US 2011 0065783A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0065783 A1 O'Donnell et al. (43) Pub. Date: Mar. 17, 2011

(54) HYDROXYLATED NEBIVOLOL (52) U.S. Cl...... 514/.456 METABOLITES (76) Inventors: John P. O'Donnell, Morgantown, (57) ABSTRACT WV (US); Walter Owens, Hydroxylated nebivolol metabolites increase NO release Morgantown, WV (US); Joseph from human endothelial cell preparations in a concentration Duncan, Morgantown, WV (US); dependent fashion following acute administration. In addi Andrew Shaw, Morgantown, WV tion, hydroxylated nebivolol metabolites, including but not (US); Jinn Wu, Princeton Junction, limited to 4-hydroxy-6,6'difluoro-, 4-hydroxy-5-phenol-6, NJ (US) 6'difluoro-, and 4-hydroxy-8-pheno-6,6'difluoro-, have the ability to increase the capacity for NO release in human (21) Appl. No.: 12/908,336 endothelial cells following chronic administration. This invention provides hydroxvlated nebivolol metabolites and (22) Filed: Oct. 20, 2010 S. Spin E. and/or at least one Related U.S. Application Data hydroxylated metabolite of nebivolol and/or at least one addi tional compound used to treat cardiovascular diseases or a (63) Continuation of application No. 1 1/342,497, filed on pharmaceutically acceptable salt thereof. In addition, this Jan. 30, 2006. invention provides methods of treating and/or preventing vas cular diseases by administering at least one hydroxylated (60) Provisional application No. 60/ 648.5 51, filed on Jan. metabolite of nebivolol that is capable of releasing a thera 31, 2005, provisional application No. 60/755,856, peutically effective amount of nitric oxide to a targeted site filed on Jan. 3, 2006. affected by the vascular disease. Also, this invention is O O directed to the treatment and/or prevention of migraine head Publication Classification aches administering at least one hydroxylated metabolite of (51) Int. Cl. nebivolol. This invention may also be used in conjunction A6 IK3I/353 (2006.01) with or as a single treatment of metabolic syndrome disor A6IP 9/12 (2006.01) ders. Patent Application Publication Mar. 17, 2011 Sheet 1 of 19 US 2011/0065783 A1

FIGURE 1

4OO

350

300

250

200

150

100 Patent Application Publication Mar. 17, 2011 Sheet 2 of 19 US 2011/0065783 A1

FIGURE 2

500

400

3OO 200 Ø 1 OO Patent Application Publication Mar. 17, 2011 Sheet 3 of 19 US 2011/0065783 A1

FIGURE 3

500

400

300

3Se2108ON(Wu) 200

100

4-Hydroxy 5-Hydroxy 8-Hydroxy N-DAD NDACA N-DAAA Patent Application Publication Mar. 17, 2011 Sheet 4 of 19 US 2011/0065783 A1

FIGURE 4

5OO

400

200

100 Patent Application Publication Mar. 17, 2011 Sheet 5 of 19 US 2011/0065783 A1

FIGURES

-A- 4-Hydroxy 450 -O-5-Hydroxy -- 400 - -O-8-Hydroxy | l arra -O-N-OAD l > 350 -v-N-DACA

S 300 -g- N-DAAA CD 250 o 2OO 150 2 100 50

0.1 1 10 Drug Concentration (uM) Patent Application Publication Mar. 17, 2011 Sheet 6 of 19 US 2011/0065783 A1

FIGURE 6

-A-4-Hydroxy 450 -O-5-Hydroxy - I-A 400 - -O-8-Hydroxy l l -O-N-DAD l > 350 -v- NDACA

S 300-4-N-DAAA C) 250 o 2OO s 150 2 100 50

O.1 1 1O Drug Concentration (uM) Patent Application Publication Mar. 17, 2011 Sheet 7 of 19 US 2011/0065783 A1

FIGURE 7

OWhites A = 4(R)-hydroxy-7-fluoro-6-hydroxy--nebivolol 500 a,b,c Backs B = 4'(R)-Hydroxy-5-fluoro-6-hydroxy--nebivolo C = 4 (S)-Hydroxy-7'-fluoro-6'-hydroxy--nebivolol S a.b.c D = 5-fluoro-6-hydroxy--nebivolol C m/ E = 4'(R)-Hydroxy--nebivolol N- 400 F = 4(S)-Hydroxy--nebivolol 3 (5 CD 3OO a, C Y b O C Z 200 a,c -Y b,c S a,b 100 a,b

O A B C D E F Nebiva L-Nebivod-Nebivo

"p < 0.001 versus cognate Nebiv treatment; p < 0.05 versus oognate L-Nebiv treatment; p < 0.001 versus cognate D-Nebiv treatment (p values from ANOVA Student-Newman-Keuls Mutiple Comparisons Test) Patent Application Publication Mar. 17, 2011 Sheet 8 of 19 US 2011/0065783 A1

