Methods For Avoiding Edema in the Treatment of Metabolic, Inflammatory, and Cardiovascular Disorders

1 . A method for treating or preventing inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a edema-sparing PPARγ modulator.

2 . The method of claim 1 , wherein the subject has a condition which contra-indicates the administration of a PPARγ modulator which causes edema.

3 . The method of claim 1 , wherein the subject has edema or excess fluid retention.

4 . The method of claim 1 , wherein the subject has cardiac insufficiency.

5 . The method of claim 1 , wherein the administration is chronic.

6 . The method of claim 1 , wherein the subject is human.

7 . A method of claim 1 , comprising the step of first identifying the subject as having an indication for which an edema causing agent is contra-indicated.

8 . A method of claim 1 , wherein the modulator is a compound of formula I:

wherein R is a member selected from the group consisting of a hydroxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, lower aralkoxy, di-lower alkylamino-lower alkoxy, lower alkanamido lower alkoxy, benzamido-lower alkoxy, ureido-lower alkoxy, N′-lower alkyl-ureido-lower alkoxy, carbamoyl-lower alkoxy, halophenoxy substituted lower alkoxy, carbamoyl substituted phenoxy, carbonyl-lower alkylamino, N,N-di-lower alkylamino-lower alkylamino, halo substituted lower alkylamino, hydroxy substituted lower alkylamino, lower alkanolyloxy substituted lower alkylamino, ureido, arylsulfonamido, alkylsulfonamido and lower alkoxycarbonylamino; and each X is independently a halogen; or a pharmaceutically acceptable salt thereof.

9 . A method of claim 1 , wherein the modulator is a compound of Formula II,

wherein:

each X is independently a halogen and

R 2 is a member selected from the group consisting of: C 1 -C 5 alkyl, C 1 -C 8 -cyclic alkyl, C 2 -C 5 alkenyl, and C 2 -C 5 alkynyl, wherein the groups are optionally substituted with one or more halogen atoms; phenyl, naphthyl and pyridyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w ; —(CHR 3 )R 4 ; —R 7 OR 3 ; —R 7 O 2 CR 8 NR 3 R 4 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q O 2 CR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 )qNR 4 COR 9 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 CONR 3 R 4 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 COOR 10 ; —(CH 2 ) o CH(R 3 )(CH 2 ) q NR 4 SO 2 R 11 ; —(CHR 3 ) p CO 2 R 12 ; —(CHR 3 ) p NR 3 R 4 ; —(CHR 3 ) s CONR 13 R 14 ;

wherein m is 0 to 2, o and q are 0 to 5, p is 1 to 5, s is 1 to 3, t is 1 to 5, u is 0 to 1, v is 1 to 3, and w is 1 to (2v+1); and wherein R 3 and R 4 are independently H, C 1 -C 5 alkyl, phenyl or benzyl; and wherein R 5 is H, C 1 -C 5 alkyl or NR 3 R 4 ; and wherein R 6 is phenyl, naphthyl, pyridyl, imidazolyl, indoxyl, indolizinyl, oxazolyl, thiazolyl, pyrimidyl, or 1-pyrazolyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w ; and wherein R 7 is a C 1 -C 8 saturated or unsaturated, straight-chain, branched or cyclic alkylene or alkylidene group optionally substituted with one or more groups selected from halo, hydroxyl, thiol, amino, monoalkyl amino, dialkyl amino, acylamino, carboxyl, alkylcarboxyl, acyl, aryl, aroyl, aralkyl, cyano, nitro, alkoxy, alkenyloxy, alkylcarbonyloxy and arylcarbonyloxy; and wherein R 8 is a C 1 -C 8 straight-chain or branched alkylene or alkylidene optionally substituted with one or more groups selected from amino, monoalkyl amino, dialkyl amino, acylamino, hydroxyl, thiol, methylthiol, carboxyl and phenyl; and wherein R 9 and R 10 are independently H, C 1 -C 5 alkyl, optionally substituted with one or more groups consisting of C 1 -C 5 alkoxy aryl and heteroaryl, wherein the aryl is phenyl or naphthyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w , and wherein the heteroaryl is pyridyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w ; and wherein R 11 is methyl or phenyl, wherein the phenyl is optionally substituted with methyl and/or —NO 2 ; and wherein R 12 is H, C 1 -C 5 alkyl, phenyl, benzyl, naphthyl or pyridyl, wherein the C 1 -C 5 alkyl, phenyl, naphthyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w ; and wherein R 13 and R 14 are independently the following: alkyl, alkenyl, aryl, aralkyl or cycloalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 , —CH 2 NR 3 R 4 , OOCR 18 and —C v F w ; and wherein when R 13 and R 14 are included as —(CHR 3 )CONR 13 R 14 , NR 13 R 14 is

