Syntex (u.s.a.) Inc.

John A Edwards

John H Fried

Colin C Beard

Albert R Van Horn

Gary F Cooper

Francisco S Alvarez

Pierre Crabbe

Gabriel Garay

This invention covers a compound of the formula ##STR1## wherein R is hydrogen, lower alkyl or a pharmaceutically acceptable, non-toxic salt of a compound wherein R is hydrogen; and X is hydrogen, halo, trifluoromethyl, lower alkyl or lower alkoxy; and the wavy lines represent the .alpha. or .beta. configuration with the proviso that when one wavy line is .alpha. the other is .beta..

9-oxo-15.alpha.-hydroxy-16-phenoxy and 16-substituted phenoxy

Certain 16.beta.-methyl-3-oxoandrost-4-ene and 16.beta.-methyl-3-oxoandrosta-1,4-diene 17.beta.-thiocarboxylic acid esters are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 6.alpha.-position with fluoro or chloro; optionally substituted at the 9.alpha. position with fluoro, chloro or bromo; substituted at the 11 position with a keto, a .beta.-hydroxy or a .beta.-chloro (the latter only when there is a 9.alpha.-chloro); and substituted with 17.alpha.-hydroxy (or an ester thereof).

Thio etianic acid derivatives

Certain 3-ketoandrost-4-ene and 3-ketoandrosta-1,4-diene 17 beta-carboxylic acids and esters substituted at the 6 alpha and 6 beta positions with fluorine substituents are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 9 alpha position with fluoro, chloro or bromo; substituted at the 11 with a keto, a beta-hydroxy or a beta-chloro (the latter only when there is a 9 alpha-chloro); substituted at 16 alpha (or 16 beta) with methyl or hydrogen when there is a 17 alpha-hydroxy (or an ester).

6 Alpha, 6 beta-difluoro-etianic acid derivatives

Certain 3-oxoandrost-4-ene and 3-oxoandrosta-1,4-diene 17 beta-thiocarboxylic acid esters are useful as antiinflammatory steroids. These compounds are optionally substituted at the 6 alpha-position with fluoro, or chloro; optionally substituted at the 9 alpha position with fluoro, chloro or bromo; substituted at the 11 position with a keto, a beta-hydroxy on a beta-chloro (the latter only when there is a 9 alpha-chloro); substituted at 16 alpha, 17 alpha-positions with isopropylidenedioxy; and substituted at 16 alpha (or 16 beta) with methyl or hydrogen when there is a 17 alpha-hydroxy (or an ester).

Thioetianic acid derivatives

Certain 3-oxoandrost-4-ene and 3-oxoandrosta-1,4-diene 17 beta-thiocarboxylic acid esters substituted at the 6 alpha, 6 beta-positions with fluorine substituents are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 9 alpha position with fluoro, chloro or bromo; substituted at the 11 with a keto-, a beta-hydroxy or a beta-chloro (the latter only when there is a 9 alpha-chloro); substituted at 16 alpha, 17 alpha-positions with isopropylidenedioxy; and substituted at 16 alpha (or 16 beta) with methyl or hydrogen when there is a 17 alpha-hydroxy (or an ester).

17 Beta-thiocarboxylic acid esters of 6 alpha, 6

Novel 16-phenoxy and 16-(o, m or p)-substituted phenoxy derivatives of (dl)-9-keto-11.alpha.,15.alpha.-dihydroxy-17,18,19,20-tetranorprosta-4,5,1 3-trans-trienoic acid, the pharmaceutically acceptable, non-toxic lower alkyl esters and salts thereof and processes for the production of such compounds. These compounds possess prostaglandin-like activities and thus are useful in the treatment of mammals where prostaglandins are indicated. They are particularly useful as inhibitors of gastric acid secretion; and as agents for the control of asthmatic attack, because of their bronchodilating activity.

(dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid

1-Amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and/or substituted amino derivatives thereof; 3-(4- or 5-substituted thiazol-2-oxy)-1,2-epoxypropane and 5-(4- or 5-substituted thiazol-2-oxymethylene)-oxazolidine and/or N- and/or 2-substituted oxazolidine derivatives thereof, and methods of making such compounds. The compounds are characterized by an aminocarbonyl or carbonylamino type substituent at the 5- or 4-position on the thiazole ring. The above 1-amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and derivatives exhibit cardiovascular activity and are useful in the treatment of abnormal heart conditions in mammals. The 3-(4- or 5-substituted thiazol-2-oxy)-1,2-epoxypropanes are useful as intermediates for the aforementioned cardiovascular agents. The 5-(4- or 5-substituted thiazol-2-oxymethylene)-oxazolidine and derivatives are intermediates for the aforementioned cardiovascular agents and further exhibit cardiovascular activity and thus are useful in the treatment of abnormal heart conditions in mammals. The 1-amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and derivatives can be prepared by base or acid hydrolysis of the corresponding 5-(4- or 5-aminocarbonylthiazol-2-oxymethylene)-oxazolidine or derivative; or by treatment of the corresponding 3-(4- or 5-substituted thiazol-2-oxy)-2,3-epoxypropane or derivative with the desired amine or amine derivative.

Certain thiazole compounds

Benzene ring substituted benzimidazole-2-carbamate derivatives represented by the formula: ##STR1## where R is a lower alkyl group having 1 to 4 carbon atoms; R.sup.1 is --SOR.sup.2, --SO.sub.2 R.sup.2, --SCN, --SR.sup.5, --OR.sup.5 or M'(CH.sub.2).sub.n MR.sup.7 where M and M' are independently O, S, ##STR2## R.sup.7 is lower alkyl having 1 to 4 carbon atoms or aryl, and n is 1-4; R.sup.2 is lower alkyl having from 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, lower alkenyl or lower alkynyl having 3 to 6 carbon atoms, or aralkyl or aryl; and

5(6)-Benzene ring substituted benzimidazole-2-carbamate derivatives

Carbalkoxythioureidobenzene derivatives represented by the following formula: ##STR1## where R is a lower alkyl group having 1 to 4 carbon atoms; R.sup.1 is --SR.sup.2, --SOR.sup.2, --SO.sub.2 R.sup.2, --OR.sup.2, --SCN, --SC(O)NR.sup.3 R.sup.4, or --M'(CH.sub.2).sub.n MR.sup.7 where n is 1-4; R.sup.2 is lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, lower alkenyl or lower alkynyl having 3 to 6 carbon atoms, aralkyl or aryl, provided that when R.sup.1 is --SO.sub.2 R.sup.2, R.sup.2 is not aralkyl or phenyl; R.sup.3 and R.sup.4 are independently hydrogen or lower alkyl having 1 to 6 carbon atoms; Y is amino, nitro, acylamino where the acyl portion has 1 to 6 carbon atoms, --NHC(O) (CH.sub.2).sub.m COOH where m is 1-6, or --NHC(S)NHCOOR; M and M' are independently O, S or ##STR2## and R.sup.7 is lower alkyl having 1 to 4 carbon atoms or aryl. The R.sup.1 substitution is either at the 4- or 5-position. The compounds are useful as pesticides, particularly as anthelmintic and antifungal agents.

This application relates to 1,5(6)-disubstituted benzimidazole-2-carbamate derivatives represented by the following formula: ##STR1## where R is lower alkyl having 1 to 4 carbon atoms; R.sup.1 is --SOR.sup.2, --SR.sup.5, --OR.sup.5 or M'(CH.sub.2).sub.n MR.sup.7 ; R.sup.2 is lower alkyl having from 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, lower alkenyl or lower alkynyl having 3 to 6 carbon atoms, or aralkyl or aryl; R.sup.5 is lower alkenyl, lower alkynyl or aralkyl; R.sup.7 is lower alkyl having 1 to 4 carbon atom, or aryl; M and M' are independently O, S, ##STR2## n is 1-4; and R.sup.8 is lower alkyl having 1 to 12 carbon atoms optionally substituted with a --COOR group where R is lower alkyl having 1 to 4 carbon atoms, aryl or aralkyl. The R.sup.1 substitution is at the 5(6)-position. The compounds are useful as pesticides, particularly as anthelmintic and antifungal agents.