FIGURE 8 TARGET CHIRAL METABOLITES - (R.S.S,S) SERIES - 10 COMPOUNDS Sample ID Structure Structure 4-(S)-OH

Amine 1 Armine 2 Amine 3

Epoxide 2

Epoxide 3 Epoxide 4 Patent Application Publication Mar. 17, 2011 Sheet 9 of 19 US 2011/0065783 A1

FIGURE 9 The Synthesis of Amine 1 OH A. -ea O 9 - LiOHPY BAB - A. F NaHCO3/Tol O O OH Osul- (S)-6

al-Ha1) NaH/THF BusSnH/Tol 2) CS2 al-es OH 3) Mel SMe (R, S)-8 Sir

OH OH H o OH o OTs HCMeOH TsC/Py 1 N. NaN/DMF re-as- Hans-e- a-H-e- F f CH2Cl2 F (R, S)-10 (R, S)-11 (R, S)-2

OH o N3 PdfC --e- F H2/EtOh

(R, S)-13 Armine 1 Patent Application Publication Mar. 17, 2011 Sheet 10 of 19 US 2011/0065783 A1

FIGURE 10 The Synthesis of Epoxide 1

O oxO o, A. OA. O NaBH ch'? 1) NaH/THF cri'?O. BuSnH/Tol F 2. 2) CS2 F O Oh 3) Met Ö SMe

(S,S)-9 oA OH OH o. O o, OH o OTs Y., HC/MeOH A. TsC/Py A, MeONa/CH2Cl2 -e- al-S-e- sell-es F F CH2Cl2 F (S,S)- (S,S)-11 (S,S)-12 10

Epoxide 1 Patent Application Publication Mar. 17, 2011 Sheet 11 of 19 US 2011/0065783 A1

FIGURE 11 The Synthesis of Amine 2, part 1

Oh OAC ACOfPc2O/Py AC- OH 1) LDA OH O A. 3. F 10. 2) A. F NaHCO3/TolLiOH/TBAB F O O O O OH 4. 5 Oss--/ (S)-6

a---le1) NaH/THF 2) CS2 3) Mel

H O Oa: BH3 DMS - He 2 NaOH, H2O2 F F (R, S)-14 OH ÖH cis-(R, S)-15 trans-(R, S)-15 Patent Application Publication Mar. 17, 2011 Sheet 12 of 19 US 2011/0065783 A1

FIGURE 12 The Synthesis of Amine 2, part 2 oA oA OH o O H O o OH Ac2OPy ACOH SCIPSC/y F F F ÖH ÖAc ÖAc trans-(R, S)-15 (R, S)-16 (R, S)-17 OH OH OH o OTs o N o, N3 al-R->NaN/DMF K2CO3/MeOHa-ra --- H F s F F 2 ÖAc ÖAc CH (R, S)-18 (R, S)-19 (R, S)-20

Patent Application Publication Mar. 17, 2011 Sheet 13 of 19 US 2011/0065783 A1

FIGURE 13 The Synthesis of Epoxide 2

o, O H oAO O, Harris1) NaH/THF A F 2) CS2 F OH 3) Mel Ö SMe (S,S)-8 S (S,S)-9

H g-A o A O H -> O,2 NaOH,BH3 DMS H2O2 or '-'.-- F 2 F F CH (S,S)-14 cis-(S,S)-15

TsC/Py -b-

OAC OAC trans-(S,S)-15 (S,S)-17

OH

(S,S)-18 Epoxide 2

Patent Application Publication Mar. 17, 2011 Sheet 15 of 19 US 2011/0065783 A1

FIGURE 1S The Synthesis of Epoxide 3

--e-1) Na H/THF BusSnH/Tol 2) CS2 Hereal-e- F OH 3) Mel F Ö. SMe (S,S)-27 A. m (S,S)-28S A

O O O, H O H O 1) s-Buli BnBr/Py HCMeOH -b- se arr-e- 2) (MeO)3B 3) H2O2 (S,S)-29

se-asPa/H

Epoxide 3

Patent Application Publication Mar. 17, 2011 Sheet 18 of 19 US 2011/0065783 A1

FIGURE 182

Coupling of AMINE-X and EPOXIDE-Y: the synthesis of final nebivolol metabolites, part 1 1) iProH, refl. AMINE-X + EPOXOE-Y Target Molecule

Entry Amine Epoxide Target molecules

Qh :

f : f dh

H H gh

f

H Qh :

f OH

H gh

f i Oh dH Patent Application Publication Mar. 17, 2011 Sheet 19 of 19 US 2011/0065783 A1

FIGURE 18b.

