was directly transformed into its hydrochloride salt using diethylether saturated with hydrochloric acid (0.37 g, m.p. 149-151°C).

B. Preparation of I where m and n are 1, R¹, R², R³ and R⁵ are hydrogen, R⁴ is hydroxy, R⁶ is methyl, W is -SO₂-, X is a single bond, Y is -C(O)-, and Z is - (CH₂)₂-

Similarly, following the procedures of Example 6A above, but replacing 3,4-dihydro-8-methyl-5-hydroxycarbostyril in 6B by 3,4-dihydro-5-hydroxycarbostyril and 3,4-dihydro-8-methoxy-5-hydroxycarbostyril

respectively, the following compounds of Formula I were prepared:

3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}carbostyril hydrochloride, m.p. 253-255ºC; and

3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}carbostyril hydrochloride, m.p. 240-242°C.

C. Preparation of I where m and n are 1, R⁴ is hydroxy and R⁵ is hydrogen, varying R¹, R², R³, R⁶, W, X, Y and Z

Similarly, following the procedures of Example 6A above, but optionally replacing 4- [2- (benzylamino) ethyl] methane-sulfonanilide with other compounds of Formula (21b), and optionally replacing 3, 4-dihydro-8-methyl-5-(2,3-epoxypropoxy)carbostyril with other compounds of Formula

(16), the following compounds of Formula I where m and n are 1, R⁴ is hydroxy, and R⁵ is hydrogen are prepared:

3,4-dihydro-5-{2-hydroxy-3-[N-(2-(4-acetamidophenyl)-ethyl)amino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide;

3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide; 3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide;

3,4-dihydro-8-trifluoromethyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide;

3,4-dihydro-5-{2-hydroxy-3-[N-(3-(4-methanesulfonamidophenyl)propyl)methylamino]propoxy}-1H-2,1-benzothiazine-2,2-dioxide;

4-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)-amino]propoxy}indolin-2-one;

3,4-dihydro-8-methyl-5-{2-hydroxy-3-[N-(3-(4-methanesulfonamidophenyl)propyl)amino]propoxy}carbostyril;

8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}carbostyril;

3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(3-(4-methanesulfonamidophenyl)propyl)amino]propoxy}carbostyril;

3,4-dihydro-8-trifluoromethyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}carbostyril; and

8-methyl-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)amino]propoxy}carbostyril.

EXAMPLE 7

In vitro Determination of Effects

on the Effective Refractory Period

Right ventricular papillary muscles from guinea-pigs were stimulated at 1 Hz and continuously superfused with physiological salt solution.

Ventricular Effective Refractory Period (VERP) was determined after 20 minutes incubation with each concentration of drug, compared with control values and expressed as % increase in VERP.

Concentrations of the drug which increased VERP by 15% were

calculated from concentration-effect curves and the test results are as follows:

Compound PE C₁₅ ( - logM)

No . 1 7 .39

No . 2 6 .64

No . 3 6.24

No . 4 6 .15 pEC₁₅ is inverse logarithm of the molar concentration producing 15% of VERP increase. Compound No. 1 is 3,4-dihydro-8-methyl-5{2-[N-(2-(4- methanesulfonamidophenyl)ethyl)methylamino]-ethoxy}carbostyril. Compound No. 2 is 3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril. Compound No. 3 is (2S)-3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]propoxy}carbostyril. Compound No. 4 is (2R)-3,4-dihydro-8-methoxy-5-{2-hydroxy-3-[N-(2-(4-methanesulfonamidophenyl)-ethyl)methylamino]propoxy}carbostyril.

The compounds of Formula I thus demonstrated increased VERP activity in this assay, indicating antiarrhythmic activity.

EXAMPLE 8

In vivo Determination of Antiarrhythmic Effects

The techniques followed to measure in vivo the effects of compounds of Formula I on cardiac electrical activity are an exact replication of those described by Poizot (ref. cited above). They are adaptations to the guinea-pig of methods previously developed by Lhoste et al. (Eur. Journal of Pharmacology, 39 , 171-177, 1976) and by Harper et al. ( Cardiovascular Research, 13, 303-310, 1979), in dog and man, respectively, and in vitro by Ellis (Annal . N. Y. Acad. Sci . , 64 , 552-63, 1956).

In an anesthetized, artificially-ventilated guinea-pig, surface electrodes are installed for right ventricular stimulation and Electro Cardiogram (ECG) recording (lead II). Afterwards, the heart is paced to determine the VERP calculated from the maximum driving frequency. After a control period of 15 minutes the antiarrhythmic agent to be studied is injected intravenously at increasing doses and at 30 minute intervals. The ECG parameters, QTc (indicative of action potential duration) and RR (indicative of cardiac frequency) intervals are measured at the end of each 30 minute period and the maximum driving frequency is determined.

