Phenylethanolamine compounds useful as .beta. 3 agonists, process for producing the same, and intermediates in the production of the same

A process for producing a phenylethanolamine compound represented by general formula [I]:

• ##STR10## (where R.sub.1 represents hydrogen or halogen;
• R.sub.2 represents hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted with one or two lower alkoxycarbonyl or carboxy groups, lower alkoxy substituted with lower alkylaminocarbonyl which may be substituted with lower alkoxy, lower alkoxy substituted with cyclic aminocarbonyl of 4 to 6 carbon atoms, lower alkoxycarbonyl or carboxy;
• R.sub.3 represents hydrogen, hydroxy, lower alkoxy or lower alkoxy substituted with one or two lower alkoxycarbonyl or carboxy groups;
• R.sub.2 and R.sub.3 may be bonded to each other to form methylenedioxy substituted with carboxy or lower alkoxycarbonyl;
• and m and n are 0 or 1), or a pharmacologically acceptable salt thereof, which process involves reacting a compound of formula [II] ##STR11## with a compound of formula [III] or its salt, ##STR12## to produce a compound of formula [I] (where R.sub.1, R.sub.2, R.sub.3, m and n have the same definitions given above), or a pharmacologically acceptable salt thereof.

A production process which comprises protecting the amino group of a compound of formula [VII] ##STR17## (where R.sub.1 represents hydrogen or halogen;

• R.sub.6 represents hydrogen or hydroxy;
• and m and n are 0 or 1), with a protecting group for making a compound of formula [VIII] ##STR18## (where R.sub.1, R.sub.6, m and n have the same definitions given above;
• and P represents an N-protecting group), and then reacting the compound of formula [VIII] with a compound of formula [IX] or [IX'] ##STR19## (where R.sub.7 represents lower alkyl substituted with one or two lower alkoxy carbonyl groups;
• R.sub.8 represents lower alkoxy carbonyl;
• and X represents an acid residue), and subsequently removing the N-protecting group to produce a compound of formula [X] ##STR20## (where R.sub.1, m and n have the same definitions given above;
• R.sub.9 represents lower alkoxy substituted with one or two lower alkoxy carbonyl groups;
• R.sub.10 represents hydrogen or lower alkoxy substituted with one or two lower alkoxy carbonyl groups;
• and R.sub.9 and R.sub.10 may be bonded to each other to form methylene dioxy substituted with lower alkoxy carbonyl), or a pharmacologically acceptable salt thereof.

A production process which comprises subjecting a compound of formula [X ] ##STR21## (where R.sub.1 represents hydrogen or halogen;

• R.sub.9 represents lower alkoxy substituted with one or two lower alkoxy carbonyl groups;
• R.sub.10 represents hydrogen or lower alkoxy substituted with one or two lower alkoxy carbonyl groups;
• R.sub.9 and R.sub.10 may be bonded to each other to form a methylene dioxy substituted with lower alkoxy carbonyl;
• and m and n are 0 or 1), or its salt, to de-esterification reaction to produce a compound of formula [XI] ##STR22## (where R.sub.1, m and n have the same definitions given above;
• R.sub.11 represents lower alkoxy substituted with one or two carboxy groups;
• R.sub.12 represents hydrogen or lower alkoxy substituted with one or two carboxy groups;
• and R.sub.11 and R.sub.12 may be bonded to each other to form methylene dioxy substituted with carboxy), or a pharmacologically acceptable salt thereof.

A production process which comprises reacting a compound of formula [X] ##STR23## (where R.sub.1 represents hydrogen or halogen;

• R.sub.9 represents lower alkoxy substituted with one or two lower alkoxy carbonyl groups;
• R.sub.10 represents hydrogen;
• and m and n are 0 or 1), or its salt, or a compound of formula [XI] ##STR24## (where R.sub.1, m and n have the same definitions given above;
• R.sub.11 represents lower alkoxy substituted with one or two carboxy groups;
• and R.sub.12 represents hydrogen), or its salt, with a lower alkyl amine which may be substituted with lower alkoxy, or a cyclic amine of 4 to 6 carbon atoms, to produce a compound of formula [XII] ##STR25## (where R.sub.1, m and n have the same definitions given above;
• R.sub.13 represents lower alkoxy substituted with a lower alkyl amino carbonyl group which may be substituted with one or two lower alkoxy groups or lower alkoxy substituted with a cyclic amino carbonyl group of 4 to 6 carbon atoms;
• and R.sub.14 represents hydrogen), or a pharmacologically acceptable salt thereof.

A production process which comprises producing a compound of formula [XV] ##STR26## (where R.sub.1 represents hydrogen or halogen;

• R.sub.2 represents hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted with one or two lower alkoxy carbonyl or carboxy groups, lower alkoxy substituted with lower alkyl amino carbonyl which may be substituted with lower alkoxy, lower alkoxy substituted with cyclic amino carbonyl of 4 to 6 carbon atoms, lower alkoxy carbonyl or carboxy;
• R.sub.3 represents hydrogen, hydroxy, lower alkoxy or lower alkoxy substituted with one or two lower alkoxy carbonyl or carboxy groups;
• R.sub.2 and R.sub.3 may be bonded with each other to form methylene dioxy substituted with carboxy or lower alkoxy carbonyl;
• and n is 0 or 1), by reacting a compound of formula [XIII ] ##STR27## (where R.sub.1 has the same definition given above), with a compound of formula [XIV] ##STR28## (where R.sub.2, R.sub.3 and n have the same definitions given above), and then reducing the resulting imino group of the compound of formula [XV]to produce a compound of formula [I] ##STR29## (where R.sub.1, R.sub.2, R.sub.3 and n have the same definitions given above, and m is 0), or a pharmacologically acceptable salt thereof.

A production process which comprises producing a compound of formula [I ] ##STR30## (where R.sub.1 represents hydrogen or halogen;

• R.sub.2 represents hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted with one or two lower alkoxy carbonyl or carboxy groups, lower alkoxy substituted with lower alkyl amino carbonyl which may be substituted with lower alkoxy, lower alkoxy substituted with cyclic amino carbonyl of 4 to 6 carbon atoms, lower alkoxy carbonyl or carboxy;
• R.sub.3 represents hydrogen, hydroxy, lower alkoxy or lower alkoxy substituted with one or two lower alkoxy carbonyl or carboxy groups;
• R.sub.2 and R.sub.3 may be bonded with each other to form methylene dioxy substituted with carboxy or lower alkoxy carbonyl;
• m is 0;
• and n is 0 or 1), or a pharmacologically acceptable salt thereof, from a compound of formula [XIII] ##STR31## (where R.sub.1 has the same definition given above), and a compound of formula [XIV] ##STR32## (where R.sub.2, R.sub.3 and n have the same definitions given above), by direct catalytic hydrogen reduction reaction.

A compound of formula [XV] ##STR38## (where R.sub.1 represents hydrogen or halogen;

• R.sub.2 represents hydrogen, hydroxy, lower alkoxy, lower alkoxy substituted with one or two lower alkoxy carbonyl or carboxy groups, lower alkoxy substituted with lower alkyl amino carbonyl which may be substituted with lower alkoxy, lower alkoxy substituted with cyclic amino carbonyl of 4 to 6 carbon atoms, lower alkoxy carbonyl or carboxy;
• R.sub.3 represents hydrogen, hydroxy, lower alkoxy or lower alkoxy substituted with one or two lower alkoxy carbonyl or carboxy groups;
• R.sub.2 and R.sub.3 may be bonded with each other to form methylene dioxy substituted with carboxy or lower alkoxy carbonyl;
• and n is 0 or 1).