Coupling of AMINE-X and EPOXIDE-Y: the synthesis of final nebivolol metabolites, part 2 1) PrOH, refl. AMINE-X + EPOXIDE-Y --> Target Molecule

Entry Amine Epoxide Target molecules

9H gh - o lo

6 f rt i f ÖH 4’-(R)-OH-(R.S.S,S)-NEB

5-F-6-OH-(R.S.S,S)-NEB OH H gh f o o

8 HO rt F 7-F-6-OH-(R.S.S,S)-NEB

9

4'-(R)-OH-5-F-6-OH-(R.S.S,S)-NEB 9 gh F o Nullo

O HO -richi F ÖH US 2011/0065783 A1 Mar. 17, 2011

HYDROXYLATED NEBVOLOL also be used in conjunction with or as a single treatment of METABOLITES metabolic syndrome disorders. BRIEF DESCRIPTION OF THE FIGURES 0001. This application claims priority under 35 USC S119 0005 FIG. 1: The effects of nebivolol and metabolites on to U.S. Provisional Application No. 60/648,551, filed Jan. 31, peak NO release from human endothelial cells following 2005 and to U.S. Provisional Application No. 60/755,856, acute treatment (50 uM treatment). filed Jan. 3, 2006. 0006 FIG. 2: The effects of nebivolol and metabolites on peak NO release from human endothelial cells following FIELD OF THE INVENTION acute treatment (50 uM treatment). 0007 FIG. 3: The effects of nebivolol and metabolites on 0002 Metabolites of nebivolol possess pharmacological peak NO release from human endothelial cells following properties that may be beneficial in treating a variety of dis acute treatment (10 uM treatment). eases, such as cardiovascular diseases, which could include 0008 FIG. 4: Shows peak NO release following treatment hypertension, atherosclerosis, and congestive heart failure. In with acetylcholine, nebivolol and nebivolol metabolites (5 particular, nebivolol and its key metabolites have effects on uM Treatment) NO metabolism, independent of B-selective interactions and 0009 FIG. 5: Shows the concentration-response effects the favorable effects of nebivolol metabolites on endothelial following acute treatment with nebivolol metabolites. NO release has implications for its use in the treatment of 0010 FIG. 6: Shows the concentration-response follow cardiovascular disorders. This invention describes hydroxy ing acute treatment with nebivolol, nebivolol enantiomers lated nebivolol metabolites, compositions comprising at least and 4-hydroxy nebivolol. one hydroxyl nebivolol metabolite and methods of using such 0011 FIG. 7: Shows the amount of NO released as mea compositions to treat and/or prevent cardiovascular diseases sured following acute drug treatment (1.0 uM) of HUVECs or disorders. isolated from White (open bars) and Black American (solid bars) donors using hydroxylated nebivolol. Values are BACKGROUND OF THE INVENTION meantS.D. (n=5). 0003. The normal production of endothelial nitric oxide is 0012 FIG. 8: Target chiral metabolites to be synthesized important for maintenance of vascular function. Increasing —(R.S.S.S.) Series—10 Compounds. endothelial NO release results in a reduction in smooth 0013 FIG. 9: The Synthesis of Amine 1. muscle cell contractility and decreased vascular resistance. (0014 FIG. 10: The synthesis of Epoxide 1. Under conditions of hypertension and hyperlipidemia, how (0015 FIG. 11: The synthesis of Amine 2, part 1 ever, endothelial dysfunction produces a marked decrease in 0016 FIG. 12: The synthesis Amine 2, part 2. NO release, resulting in: 1) increased vasoconstriction and (0017 FIG. 13: The synthesis of Epoxide 2 vasospasm; 2) greater monocyte and LDL infiltration; 3) pro (0018 FIG. 14: The synthesis of Amine 3. liferation of vascular smooth cells; 4) increased oxidative (0019 FIG. 15: The synthesis of Epoxide 3. stress; and 5) increased platelet aggregation. It has been Sug (0020 FIG. 16: The synthesis of Amine 4. gested that Substances that restore endothelial function and (0021 FIG. 17: The synthesis of Epoxide 4. NO metabolism have benefit in the treatment of various car 0022 FIG. 18a; Coupling of Amine-X and Epoxide-Y to diovascular disorders, including coronary artery disease and produce targeted hydroxylated nebivolol metabolites, part 1. heart failure. (0023 FIG. 18b; Coupling of Amine-X and Epoxide-Y to produce targeted hydroxylated nebivolol metabolites, part 2. SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION 0004 Hydroxylated nebivolol metabolites increase NO Definitions release from human endothelial cell preparations in a concen tration dependent fashion following acute administration. In 0024 For convenience, before further description of the addition, several hydroxylated nebivolol metabolites, includ present invention, certain terms employed in the specifica ing but not limited to 