Certain benzothiazine dioxide endothelin antagonists and...

Details Certain benzothiazine dioxide endothelin antagonists and... Certain benzothiazine dioxide endothelin antagonists and...

2001-12-05

2003-04-08

Shah, Mukund (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

Reexamination Certificate

active

06545150

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to improved syntheses of known and novel benzothiazine dioxide which are potent and selective endothelin antagonists. The processes of the instant invention are improved over those recited in U.S. Pat. No. 5,599,811 which is hereby incorporated by reference.
The compounds of the instant invention exhibit very significant improvements over those described in U.S. Pat. No. 5,599,811. These improvements include: binding affinity to the ETA receptor, ETA selectivity, functional activity, long pharmacokinetic half-life, high bioavailability, in vivo activity in inhibiting the pressor effect caused by bET-1, oral activity with relatively long duration of action, and efficacy in acute hypoxic pulmonary hypertension in rats.
The processes of the instant invention provide more facile syntheses with higher yields. They are short, clean, reproducible and no tedious chromatography is needed. Moreover, the processes are scaleable and therefore useful for large-scale development.
The present invention also relates to antagonists of endothelin useful as pharmaceutical agents, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, essential renovascular malignant and pulmonary hypertension, cerebral infarction and cerebral ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, benign prostatic hyperplasia, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes.
Also, the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma.
SUMMARY OF THE INVENTION
This invention is improved processes for the preparation of compounds of Formula 1
or a pharmaceutically acceptable salt thereof wherein
R
1
is hydrogen, alkyl, or alkoxy;
R
2
is hydrogen or alkoxy;
R
3
is alkyl or alkoxy;
R
2
and R
3
may be joined to form a ring
R
4
is hydrogen or alkyl;
R
5
is hydrogen, alkyl, alkoxy, halogen at the 2 or 3, or 4, or 5 positions or R
5
is a 3,4-methylenedioxo; and
R
6
is CF
3
, halogen, alkyl, benzyl, phenyl, hydroxy, or pyrrole comprising:
a) alkylating a compound of formula A
 using 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 TiCl
4
in solvent at −78° C., 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
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 at about 100° C. to produce a compound of Formula 1.
The free acid of Formula 1 is obtained by sponification of the ester with, for example, LiOH in THF/MeOH or in dioxane. Any strongly alkaline solution in methanol can be used.
Compounds of the invention are those prepared by the above process, especially those selected from:
4-(3,5-Dimethoxy-phenyl)-2-(2-trifluoromethyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
2-(2-Chloro-phenyl)-4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
2-(2-Bromo-phenyl)-4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
2-(2-Chloro-phenyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
2-(2-Benzyl-phenyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
2-(2,6-Dimethyl-phenyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid monosodium salt;
4-(7-Methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-ethyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1 ,3]dioxol-5-yl-2-(2-propyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-isopropyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-butyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-fluoro-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-hydroxy-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,3-dichloro-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,4-dichloro-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-chloro-4-methoxy-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(3-chloro-2-methyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,6-dimethyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-1,1-dioxo-2-(2-pyrrol-1-yl-phenyl)-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(3,4-dimethyl-isoxazol-5-yl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid;
4-(6-Methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid; and
4-(3,5-Dimethyl-phenyl)-2-(2-trifluoromethyl-phenyl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid.
The invention is also a process for the preparation of a compound of Formula 1
comprising:
a) treating aryl bromide with n-butyl lithium followed by zinc bromide to generate an aryl zinc bromide of Formula Y
b) reacting the product of step a) above with
 in THF in the presence of a palladium catalyst to produce a compound of Formula 1
The free acid of Formula 1 is obtained by sponification of the ester.
The following three compounds are obtained by the above process:
2-(2-Bromo-phenyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid monosodium salt;
4-(7-Ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1&lgr;
6
-benzo[e][1,2]thiazine-3-carboxylic acid, potassium salt; and
4-Benzo[1,3]dioxol-5-yl-

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