METHODS OF TREATING AND PREVENTING ENDOTHELIAL DYSFUNCTION USING BARDOXOLONE METHYL OR ANALOGS THEREOF

1 . A method of treating or preventing endothelial dysfunction or cardiovascular disease in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:

wherein:

R 1 is —CN, halo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or methyl;

R 3 and R 4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R c ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkylsulfonyl-amino (C≦8) , or substituted versions of any of these groups;

-alkanediyl (C≦8) -R b , -alkenediyl (C≦8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or thio; or

heteroaryl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralk-oxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonyl-amino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) , —OC(O)CH 2 NHC(O)O-t-butyl, —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH,

or thio; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , hetero-aryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkyl-sulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH-heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups;

R c and R 3 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≦4) ; or

R c and R 4 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≦4) ; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , hetero-aryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof,

wherein the patient has been identified as not having at least one of the following characteristics:

(a) a history of left-sided myocardial disease;

(b) an elevated B-type natriuretic peptide (BNP) level;

(c) an elevated albumin/creatinine ratio (ACR); and

(d) chronic kidney disease (CKD).

2 . The method of claim 1 , wherein the patient has pulmonary arterial hypertension or exhibits one or more symptoms of pulmonary arterial hypertension.

3 . The method of either claim 1 , wherein the patient has been identified as not having at least two, at least three, or all four of the characteristics.

4 - 5 . (canceled)

6 . The method of claim 1 , wherein the pressure in the pulmonary artery of the patient has been measured and/or will be measured.

7 . (canceled)

8 . The method of claim 1 , wherein the patient does not have a history of left-sided myocardial disease.

9 . (canceled)

10 . The method of claim 1 , wherein the patient does not have a history of heart failure.

11 - 15 . (canceled)

16 . The method of claim 1 , wherein the elevated BNP level is greater than 200 pg/mL.

17 - 18 . (canceled)

19 . The method of claim 1 , wherein the elevated ACR is greater than 300 mg/g.

20 . The method of claim 1 , wherein the patient's estimated glomerular filtration rate (eGFR) is greater than or equal to 45 mL/min/1.73 m 2 .

21 - 22 . (canceled)

23 . The method of claim 1 , wherein the patient is less than 75 years old.

24 - 28 . (canceled)

29 . The method of claim 1 , wherein the patient has been identified as not having COPD.

30 . (canceled)

31 . The method of claim 1 , wherein the patient is not a smoker.

32 . (canceled)

33 . The method of claim 1 , wherein the patient does not suffer from renal disease.

34 - 40 . (canceled)

41 . The method of claim 1 , wherein the patient does not have CKD.

42 - 52 . (canceled)

53 . The method of claim 1 , wherein the patient has been identified as not having cancer.

54 . (canceled)

55 . The method of claim 1 , wherein the patient has been identified as not having type 2 diabetes.

56 . The method of claim 1 , wherein the patient has been identified as having cardiovascular disease.

57 . The method of claim 56 , wherein the patient has been identified as having or at risk of having atherosclerosis, restenosis, pulmonary hypertension, pulmonary arterial hypertension, or thrombosis.

58 - 62 . (canceled)

63 . A method of treating or preventing pulmonary arterial hypertension in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of the formula:

wherein:

R 1 is —CN, halo, —CF 3 , or —C(O)R a , wherein R a is —OH, alkoxy (C1-4) , —NH 2 , alkylamino (C1-4) , or —NH—S(O) 2 -alkyl (C1-4) ;

R 2 is hydrogen or methyl;

R 3 and R 4 are each independently hydrogen, hydroxy, methyl or as defined below when either of these groups is taken together with group R c ; and

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO;

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkylsulfonyl-amino (C≦8) , or substituted versions of any of these groups;

-alkanediyl (C≦8) -R b , -alkenediyl (C≦8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or thio; or

heteroaryl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralk-oxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonyl-amino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) , —OC(O)CH 2 NHC(O)O-t-butyl, —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH,

or thio; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , hetero-aryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkyl-sulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH-heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups;

R c and R 3 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≦4) ; or

R c and R 4 , taken together, are —O— or —NR d —, wherein R d is hydrogen or alkyl (C≦4) ; or

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , hetero-aryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

64 - 117 . (canceled)

118 . The method of claim 63 , further defined as a method of reducing the pressure in a patient's pulmonary artery,

wherein the patient has been identified as having pulmonary arterial hypertension.