4-hydroxy-6,6'difluoro-, 4-hydroxy-5- tion, examples and appended claims are collected here. These phenol-6,6'difluoro-, and 4-hydroxy-8-pheno-6,6'difluoro definitions should be read in light of the remainder of the have the ability to increase the capacity for NO release in disclosure and understood as by a person of skill in the art. human endothelial cells following chronic administration. Unless defined otherwise, all technical and scientific terms This invention provides hydroxylated nebivolol metabolites used herein have the same meaning as commonly understood and compositions comprising nebivolol and/or at least one by a person of ordinary skill in the art. hydroxylated metabolite of nebivolol and/or at least one com 0025. The articles “a” and “an are used herein to refer to pound used to treat cardiovascular diseases or a pharmaceu one or to more than one (i.e., to at least one) of the grammati tically acceptable salt thereof. In addition, this invention pro cal object of the article. By way of example, “an element' vides methods of treating and/or preventing vascular diseases means one element or more than one element. characterized by nitric oxide insufficiency, by administering 0026. About the same time” means that within about at least one hydroxylated metabolite of nebivolol that is thirty minutes of administering one compound (nebivolol) to capable of releasing a therapeutically effective amount of the patient, the other active compound(s) is/are administered nitric oxide to a targeted site affected by the vascular disease. to the patient. About the same time' also includes simulta Also, this invention is directed to the treatment and/or pre neous administration of the compounds. vention of migraine headaches administering at least one 0027. The phrase “angiotensin converting enzyme inhibi hydroxylated metabolite of nebivolol. This invention may tor” or ACE inhibitor as used herein refers to a compound US 2011/0065783 A1 Mar. 17, 2011 that inhibits any enzyme from converting angiotensin to any perindopril (Aceon), quinapril (Accupril), ramipril (Altace) other form. Angiotensin Converting Enzyme (ACE) Inhibi and trandolapril (Mavik)); (9) angiotensin II antagonists tOrs (candesartan (Atacand), eprosartan (Teveten), irbesartan 0028 ACE inhibitors are effective antihypertensive agents (Avapro), losartan (Cozaar), olmesartan (Benicar), telmisar that competitively inhibit angiotensin converting enzymes tan (Micardis) and Valsartan (Diovan); (10) calcium channel and prevent the conversion of angiotensin I to angiotensin II. blockers—non-dihydropyridines (including diltiazem Non-limiting examples of ACE inhibitors include alacepril, extended release (Cardizem CD, Dilacor XR, Tiazac), dilt benazepril, captopril, ceronapril, cilaZapril, delapril, enala iazem extended release (Cardizem LA), Verapamil immediate pril, enalaprilat, fosinopril, imidapril, lisinopril, perindopril, release (Calan, Isoptin), Verapamil long acting (Calan SR, quinapril, ramiprilat, ramipril, spirapril, temocapril, and tran Isoptin SR) and Verapamil Coer (Covera HS, Verelan PM)); dollapril. Other ACE inhibitors may be identified using stan (11) calcium channel blockers-dihydropyridines (including dard assaying techniques known to one of ordinary skill in the amlodipine (Norvasc), felodipine (Plendil), isradipine (Dy art. naCircCR), nicardipine sustained release (Cardene SR), nife 0029. The phrase “angiotensin II receptor antagonist” or dipine long-acting (Adalat CC, Procardia XL) and nisol “ARB” refers to a compound that binds to a receptor site on dipine (Sular)); (12) alpha-blockers (including doxazocin angiotensin II but does not cause any physiological changes (Cardura), prazosin (Minipress) and terazosin (Hytrin)); (13) unless another receptor ligand is present. central alpha-agonists and other centrally acting drugs (in 0030 Angiotensin II Receptor Antagonist (ARB): ARBs cluding clonidine (Catapres), clonidine patch (Catapres are effective antihypertensive agents that have a very favor TTS), methyldopa (Aldomet), reserpine, and guanfacine); able side effect profile. Their mechanism of action is related (14) direct vasodilators (including hydralazine (Apresoline) to the selective blocking of the vasoconstrictor and aldoster and minoxidil (Loniten); (15) ACEIs and CCBs (including one-secreting effects of angiotensin. Non-limiting examples amlodipine/benazepril hydrochloride, enalapril maleate/ of ARBs include candesartan, eprosartan, irbesartan, losar felodipine and trandolapril/verapamil); (16) ACEIs