Certain benzothiazine dioxide endothelin antagonists and processes for their preparation

A process for the preparation of a compound of Formula 1

• 102
• comprising:
• a) treating aryl bromide with n-butyl lithium followed by zinc bromide to generate an aryl zinc bromide of formula Y
• 103
• b) reacting the product of step a) above with
• 104
• in THF in the presence of a palladium catalyst to produce Formula 1
• 105
• .

A process for the preparation of a compound of formula B

• 106
• comprising
• a) reacting a phenyl sulfonyl chloride with 1 equivalent of aniline to produce a sulfonamide of formula F
• 107
• b) lithiating the product of step a) above at low temperatures and quenching with CO2 to form a compound of formula G
• 108
• c) treating the product of step b) above with acetic anhydride and a catalytic amount of methanesulfonic acid to produce a compound of formula H
• 109
• d) treating the product of step c) above with NaOMe followed by methyl bromoacetate to produce a compound B as above.

A process for the preparation of a compound of Formula 1 as above which comprises

• a) refluxing
• 110
• with one equivalent of pyridine and DMAP to produce cyclic
• intermediate of formula
• 111
• b) treating the product of Step a) above with potassium hexamethyldisilylazide followed by t-butyl acetate in THF to produce the keto ester of formula I
• 112
• c) brominating the product from Step b) above to produce an intermediate of formula J
• 113
• d) cyclizing the product of Step c) above using potassium carbonate in DMF to produce enol of formula K
• 114

A compound according to claim 9 wherein the product produced is:

• (6-Methyl-benzo[1,3]dioxol-5-yl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid tert-butyl ester;
• (2-Bromo-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester;
• (2-Chloro-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester;
• and
• (6-Chlorobenzo[1,3]dioxol-5-yl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e]1,2]thiazine-3 carboxylic acid tert-butyl ester.

A process for the preparation of a compound of Formula 1 as above which comprises:

• a) reacting 2-methylanaline with benzenesulfonyl chloride to produce a compound of formula F
• 115
• b) treating the product of step a) above with n-butyl lithium and then with a solution of 3-methoxy-4,5methylenedioxybenzaldehyde to produce a compound of formula M
• 116
• c) treating the product of step b) above with sodium hydride followed by methyl bromoacetate to produce a compound of formula N
• 117
• d) oxidizing the product of step c) above to produce the corresponding keto ester of formula O
• 118
• e) cyclizing the product of step d) above by treating with a base or a Lewis acid in an appropriate solvent to produce the corresponding ester of Formula 1
• 119
• f) sponifying the esters in alkaline solutions produce the corresponding free acid.

A compound selected from:

• (3,5-Dimethoxyphenyl)2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• (2-Chloro-phenyl)4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• (2-Bromo-phenyl)4-(3,5-dimethoxy-phenyl)1,1-dioxo-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• (2-Chloro-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid;
• (2-Benzylphenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• (2,6-Dimethyl-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid monosodium salt;
• (7-Methoxybenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine 3-carboxylic acid;
• (2-Bromo-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1 %6-benzo[e][1,2]thiazine-3-carboxylic acid monosodium salt;
• 4-Benzo[1,3]dioxol-5-yl 1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro1 )6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2ethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2propylphenyl)1,1dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2isopropylphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2butylphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2-fluorophenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2-hydroxyphenyl)1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid;
• 4-Benzo [1,3]dioxol-5-yl-2-(2,3-dichlorophenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2,4dichlorophenyl)1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2-chloro-4-methoxyphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo [1,3]dioxol-5-yl-2-(3chloro-2methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2,6dimethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl 1,1-dioxo-2-(2pyrrol 1-yl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(3 ,4dimethylisoxazol5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• 4-Benzo[1,3]dioxol-5-yl-2-(2benzylphenyl)1,1dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• (6-Methoxybenzo[1,3]dioxol-5-yl)1,1dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1),6-benzo[e][1,2]thiazine-3-carboxylic acid;
• and
• (3,5-Dimethyl-phenyl)2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.

A compound selected from:

• (6-Methyl-benzo[1,3]dioxol-5-yl)-4hydroxy-1,1dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• (2-Bromo-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid;
• (2-Chloro-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
• and
• (6-Chlorobenzo[1,3]dioxol-5-yl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.