119 - 230 . (canceled)

231 . The method of claim 1 , wherein the patient is a human patient.

232 . The method of claim 1 , wherein the compound is further defined as:

wherein:

Y is:

—H, —OH, —SH, —CN, —F, —CF 3 , —NH 2 or —NCO; alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦8) , heterocycloalkyl (C≦12) , alkoxy (C≦8) , aryloxy (C≦12) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , alkylthio (C≦8) , acylthio (C≦8) , alkylsulfonyl-amino (C≦8) , or substituted versions of any of these groups;

-alkanediyl (C≦8) -R b , -alkenediyl (C≦8) -R b , or a substituted version of any of these groups, wherein R b is:

hydrogen, hydroxy, halo, amino or thio; or

heteroaryl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralk-oxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , alkenylamino (C≦8) , arylamino (C≦8) , aralkylamino (C≦8) , heteroarylamino (C≦8) , alkylsulfonyl-amino (C≦8) , amido (C≦8) , —OC(O)NH-alkyl (C≦8) , —OC(O)CH 2 NHC(O)O-t-butyl, —OCH 2 -alkylthio (C≦8) , or a substituted version of any of these groups;

—(CH 2 ) m C(O)R c , wherein m is 0-6 and R c is:

hydrogen, hydroxy, halo, amino, —NHOH,

or thio; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , hetero-aryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , alkenyloxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkylamino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , alkyl-sulfonylamino (C≦8) , amido (C≦8) , —NH-alkoxy (C≦8) , —NH-heterocycloalkyl (C≦8) , —NHC(NOH)-alkyl (C≦8) , —NH-amido (C≦8) , or a substituted version of any of these groups;

—NHC(O)R e , wherein R e is:

hydrogen, hydroxy, amino; or

alkyl (C≦8) , alkenyl (C≦8) , alkynyl (C≦8) , aryl (C≦8) , aralkyl (C≦8) , hetero-aryl (C≦8) , heterocycloalkyl (C≦8) , alkoxy (C≦8) , aryloxy (C≦8) , aralkoxy (C≦8) , heteroaryloxy (C≦8) , acyloxy (C≦8) , alkyl-amino (C≦8) , dialkylamino (C≦8) , arylamino (C≦8) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt or tautomer thereof.

233 . The method of claim 232 , wherein the compound is further defined as:

234 . The method of claim 233 , wherein at least a portion of the compound is present as a crystalline form having an X-ray diffraction pattern (CuKα) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4° 2θ.

235 . The method of claim 234 , wherein the X-ray diffraction pattern (CuKα) is substantially as shown in FIG. 1A or FIG. 1B .

236 . The method of claim 233 , wherein at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα) with a halo peak at approximately 13.5° 2θ, substantially as shown in FIG. 1C , and a transition glass temperature (T g ).

237 . The method of claim 236 , wherein the T g value is in the range of about 120° C. to about 135° C.

238 . The method of claim 237 , wherein the T g value is in the range of about 125° C. to about 130° C.

239 . The method according to any one of claim 1 , wherein the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 300 mg of the compound.

240 . The method of claim 239 , wherein the daily dose is from about 0.5 mg to about 200 mg of the compound.

241 - 256 . (canceled)

257 . The method of claim 1 , wherein the compound is administered orally, intraarterially or intravenously.

258 . The method of claim 1 , wherein the compound is formulated as a hard or soft capsule or a tablet.

259 . The method of claim 1 , wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient.

260 . The method of claim 259 , wherein the excipient is a methacrylic acid—ethyl acrylate copolymer.

261 . The method of claim 260 , wherein the copolymer comprises methacrylic acid and ethyl acrylate at a 1:1 ratio.

262 . The method claim 1 , further comprising a second therapy.

263 . The method of claim 262 , wherein the second therapy comprises administering to said patient a pharmaceutically effective amount of a second drug.

264 . The method of claim 263 , wherein the second drug is a Rho kinase inhibitor, a tyrosine kinase inhibitor, an epoprostenol derivative, a serotonin receptor antagonist, an endothelin receptor antagonist, a phosphodiesterase (PDE) inhibitor, a calcium channel blocker, a soluble guanylate cyclase stimulator, or nitric oxide.

265 - 272 . (canceled)