and wherein R 15 is C v F w or C 1 -C 5 alkyl, wherein C 1 -C 5 alkyl is optionally substituted with the following substituents: C 1 -C 5 alkoxy; phenyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w ; benzyl, optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w ; and wherein R 16 is H, C 1 -C 5 alkyl or benzyl; and wherein R 17 is C 1 -C 5 alkyl, C 3 -C 8 cyclic alkyl, phenyl or benzyl; and wherein R 18 is H, alkyl, aryl, aralkyl or cycloalkyl, where the group is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —NO 2 , —S(O) m (C 1 -C 5 alkyl), —OH, —NR 3 R 4 , —CO 2 R 5 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 3 R 4 and —C v F w .

10 . A method of claim 1 , wherein the modulator is a compound having a formula selected from the group consisting of:

wherein

X is a member selected from the group consisting of O, S, SO, SO 2 and NR, wherein R is H, (C 1 -C 8 )alkyl, COR a , COOR a and CONR a R b wherein R a and R b are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl;

Y is a member selected from the group consisting of CH 2 OR c , CO 2 R c , CHO, CONR c R m , CH(═NR c ), CH(═NOR c ) and carboxylic acid surrogates, wherein R c is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, aryl, aryl(C 1 -C 8 )alkyl and (C 1 -C 8 )alkylene-Z, wherein Z is selected from the group consisting of COR d , COOR d , NR d R e , NR d CONR e R f , NR d COR e , NR d COOR e and CONR d R e wherein R d , R e and R f are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl and phenyl, or optionally two of R d , R e and R f when attached to the same nitrogen atom are combined to form a five- or six-membered ring; and wherein R m is selected from the group consisting of H, (C 1 -C 8 )alkyl, aryl, OH and SO 2 R n , wherein R n is selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, aryl(C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl, (C 1 -C 8 )alkoxy, aryloxy, alkylamino, dialkylamino, arylamino, diarylamino, haloalkylamino and di(haloalkyl)amino, and R m and R c are optionally combined with the nitrogen atom to which each is attached to form a five- or six-membered ring;

HAr is heteroaryl moiety, optionally substituted with from one to three substituents independently selected from the group consisting of halogen, hydroxy, (C 1 -C 8 )alkyl, aryl(C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, (C 1 -C 8 )heteroalkyl, (C 2 -C 5 )heterocyclyl, aryl, aryloxy, heterosubstituted(C 3 -C 7 )cycloalkyl, heteroalkyl substituted (C 3 -C 7 )cycloalkyl, (C 1 -C 8 )haloalkyl, O(C 1 -C 8 )haloalkyl, nitro, cyano, CO 2 R g , COR g , NR g R h , S(O) q R g , SO 2 NR g R h , NR g CONR h R i , NR g COR h , NR g COOR h and CONR g R h , wherein R g , R h and R i are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl, or optionally two of R g , R h and R i when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript q is an integer of from 0 to 2;

each R 1 and R 3 is a member independently selected from the group consisting of halogen, hydroxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )heteroalkyl, (C 2 -C 5 )heterocyclyl, heterosubstituted(C 3 -C 7 )cycloalkyl, heteroalkyl substituted (C 3 -C 7 )cycloalkyl, O(C 1 -C 8 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl, S(O) r -phenyl, COR j , COOR j , NR j R k , S(O) r R j , SO 2 NR j R k , NR j CONR k R l , NR j COR k , NR j COOR k and CONR j R k wherein the phenyl ring is optionally substituted and R j , R k and R l are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl, or optionally two of R j , R k and R l when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript r is an integer of from 0 to 2;

R 2 is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, aryl(C 1 -C 8 )alkyl and (C 1 -C 4 )alkylene-Z, wherein Z is as defined above;

the subscript m is an integer of from 0 to 4;

the subscript p is an integer of from 0 to 3; and

pharmaceutically acceptable salts thereof.