Compounds of Formula I induced a prolongation of the QTc and RR intervals of the ECG as well as a decrease in the maximum driving frequency and are therefore effective anti-arrhythmic agents.

For example, 3,4-dihydro-8-methyl-5{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]-ethoxy}carbostyril when treated under the conditions of this example, effectively prolonged the QTc (ED₂₀: 4mg/Kg) and the VERP (ED₂₀: 2.5mg/Kg) parameters.

EXAMPLE 9

The following example illustrates the preparation of representative pharmaceutical formulations containing an active compound of Formula I, e.g. 3,4-dihydro-8-methoxy-5{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)-methylamino]ethoxy}carbostyril. CAPSULE FORMULATION

The composition contains: % wt./wt.

Active Ingredient 20.0 %

Pregelatinised Starch 79.5 %

Magnesium Stearate 0.5 %

A weight of formulation sufficient to give a suitable dose of active ingredients are mixed and dispensed into capsules. TABLET FORMULATION

The composition contains: % wt./wt.

Active Ingredient 20,0 %

Magnesium Stearate 0.5 %

Crosscarmellose Sodium 4.0 %

Lactose 74.5 %

PVP (polyvinylpyrrolidone) 1.0 %

The above ingredients with the exception of the magnesium stearate and half of the crosscarmellose sodium are combined and granulated using water as a granulating liquid. The formulation is then dried, mixed with the magnesium stearate and the remaining crosscarmellose sodium and formed into tablets with an appropriate tableting machine.

ORAL SOLUTION FORMULATION

The composition contains: % wt./wt.

Active Ingredient 250-1500 mg

Citric Acid Monohydrate 105 mg

Sodium Hydroxide 18 mg

Water q.s. to 100 ml

The citric acid monohydrate and sodium hydroxide are dissolved in a sufficient quantity of water. The active ingredient is dissolved in this solution. Sufficient flavoring is added. A sufficient quantity of water is then added with stirring to provide 100 ml of the solution which is filtered and bottled.

SUPPOSITORY FORMULATION

The composition contains: % wt./wt.

Active Ingredient 1.0 %

Polyethylene Glycol 1000 74.5 %

Polyethylene Glycol 4000 24.5 %

The ingredients are melted together and mixed on a steam bath and poured into molds containing 2.5 g total weight. PARENTERAL FORMULATION (IV)

Active Ingredient 2.5 - 15.0 mg

Dextrose Monohydrate q.s. to make isotonic

Citric Acid Monohydrate 1.05 mg

Sodium Hydroxide 0.18 mg

Water for Injection q.s. to 1.0 ml

The citric acid monohydrate and sodium hydroxide are dissolved in a sufficient quantity of the water for injection. The active ingredient is dissolved in the resulting solution followed by the dextrose monohydrate. The remainder of the water for injection is added with stirring. The solution is filtered, filled into 1.0 ml ampoules which are sealed. The content of the ampoules is then sterilized by autoclaving. EXAMPLE 10

Toxicity

A 4-week rat toxicity study was performed with 3, 4 -dihydro-8-methyl-5{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]ethoxy}carbostyril given by i.v. route at daily doses of 0, 1, 5 and 15 mg/Kg. No

histopathological changes were seen.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such

modifications are intended to be within the scope of the claims appended hereto.

Claims

WHAT IS CLAIMED IS:

1. A compound represented by the formula:

wherein:

m is 0, 1 or 2;

n is 0, 1 or 2;

R¹ is hydrogen, lower alkyl, or phenyl lower alkyl;

R³ is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy;

R⁵ is hydrogen or lower alkyl;

R⁶ is lower alkyl;

W and Y are independently -SO₂- or -C(O)-;

X is oxygen, -S(O)_p-, -CH₂-, or a single bond;

wherein p is 0, 1 or 2; and

Z is -CH=CH- or -(CH₂)_q-, wherein q is 1 or 2;

or a pharmaceutically acceptable acid addition salt, ester or N-oxide thereof.

2. The compound of Claim 1 wherein W is -SO₂-.

3. The compound of Claim 2 wherein Z is -(CH₂)₂-.

4. The compound of Claim 3 wherein Y is -C(O)

5. The compound of Claim 4 wherein X is a single bond.

6. The compound of Claim 5 wherein R¹ and R³ are hydrogen.

7. The compound of Claim 6 wherein n is 1.

8. The compound of Claim 7 wherein R⁶ is methyl.

The compound of Claim 8 wherein R⁵ is lower alkyl preferably methyl .