and tan, and Valsartan. Other ARBs may be identified using stan diuretics (including benazepril/hydrochlorothiazide, capto dard assaying techniques known to one of ordinary skill in the pril/hydrochlorothiazide, enalapril maleate/hydrochlorothi art. azide, lisinopril/hydrochlorothiazide, moexipril HCl/hydro 0031. The term “antagonist' is art-recognized and refers chlorothiazide and quinapril/hydrochlorothiazide: (17) to a compound that binds to a receptor site, but does not cause ARBs and diuretics (including candesartan cilexetil/hydro a physiological change unless another receptor ligand is chlorothiazide, eprosartan mesylate/hydrochlorothiazide, present. irbesartan/hydrochlorothiazide, losartan potassium/hydro 0032. The term “bioavailable' is art-recognized and refers chlorothiazide, telmisartan/hydrochlorothiazide, Valsartan/ to a form of the subject invention that allows for it, or a portion hydrochlorothiazide: (18) beta blockers and diuretics (includ of the amount administered, to be absorbed by, incorporated ing atenolol/chlorthalidone, bisoprolol fumarate/ to, or otherwise physiologically available to a subject or hydrochlorothiazide, metoprolol tartrate? patient to whom it is administered. hydrochlorothiazide, nadolol/bendrofluthiazide and timolol 0033 “Black” refers to a person of African descent or an maleate/hydrochlorothiazide; (19) centrally acting drug and African-American person but is not necessarily limited to diuretic (including methyldopa/hydrochlorothiazide, reser those of African origin (e.g., Carribean). pine/chlorothiazide and reserpine/hydrochlorothiazide); (20) 0034). “Therapeutically effective amount” refers to the diuretic and diuretic (amiloride HC1/hydrochlorothiazide, amount of the compound and/or composition that is effective spironolactone/hydrochlorothiazide and triamterene/hydro to achieve its intended purpose. chlorothiazide. 0035. The phrase “cardiovascular agent' or “cardiovascu 0036 Cardiovascular disease or disorder refers to any car lar drug” refers to a therapeutic compound that is useful for diovascular disease or disorder known in the art, including, treating or preventing a cardiovascular disease. Non-limiting but not limited to, wherein the cardiovascular disease is examples of Suitable compounds include (1) thiazide diuret selected from the group consisting of congestive heart failure, ics (including chlorothiazide (Diuril), chlorthalidone, hydro hypertension, pulmonary hypertension, myocardial and cere chlorothiazide, polythiazide (Renese), indapamide (LoZol) bral infarctions, atherosclerosis, atherogenesis, thrombosis, and metolaZone (Mykrox, ZaroXolyn)); (2) loop diuretics ischemic heart disease, post-angioplasty restenosis, coronary (including bumetanide (Bumex) and furosemide (Lasix), artery diseases, renal failure, stable, unstable and variant torsemide (Demadex)); (3) potassium-sparing diuretics (in (Prinzmetal) angina, cardiac edema, renal insufficiency, cluding amiloride (Midamor) and triamterene (Dyrenium)); nephrotic edema, hepatic edema, stroke, transient ischemic (4) aldosterone receptor blockers (including eplerenone (In attacks, cerebrovascular accidents, restenosis, controlling spra) and spironolactone (Aldactone)); (5) beta blockers (in blood pressure in hypertension, platelet adhesion, platelet cluding atenolol (Tenormin), betaxolol (Kerlone), bisoprolol aggregation, Smooth muscle cell proliferation, pulmonary (Zebeta), metoprolol (Lopressor), metoprolol extended edema, and vascular complications associated with the use of release (Toprol XL), nadolol (Corgard), propranolol (In medical devices. deral), propranolol long acting (Inderal LA) and timolol 0037. The term “combination refers to two or more dif (Blocadren)); (6) beta blockers with intrinsic sympathomi ferent active agents which are administered at roughly about metic activity (including acebutolol (Sectral), penbutolol the same time (for example, where the active agents are in a (Levatol) and pindolol); (7) combined alpha and beta block single pharmaceutical preparation) or at different times (for ers (including carvedilol (Coreg) and labetalol (Normodyne, example, one agent is administered to the Subject before the Trandate)); (8) ACE inhibitors (including benazepril (Lo other). tensin), captopril (Capoten), enalapril (Vasotec), fosinopril 0038 The terms “drug.” “pharmaceutically active agent.” (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), “bioactive agent,” “therapeutic agent, and “active agent' US 2011/0065783 A1 Mar. 17, 2011

