Claims
- 1. A process for the preparation of a compound of Formula 1 or a pharmaceutically acceptable salt thereof whereinR1 is hydrogen, alkyl, or alkoxy; R2 is hydrogen or alkoxy; R3 is alkyl or alkoxy; R2 and R3 may be joined to form a ring R4 is hydrogen or alkyl; R5 is hydrogen, alkyl, alkoxy, halogen at the 2 or 3, or 4, or 5 positions or R5 is a fused 3,4-methylenedioxo; and R6 is CF3, halogen, alkyl, benzyl, phenyl, hydroxy, or pyrrole comprising: a) alkylating a compound of formula A with sodium hydride in DMF followed by reaction with methyl bromoacetate to produce a compound of formula B b) combining compound B in THF with a solution of TiCl4 in solvent at −78° C. and treating with triethylamine and quenching with an acid to produce a compound of formula C c) treating compound C with triflic anhydride in a solvent in the presence of pyridine for from 1 to 5 hours to produce a compound of formula d) coupling the compound D with a boronic acid of formula X in DMF and toluene in the presence of a palladium catalyst and potassium carbonate under reflux to produce a compound of Formula 1.
- 2. A process according to claim 1 wherein in Step b) compound B is treated with TiCl2 (OTf)2 and triethylamine, and quenched with pH 7 phosphate buffer and workup.
- 3. A process according to claim 1, wherein the compound prepared is a compound of Formula II or a pharmaceutically acceptable salt thereof.
- 4. A compound named 4-(7-Ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid sodium salt.
- 5. A compound named 4-(7-Ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6benzo[e][1,2]thiazine-3-carboxylic ester potassium salt.
- 6. 4-(7-Ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1,2-benzo[e][1,2]thiazine-3-carboxylic acid, and pharmaceutically acceptable salts thereof.
- 7. The compound of claim 6 that is 4-(7-ethyl-benzo[1,3]dioxol-5 -yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.
- 8. A pharmaceutical composition comprising 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
- 9. A pharmaceutical composition according to claim 8 comprising a compound selected from the group consisting of:4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid sodium salt; 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid potassium salt; and 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.
- 10. A pharmaceutical composition according to claim 8 comprising 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][i1,2]thiazine-3-carboxylic acid potassium salt.
- 11. A method of treating essential, renovascular, malignant, or pulmonary hypertension comprising administering to a host suffering therefrom a therapeutically effective amount of a compound named 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1benzo[e][1,2]thiazine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
- 12. The method according to claim 11 wherein the compound administered is selected from the group consisting of:4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid sodium salt; 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid potassium salt; and 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.
- 13. The method according to claim 12 wherein the compound administered is 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid potassium salt.
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a 371 filing of PCT/US98/16856 filed Aug. 13, 1998; priority is based on Provisional Application No. 60/058,111 filed Sep. 5, 1997, and Provisional Application No. 60/092,326 filed Jul. 9, 1998.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US98/16856 |
|
WO |
00 |
12/8/1999 |
12/8/1999 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO99/12916 |
3/18/1999 |
WO |
A |
Foreign Referenced Citations (1)
Number |
Date |
Country |
WO 9626195 |
Aug 1996 |
WO |
Provisional Applications (2)
|
Number |
Date |
Country |
|
60/058111 |
Sep 1997 |
US |
|
60/092326 |
Jul 1998 |
US |