10. The compound of Claim 9 wherein m is 0 or 1, R⁴ is hydrogen or hydroxy, R² is lower alkyl preferably methyl or lower alkoxy preferably methoxy.

11. The compound of Claim 10 wherein R⁵ is methyl, m is 0, R² is methyl and R⁴ is hydrogen, namely 3,4-dihydro-8-methyl-5{2-[N-(2-(4-methanesulfonamidophenyl)ethyl)methylamino]-ethoxy}carbostyril.

12. The compound of Claim 10 wherein R⁵ is methyl, m is 1, R² is methoxy and R⁴ is hydroxy, namely 3,4-dihydro-8-methoxy-5{2-hydroxy-3-[N-(4-methanesulfonamidophenylethyl)-N-methyl]aminopropoxy}carbostyril, or (2R)-3,4-dihydro-8-methoxy-5{2-hydroxy-3-[N-(4-methanesulfonamidophenylethyl)-N-methyl]aminopropoxy}carbostyril or (2S)-3,4-dihydro-8-methoxy-5{2-hydroxy-3-[N-(4-methanesulfonamido-phenylethyl)-N-methyl]aminopropoxy}carbostyril.

13. A composition suitable for administration to a mammal having a disease-state that is characterized by cardiac arrhythmia, which

composition comprises a therapeutically effective amount of a compound of Claim 1 in admixture with one or more pharmaceutically acceptable non-toxic carriers.

14. A method for treating a mammal having a disease-state that is characterized by cardiac arrhythmia, which comprises administering a therapeutically effective amount of a compound of Claim 1 to said mammal.

15. A process for the preparation of a compound of the Formula I

wherein:

m is 0, 1 or 2;

n is 0, 1 or 2;

R¹ is hydrogen, lower alkyl, or phenyl lower alkyl;

R³ is hydrogen, lower alkyl, trifluoromethyl, or lower alkoxy;

R⁵ is hydrogen or lower alkyl;

R⁶ is lower alkyl;

W and Y are independently -SO₂- or -C(O)-;

X is oxygen, -S(O)_p-, -CH₂-, or a single bond;

wherein p is 0, 1 or 2; and

Z is -CH=CH- or -(CH₂)_q-, wherein q is 1 or 2;

or a pharmaceutically acceptable acid addition salt, ester or N-oxide thereof, comprising:

(a) reacting a compound of the formula:

where R¹, R², R³, Y and Z are as defined in the preamble, with a compound of the formula:

where R⁵ is lower alkyl and R⁶, W and X are as defined in the preamble, to form a compound of Formula I wherein m and n are 1, R⁴ is hydroxy, R⁵ is lower alkyl and the other substituents are as defined in the preamble; or

(b) reacting a compound of the formula:

where R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the preamble, with a compovind of

Formula R⁶WHalo, in which Halo is chloro or bromo and R⁶ and W are as defined in the preamble, or alternatively with an anhydride of the formula (R⁶W)₂O, to form a compound of Formula I where R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the preamble; or

(c) reacting a compound of the formula:

where R⁴ is hydrogen or lower alkyl, R³ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the preamble, with a compound of the formula:

where R⁶, W and X are as defined in the preamble, to form a compound of Formula I where R⁴ is hydrogen or lower alkyl, R⁵ is lower alkyl, and m, n. R¹, R², R³, R⁶, W, X, Y and Z are as defined in the preamble; or

(d) reacting a compound of the formula:

wherein R⁴ is hydrogen or lower alkyl, R³ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the preamble, with a compound of the formula:

where R³ is lower alkyl, and R⁶, W and X are as defined in the preamble, to form a compound of Formula I where R⁴ is hydrogen or lower alkyl, R³ is lower alkyl, and m, n, R¹, R², R³, R⁶, W, X, Y and Z are as defined in the preamble; or

(e) reacting a compound of the formula:

where L is a leaving group, and m, n, R⁴, R³, R⁶, W and X are as defined in the preamble, to form a compound of Formula I where m, n, R¹ , R², R³, R⁴, R³, R⁶, W, X, Y and Z are as defined in the preamble ; or

(f) reacting a compound of the formula:

where Bn is benzyl, and m, n, R¹, R², R³, R⁴, R⁶, W, X, Y and Z are as defined in the preamble, with hydrogen to form a compound of Formula I where R⁵ is hydrogen, and m, n, R¹, R², R³, R⁴, R⁶, W, X, Y and Z are as defined in the preamble; or

(g) reacting the free base of a compound of Formula I with an acid to give a pharmaceutically acceptable acid addition salt; or

(h) reacting an acid addition salt of a compound of Formula I with a base to give the corresponding free base; or

(i) converting an acid addition salt of a compound of Formula I to another pharmaceutically acceptable acid addition salt of Formula I .