may be used interchangeably and refer to a Substance, Such as esters, such as ethyl oleate and ethyl laurate; (13) agar, (14) a chemical compound or complex, that has a measurable buffering agents, such as magnesium hydroxide and alumi beneficial physiological effect on the body, Such as a thera num hydroxide: (15) alginic acid, (16) pyrogen-free water; peutic effect in treatment of a disease or disorder, when (17) isotonic saline; (18) IV fluids, including but not limited administered in an effective amount. Further, when these to Ringer's solution, 5% dextrose in water, and half normal terms are used, or when a particular active agent is specifi saline; (19) ethyl alcohol; (20) phosphate buffer solutions: cally identified by name or category, it is understood that Such and (21) other non-toxic compatible Substances employed in recitation is intended to include the active agent perse, as well pharmaceutical formulations. as pharmaceutically acceptable, pharmacologically active 0044) “Patient” refers to animals, preferably mammals, derivatives thereof, or compounds significantly related most preferably humans, and includes males and females. thereto, including without limitation, salts, pharmaceutically 0045 “Ouality of life” refers to one or more of a person's acceptable salts, N-oxides, prodrugs, active metabolites, iso ability to walk, climb stairs, do errands, work around the mers, fragments, analogs, Solvates hydrates, radioisotopes, house, participate in recreational activities, and/or not requir etc ing rest during the day, and/or the absence of sleeping prob 0039. The phrase “effective amount” refers to that amount lems or shortness of breath. of a Substance that produces some desired local or systemic 0046. The term “prophylactic' or “therapeutic treatment effectata reasonable benefit/risk ratio applicable to any treat is art-recognized and refers to administration to the host of ment. The effective amount of such substance will vary one or more of the Subject compositions. If it is administered depending upon the Subject and disease condition being prior to clinical manifestation of the unwanted condition treated, the weight and age of the subject, the severity of the (e.g., disease or other unwanted State of the host animal) then disease condition, the manner of administration and the like, the treatment is prophylactic, i.e., it protects the host against which can readily be determined by one of ordinary skill in developing the unwanted condition, whereas if administered the art. after manifestation of the unwanted condition, the treatment 0040 “Endothelial dysfunction” refers to the impaired is therapeutic (i.e., it is intended to diminish, ameliorate or ability of in any physiological processes carried out by the maintain the existing unwanted condition or side effects endothelium, in particular, production of nitric oxide regard therefrom). less of cause. It may be evaluated by, Such as, for example, 0047. The term “structure-activity relationship” or invasive techniques, such as, for example, coronary artery “(SAR) is art-recognized and refers to the way in which reactivity to acetylcholine or methacholine, and the like, or by altering the molecular structure of a drug or other compound noninvasive techniques. Such as, for example, blood flow alters its interaction with a receptor, enzyme, nucleic acid or measurements, brachial artery flow dilation using cuffocclu other target and the like. sion of the arm above or below the elbow, brachial artery 0048. It will be understood that “substitution' or “substi ultrasonography, imaging techniques, measurement of circu tuted with includes the implicit proviso that such substitu lating biomarkers. Such as, asymmetric dimethylarginine tion is in accordance with permitted valence of the substituted (ADMA), and the like. For the latter measurement the endot atom and the Substituent, and that the Substitution results in a helial-dependent flow-mediated dilation will be lower in stable compound, e.g., which does not spontaneously patients diagnosed with an endothelial dysfunction. undergo transformation Such as by rearrangement, cycliza 0041. The phrase “endothelial nitric oxide synthase' or tion, elimination, or other reaction. “eNOS refers to enzymes that produce nitric oxide. 0049. The term “substituted' is also contemplated to 0042. The term “pharmaceutically acceptable salts' is art include all permissible Substituents of organic compounds. In recognized and refers to the relatively non-toxic, inorganic a broad aspect, the permissible Substituents include acyclic and organic acid addition salts of compounds, including, for and cyclic, branched and unbranched, carbocyclic and het example, those contained in compositions of the present erocyclic, aromatic and nonaromatic Substituents of organic invention. compounds. Illustrative Substituents include, for example, 0043. The term “pharmaceutically acceptable carrier is those described herein above. The permissible substituents art-recognized and refers to a pharmaceutically-acceptable may be one or more and the same or different for appropriate material, composition or vehicle. Such as a liquid or Solid organic compounds. For purposes of this invention, the het filler, diluent, excipient, Solvent or encapsulating material, eroatoms such as nitrogen may have hydrogen Substituents involved in carrying or transporting any Subject composition and/or any permissible Substituents of organic compounds or component thereof from one organ, or portion of the body, described herein which satisfy the valences of the heteroat to another organ, or portion of the body. Each carrier must be oms. This invention is not intended to be limited in any acceptable in the sense of being compatible with the subject manner by the permissible Substituents of organic com composition and its components and not injurious to the pounds. patient. Some examples of materials which may serve as 0050. The term “synthetic' is art-recognized and refers to pharmaceutically acceptable excipients include: (1) Sugars, production by in vitro chemical or enzymatic synthesis. Such as lactose, glucose and Sucrose; (2) starches, such as 0051. The phrase “therapeutic effect” is art-recognized corn starch and potato starch; (3) cellulose, and its deriva and refers to a local or systemic effect in animals, particularly tives. Such as sodium carboxymethyl cellulose, ethyl cellu mammals, and more particularly humans caused by a phar lose and cellulose acetate; (4) powdered tragacanth; (5) malt, macologically active Substance. The term thus means any (6) gelatin; (7) talc.; (8) excipients, such as cocoa butter and Substance intended for use in the diagnosis, cure, mitigation, Suppository waxes; (9) oils, such as peanut oil, cottonseed oil, treatment or prevention of disease or in the enhancement of safflower oil, sesame oil, olive oil, corn oil and soybean oil; desirable physical or mental development and/or conditions (10) glycols, such as propylene glycol; (11) polyols, such as in an animal or human. The phrase “therapeutically-effective glycerin, Sorbitol, mannitol and polyethylene glycol, (12) amount’ means that amount of such a Substance that produces US 2011/0065783 A1 Mar. 17, 2011