1,5(6)-Disubstituted benzimidazole-2-carbamate derivatives having

7(8)-substituted triazinobenzimidazoles represented by the formula: ##STR1## where R is a lower alkyl group having 1 to 4 carbon atoms; R' is diloweralkylaminoalkyl (C.sub.2-6) or alkyl having 1 to 18 carbon atoms; R.sup.2 is phenylsulfinyl, phenoxyethoxy, benzyloxyethoxy, methoxyethylsulfinyl, or 3-chloroprop-1-ylsulfinyl; the R.sup.2 -substitution being at the 7(8)-position; or a pharmaceutically acceptable salt thereof. The compounds are useful as pesticides, particularly as antifungal and anthelmintic agents.

7(8)-Substituted triazinobenzimidazoles and anthelmintic compositions

Benzene ring substituted benzimidazole-2-carbamate derivatives represented by the formula: ##STR1## where R is a lower alkyl group having 1 to 4 carbon atoms; R.sup.1 is a heterocyclic ring having 1-4 hetero atoms; and M is O, S, or ##STR2## The R.sup.1 M-substitution is at the 5(6)-position. The compounds are useful as pesticides, particularly as anthelmintic and antifungal agents.

Benzene ring substituted benzimidazole-2-carbamate derivatives represented by the formula: ##STR1## where R is a lower alkyl group having 1 to 4 carbon atoms; R.sup.1 is -SOR.sup.2, -SO.sub.2 R.sup.2, -SCN, -SR.sup.5, -OR.sup.5 or M'(CH.sub.2).sub.n MR.sup.7 where M and M' are independently O, S, ##STR2## R.sup.7 is lower alkyl having 1 to 4 carbon atoms, or aryl, and n is 1-4; R.sup.2 is lower alkyl having from 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, lower alkenyl or lower alkynyl having 3 to 6 carbon atoms, or aralkyl or aryl; and R.sup.5 is lower alkenyl, lower alkynyl, or aralkyl. The R.sup.1 substitution is at the 5(6)-position. The compounds are useful as pesticides, particularly as anthelmintic and antifungal agents.

1-Amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and/or substituted amino derivatives thereof; 3-(4- or 5-substituted thiazol-2-oxy)-1,2-epoxypropane and 5-(4- or 5-substituted thiazol-2-oxymethylene)-oxazolidine and/or N- and/or 2-substituted oxazolidine derivatives thereof, are methods of making such compounds. The compounds are characterized by an aminocarbonyl or carbonylamino type substituent at the 5- or 4-position on the thiazole ring. The above 1-amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and derivatives exhibit cardiovascular activity and are useful in the treatment of abnormal heart conditions in mammals. The 3-(4- or 5-substituted thiazol-2-oxy)-1,2-epoxypropanes are useful as intermediates for the aforementioned cardiovascular agents. The 5-(4- or 5-substituted thiazol-2-oxymethylene)-oxazolidine and derivatives are intermediates for the aforementioned cardiovascular agents and further exhibit cardiovascular activity and thus are useful in the treatment of abnormal heart conditions in mammals. The 1-amino-3-(4-or 5-substituted thiazol-2-oxy)-2-propanol and derivatives can be prepared by base or acid hydrolysis of the corresponding 5-(4- or 5-aminocarbonylthiazol-2-oxymethylene)-oxazolidine or derivative; or by treatment of the corresponding 3-(4- or 5-substituted thiazol-2-oxy)-2,3-epoxypropane or derivative with the desired amine or amine derivative.

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Los Altos, CA, United States of America

John A Edwards