11 . The method of claim 1 , wherein the modulator is a compound having the formula

and all pharmaceutically acceptable salts and prodrugs thereof, wherein

X is a member selected from the group consisting of O, S, SO, SO 2 , CHR and NR, wherein R is H, (C 1 -C 8 )alkyl, COR a , COOR a and CONR a R b wherein R a and R b are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl;

Y is a member selected from the group consisting of CH 2 OR c , CO 2 R c , tetrazole, CHO, CONR c R m , CH(═NR c ) and CH(═NOR c ), wherein R c is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, aryl, aryl(C 1 -C 8 )alkyl and (C 1 -C 8 )alkylene-Z, wherein Z is selected from the group consisting of COR d , COOR d , NR d R e , NR d CONR e R f , NR d COR e , NR d COOR e and CONR d R e wherein R d , R e and R f are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl and phenyl, or optionally two of R d , R e and R f when attached to the same nitrogen atom are combined to form a five- or six-membered ring; and wherein R m is selected from the group consisting of H, (C 1 -C 8 )alkyl, aryl and OH, and R m and R c are optionally combined with the nitrogen atom to which each is attached to form a five or six-membered ring;

each R 1 and R 3 is a member independently selected from the group consisting of halogen, hydroxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 4 -C 8 )cycloalkyl-alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )heteroalkyl, (C 2 -C 5 )heterocyclyl, heterosubstituted(C 3 -C 7 )cycloalkyl, heteroalkyl substituted (C 3 -C 7 )cycloalkyl, O(C 1 -C 8 )haloalkyl, nitro, cyano, phenyl, O-phenyl, NR j -phenyl, S(O) r -phenyl, COR j , COOR j , NR j R k , S(O) r R j , SO 2 NR j R k , NR j CONR k R l , NR j COR k , NR j COOR k and CONR j R k wherein the phenyl ring is optionally substituted and R j , R k and R l are each independently selected from the group consisting of H and (C 1 -C 8 )alkyl, or optionally two of R j , R k and R l when attached to the same nitrogen atom are combined to form a five- or six-membered ring, and the subscript r is an integer of from 0 to 2;

R 2 is a member selected from the group consisting of H and (C 1 -C 8 )alkyl;

Q is CH or N

the subscript m is an integer of from 0 to 3; and

the subscript p is an integer of from 0 to 2.

12 . The method of claim 1 , wherein the modulator has the formula selected from the group consisting of:

13 . A method of treating a human subject known to have an elevated CRP level, comprising administering to the subject a therapeutically effective amount of a compound of formula I, II, III, IVa, IVb, V, VI, or VII.

14 . A method of claim 13 , wherein the subject has edema or excess fluid retention.

15 . The method of claim 13 , wherein the elevated CRP level is at least 3 mg/l.

16 . The method of claim 13 , wherein the administration is chronic.

17 . The method of claim 13 , wherein the therapeutically effective amount is from 100 to 800 mg per day by the oral route.

18 . The method of claim 13 , wherein the therapeutically effective amount is about 200 mg to about 600 mg per day by the oral route.

19 . A method of treating or preventing a cerebrovascular or cardiovascular disorder in a human patient, the method comprising the steps of:

obtaining a blood sample from the patient and determining the level of a marker for a pro-inflammatory state therein, and

administering a therapeutically effective amount of a compound of Formula I, II, III, IVa, IVb, V, VI, or VII.

20 . The method of claim 19 , wherein the marker is hsCRP or IL-6.