some desired local or systemic effect at a reasonable benefit/ materials may be incompatible with some of the reaction risk ratio applicable to any treatment. The therapeutically conditions required in some of the methods described, but effective amount of such Substance will vary depending upon alternative methods and substituents compatible with the the Subject and disease condition being treated, the weight reaction conditions will be readily apparent to one skilled in and age of the Subject, the severity of the disease condition, the art. The use of Sulfur and oxygen protecting groups is the manner of administration and the like, which can readily known in the art for protecting thiol and alcohol groups be determined by one of ordinary skill in the art. against undesirable reactions during a synthetic procedure 0052. The term “treating is art-recognized and refers to and many such protecting groups are known, e.g., T. H. curing as well as ameliorating at least one symptom of any Greene and P. G. M. Wuts, Protective Groups in Organic condition or disease. Synthesis, John Wiley & Sons, New York (1999), which is 0053. The term “metabolite' or “nebivolol metabolite' as incorporated herein in its entirety. used herein includes hydroxyl substitution at one or more of 0057 The hydroxylated metabolites have basic properties positions 3-8 and 3'-8", wherein positions 3-8 and 3'-8" shown and, consequently, they may be converted to their therapeu on the parent nebivolol compound may each independently tically active non-toxic acid addition salt forms by treatment be hydroxyl groups, while positions 3-8 and 3'-8" may each with appropriate acids, such as, for example, inorganic acids, independently be halogen atoms, such as fluorine, or each Such as hydrohalic acid, e.g. hydrochloric, hydrobromic and independently be hydrogen atoms. For example, the com the like, and Sulfuric acid, nitric acid, phosphoric acid and the pound may be mono-hydroxylated at the 4,4', 5.5' 8, or 8 like; or organic acids, such as, for example, acetic, propanoic, positions and di-fluorinated at the 6 and 6' positions. In hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, another example, the compound could also be di-hydroxy ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, lated at the 4.5', 4', 5; 4.8; 4.8, or 4.8 positions and be (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybu di-fluorinated at the 6 and 6'positions in all of these instances. tanedioic, 2-hydroxy-1,2,3-propane-tricarboxylic, methane This invention envisions and includes within its scope all Such Sulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzene structural isomers and stereoisomers and mixtures thereof, Sulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino and those not explicitly described. The terms “metabolite' 2-hydroxybenzoic and the like acids. Conversely, the salt and “nebivolol metabolite” envision and includes within its form can be converted by treatment with alkali into the free Scope all Such structural isomers and stereoisomers and mix base form. tures thereof, and those not explicitly described. 0054 The phrase “therapeutic effect” is art-recognized Hydroxylated Nebivolol Metabolites and refers to a local or systemic effect in animals, particularly 0058 Hydroxylated metabolites of nebivolol have the mammals, and more particularly humans caused by a phar ability to increase the capacity for NO release in human macologically active Substance. The term thus means any endothelial cells following (chronic) administration. While Substance intended for use in the diagnosis, cure, mitigation, not being bound by theory, the hydroxylated metabolites of treatment or prevention of disease or in the enhancement of nebivolol are thought to function via activation of the L-argi desirable physical or mental development and/or conditions nine/nitric oxide pathway. They are endothelial-dependent in an animal or human. The phrase “therapeutically-effective vasodilatory agents with additional cardio-selective (i.e., amount’ means that amount of such a substance that produces beta-selective) blocking capacity, which have the potential to some desired local or systemic effect at a reasonable benefit/ maintain endothelial function or improve endothelial dys risk ratio applicable to any treatment. The therapeutically function and be effective medications for the treatment of effective amount of such Substance will vary depending upon cardiovascular diseases, such as atherosclerosis, hyperten the Subject and disease condition being treated, the weight Sion, coronary artery disease and congestive heart failure. and age of the Subject, the severity of the disease condition, Hydroxylated nebivolol metabolites could be used as a mono the manner of administration and the like, which can readily therapy to treat or prevent the aforementioned disorders or in be determined by one of ordinary skill in the art. combination with other appropriate pharmaceutical agents 0055. The parent nebivolol compound and its hydroxy either in the same dosage form/product or concomitantly lated metabolites can be synthesized by one skilled in the art administered as separate dosage forms/products to following the methods described in, for example, U.S. Pat. adequately treat/prevent the aforementioned disorders. Since Nos. 4,654,362, 5,759,580, 6,075,046, 6,545,040 and in EPO these compounds have the capacity to increase endothelial 145 067, EP 0 334 429, and in WO95/22325 and WO nitric oxide concentrations, they may have added benefits in 96/19987: Van Lommen et al., J. Pharm. Belg., 45(6): 355 special populations such as diabetics, chronic Smokers, 360 (1990); Chandrasekhar, S. et al., Tetrahedron, 56(34): Black-Americans, patients with acute coronary syndromes 6339–6344 (2000); and Kendricket al., J. Chromatogram. A., (ACS), coronary heart disease (CHD), metabolic syndrome 729: 341-354 (1996); the disclosure of each of which are and people suffering from obesity. incorporated by reference herein in their entirety. 0059. The direct endothelial benefit for the hydroxylated 0056. The hydroxylated metabolites may also be prepared metabolites of nebivolol was observed at concentrations as by the synthetic procedures found in Appendix 1. Reactions low as 250 nM. By enhancing the ability of cells to release are performed in Solvents appropriate to the reagents, and NO, these nebivolol metabolites may have strong vasodila materials used are suitable for the transformations being tory effects and the ability to restore abnormalities in endot effected. It is understood by one skilled in the art of organic helial function associated with hypertension. Further, these synthesis that the functionality present in the molecule must metabolites have the potential for pronounced affects in spe be consistent with the chemical transformation proposed. cial populations prone to cardiovascular disease, such as This will, on occasion, necessitate judgment by the Scientist Black Americans, and these metabolites may have effects in as to the order of synthetic steps, protecting groups required, HUVEC (Human Umbilical Vein Endothelial Cells) in con and deprotection conditions. Substituents on the starting centrations as low as 250 nM. US 2011/0065783 A1 Mar. 17, 2011

