Syntex (u.s.a.) Inc.

Brian Lewis

Stefan H Unger

Karl G Untch

Belig M Berkoz

Joseph M Muchowski

1-Alkylamino-3-(3- or 4-[2-(endobicyclo[3.1.0]-hex-6-yl)ethylaminocarbonyl]-1-phenoxy)-2-propano l and substituted derivatives thereof and methods for preparing such compounds are disclosed. 5-(3- Or 4-[2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]-phenoxy)methyl 3-alkyl-2-optionally substituted oxazolidine and derivatives thereof, and methods for preparing such compounds are also disclosed. These compounds exhibit cardiovascular acitivity and are useful in the treatment of abnormal heart condition as well as hypertension in mammals. The former compounds are prepared by treatment of the corresponding 1,2-epoxy-3-(3- or 4-[2-(endobicyclo[3.1.0]hex-6-yl)-ethylaminocarbonyl]phenoxy)propane with the desired alkylamine or by base or acid hydrolysis of the corresponding 5-(3- or 4-[2-(endobicyclo[3.1.0]hex-6-yl)-ethylaminocarbonyl)-3-alkyl oxazolidine. The latter compounds are prepared from the corresponding 1-alkylamino-3-(3- or 4-[2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]-1-phenoxy)-2-propanol by treatment with an aldehyde having the desired optional substituent or by treating a 3- or 4-(2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl)-optionally substituted phenol with a 5-tosyloxy or mesyloxymethyl 3-alkyl)-methyloxazolidine-2-optionally substituted oxazolidine.

Bicyclo [3.1.0] hexyl-substituted ethylamino carbonyl phenoxy

1-Alkylamino-3-([2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]thienylox y)-2-propanols and methods for preparing these compounds are disclosed. The compounds are useful in the treatment of hypertension and abnormal heart conditions in mammals. These compounds are prepared by the treatment of the corresponding 1,2-epoxy-3-[2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]heterocyclic aryloxy)propane with an alkylamine having the desired alkyl substituent or by base or acid hydrolysis of the corresponding 2-optionally substituted-3-alkyl-5-([2-(endobicyclo[3.1.0]hex-6-yl)ethylaminocarbonyl]h eterocyclic aryloxymethyl)oxazolidine. These latter compounds can be prepared by condensing a halo-substituted thiophene with a 3-alkyl-5-hydroxymethyloxazolidine such substituted or unsubstituted at the 2-position or alternatively, by treating the former aminopropanol compounds of the present invention with an aldehyde having the desired substituent. These latter oxazolidine compounds are also active for treatment of hypertension and abnormal heart conditions.

Bicyclo[3.1.0]hexylethylaminocarbonyl-substituted heteroaryl

Processes and intermediates for preparing 1-alkylamino-3-(5-substitutedaminocarbonylthiazol-2-yloxy)-2-propanols and 5-(5-substitutedaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine and 2-substituted oxazolidine derivatives thereof and intermediates therefore. The present processes, and intermediates, reduce the number of transformations necessary to produce these products as compared with the prior processes. The products are useful to treat abnormal heart conditions and/or hypertension in mammals. The intermediates are 2-alkylsulfinyl-5-substitutedaminocarbonylthiazoles and 2-alkylsulfonyl-5-substitutedaminocarbonylthiazoles.

Certain thiazole-5-carboxamide compounds

1-Alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanol; 5-(5-alkynylaminocarbonyl-thiazol-2-yloxymethylene)-N-alkyloxazolidine and/or 2-substituted oxazolidine derivatives thereof, and methods of making such compounds. The compounds exhibit cardiovascular activity and are useful in the treatment of abnormal heart conditions in mammals. The compounds are also useful in the treatment of hypertension in mammals. The 5-(5-alkynyl-aminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidines and derivatives are also intermediates for the 1-alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanols. The 1-alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanols can be prepared by base or acid hydrolysis of the corresponding 5-(5-alkynylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine or derivative; or by treatment of the corresponding 3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2,3-epoxypropane with the desired alkylamine. Similarly the 5-(5-alkynylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine or derivative can be prepared from the corresponding 1-alkylamino-3-(5-alkynylaminocarbonylthiazol-2-yloxy)-2-propanols via treatment with an aldehyde or ketone.

Thiazole cardiovascular agents

1-Alkylamino-3-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxy)-2-propanol; 5-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxymethylene-N-alkyloxazolid ine and/or 2-substituted oxazolidine derivatives thereof, and methods of making such compounds. The compounds exhibit cardiovascular activity and are useful in the treatment of abnormal heart conditions in mammals. The compounds are also useful in the treatment of hypertension in mammals. The 5-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazoli dines and derivatives are also intermediates for the 1-alkylamino-3-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxy)-2-propanol s. The 1-alkylamino-3-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxy)-2-propanol s can be prepared by base or acid hydrolysis of the corresponding 5-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazoli dine or derivative; or by treatment of the corresponding 3-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxy)-2,3-epoxypropane with the desired alkylamine. Similarly the 5-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazoli dine or derivative can be prepared from the corresponding 1-alkylamino-3-(5-carbocyclicalkylaminocarbonylthiazol-2-yloxy)-2-propanol s via treatment with an aldehyde or ketone.

1-Alkylamino-3-(5-alkenylaminocarbonylthiazol-2-yloxy)-2-propanol; 5-(5-alkenylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine and/or 2-substituted oxazolidine derivatives thereof, and methods of making such compounds. The compounds exhibit cardiovascular activity and are useful in the treatment of abnormal heart conditions in mammals. The compounds are also useful in the treatment of hypertension in mammals. The 5-(5-alkenylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidines and derivatives are also intermediates for the 1-alkylamino-3-(5-alkenylaminocarbonylthiazol-2-yloxy)-2-propanols. The 1-alkylamino-3-(5-alkenylaminocarbonylthiazol-2-yloxy)-2-propanols can be prepared by base or acid hydrolysis of the corresponding 5-(5-alkenylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine or derivative; or by treatment of the corresponding 3-(5-alkenylaminocarbonylthiazol-2-yloxy)-2,3-epoxypropane with the desired alkylamine. Similarly the 5-(5-alkenylaminocarbonylthiazol-2-yloxymethylene)-N-alkyloxazolidine or derivative can be prepared from the corresponding 1-alkylamino-3-(5-alkenylaminocarbonylthiazol-2-yloxy)-2-propanols via treatment with an aldehyde or ketone.

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Mountain View, CA, United States of America

Brian Lewis