21 . The method of claim 20 , wherein the marker is hsCRP and the determined level is at least 3 mg/I.

22 . The method of claim 19 , wherein the patient has edema.

23 . The method of claim 19 , wherein the administering is chronic.

24 . The method of claim 19 , wherein the patient further has hyperglycemia or type 2 diabetes.

25 . The method of claim 19 , wherein the patient further has metabolic syndrome.

26 . The method of claim 19 , wherein the patient further has insulin resistance.

27 . The method of claim 19 , wherein the cardiovascular disorder is selected from the group consisting of hypertension, coronary arterial disease, myocardial infarction, peripheral vascular atherosclerosis, and congestive heart failure.

28 . The method of claim 19 , wherein the therapeutically effective amount is from 100 to 800 mg per day by the oral route.

29 . The method of claim 19 , wherein the therapeutically effective amount is about 200 mg to about 600 mg per day by the oral route.

30 . A method of lowering a CRP level in a subject in need thereof, said method comprising:

obtaining a body fluid sample from the subject and determining the CRP level therein, and

administering a therapeutically effective amount of a edema-sparing PPARγ modulator of Formula I, II, III, IVa, IVb, V, VI, or VII;

wherein the CRP level is lowered.

31 . The method of claim 30 , wherein the subject is obese and hypertensive and over 50 years of age.

32 . The method of claim 30 , wherein the therapeutically effective amount is from 100 to 800 mg per day by the oral route.

33 . The method of claim 30 , wherein the therapeutically effective amount is from about 200 mg to about 600 mg.

34 . The method of claim 30 , wherein the body fluid is blood.

35 . A method of treating a patient in need of therapy with a PPARγ modulator, said method comprising the steps of:

evaluating whether the patient has edema, and

administering a compound of formula I, II, III, IVa, IVb, V, VI, or VII.

36 . A method for treating a patient having edema or at risk of having edema and a metabolic disorder or edema and a cardiovascular disorder, said method comprising administering to said patient an effective amount of a PPARγ modulatory compound selected from the group consisting of formula I, II, III, IVa, IVb, V, VI, or VII.

37 . The method of claim 36 , wherein said cardiovascular disorder is selected from the group consisting of hypertension, stroke, coronary arterial disease, myocardial infarction, peripheral vascular atherosclerosis, and congestive heart failure.

38 . The method of claim 36 , wherein the metabolic disorder is insulin resistance, metabolic syndrome, impaired fasting glucose, impaired glucose tolerance, polycystic ovary disease, or “pre-diabetes”, or any condition characterized by insulin resistance of any degree.

39 . A method of treating a patient having edema and in need of therapy with a PPARγ modulator, said method comprising the steps of:

first evaluating whether the patient has edema, and then

administering a compound of formula I, II, III, IVa, IVb, V, VI, or VII.

40 . A method of treating a patient who has experienced weight gain or edema when treated with a first PPARγ modulator, said method comprising stopping administration of the first PPARγ modulator and administering a second PPARγ modulator which is a compound of formula I, II, III, IVa, IVb, V, VI, or VII.

41 . The method of claim 40 , wherein the first PPARγ modulator is troglitazone, pioglitazone, or rosiglitazone.

42 . A method of treating or preventing a metabolic disorder in a human patient, the method comprising the steps of:

obtaining a blood sample from the patient and determining the level of a marker for a pro-inflammatory state therein, and

administering a therapeutically effective amount of a compound of Formula I, II, III, IVa, IVb, V, VI, or VII.

43 . The method of claim 42 , wherein the marker is hsCRP or IL-6.

44 . The method of claim 43 , wherein the marker is hsCRP and the determined level is at least 3 mg/l.

45 . The method of claim 42 , wherein the patient has edema.

46 . The method of claim 42 , wherein the administering is chronic.

47 . The method of claim 42 , wherein the patient has hyperglycemia or type 2 diabetes.

48 . The method of claim 42 , wherein the subject has metabolic syndrome.

49 . The method of claim 42 , wherein the subject has insulin resistance.