0060. The hydroxylated nebivolol metabolites are repre the other cardiovascular agent is an ARB, the amount of ARB sented by the formula (I) may be anywhere from about 1 mg to about 1200 mg. The amount of the other cardiovascular agent will depend in part

on the particular cardiovascular agent used. 0064. In addition to ACE inhibitors and ARBs, additional cardiovascular agents include, but are not limited to adrener gic blockers, adrenergic agonists, agents for pheochromocy toma, antianginal agents, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, antidiabetics, antiinflanunatory agents, calcium channel blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin receptor antagonists, HMG wherein positions 3-8 and 3'-8" shown on the parent nebivolol Co-A reductase inhibitors, inotropic agents, rennin inhibi compound may each independently be hydroxyl groups (and tors, vasodilators, vasopressors, AGE crosslink breakers (ad at least one of them is an —OH), while positions 3-8 and 3'-8" vanced glycosylation end-product crosslink breakers, such as may each independently be halogen atoms, such as fluorine, alagebrium, see U.S. Pat. No. 6,458.819), and AGE formation or each independently be hydrogen atoms. For example, the inhibitors (advanced glycosylation end-product formation compound may be mono-hydroxylated at the 4,4', 5.5', 8, or 8 inhibitors, such as pimagedine). Cardiovascular agents fall positions and di-fluorinated at the 6 and 6' positions. In ing within these general categories are exemplified by the another example, the compound could be di-hydroxylated at following: the 4.5', 4', 5; 4.8', 4',8, or 4.8 positions and be di-fluorinated Angiotensin I Converting Enzymes (ACEs) and Angio at the 6 and 6' positions in all of these instances. This inven tensin II Receptor Antagonists (ARBs) tion envisions and includes within its scope all such structural 0065 Angiotensin II receptor antagonists' (ARBs) are isomers and Stereoisomers and mixtures thereof, and those compounds which interfere with the activity of angiotensin II not explicitly described. by binding to angiotensin II receptors and interfering with its 0061. It is to be understood that the hydroxylated nebiv activity. Angiotensin I and angiotensin II are synthesized by olol metabolites can exist as the optically pure enantiomers, the enzymatic renin-angiotensin pathway. The synthetic pro pure diastereomers, mixtures of enantiomers, mixtures of cess is initiated when the enzyme renin acts on angiotensino diastereomers, racemic mixtures of enantiomers, diastereo gen, a pseudoglobulin in blood plasma, to produce the meric racemates or mixtures of diastereomeric racemates. It decapeptide angiotensin I. Angiotensin I is converted by is to be understood that the compound has at a minimum 4 angiotensin converting enzyme (ACE) to angiotensin II (an Stereocenters, and if the pyran ring(s) is/are Substituted with a giotensin-1-8 octapeptide). The latter is an active pressor hydroxyl functionality, the compound has minimum of 5 Substance which has been implicated as a causative agent in Stereocenters. This inventions anticipates all combinations of several forms of hypertension in various mammalian species, Stereoisomers. e.g., humans. 0062 For instance, the hydroxy-substituted nebivolol 0.066 Angiotensin II receptor antagonists (ARBs) are metabolites 4.5'-dihydroxy-6,6'-difluoro, 4,8-dihydroxy-6, well known and include peptide compounds and non-peptide 6'-difluoro- and 4-hydroxy-6,6'-difluoro-increase NO release compounds. Most angiotensin II receptor antagonists are from human endothelial cell in concentration dependent fash slightly modified congeners in which agonist activity is ion following acute administration. For example, the 4.5'- attenuated by replacement of phenylalanine in position 8 with dihydroxy-6,6'-difluoro-, and 4,8-dihydroxy-6,6'-difluoro Some other amino acid; stability can be enhanced by other are agonists of NO release, with a maximum of about 330-350 replacements that slow degeneration in vivo. nMNO at a 50 uM drug concentration (see FIGS. 1 and 2). 0067 Examples of angiotensin II receptor antagonists The hydroxylated metabolites of nebivolol are thought to include: telmisartan; olmesartan; peptidic compounds (e.g., function as anti-oxidants and prevent lipid peroxidation. Saralasin and related analogs); N-Substituted imidazole-2- one (U.S. Pat. No. 5,087.634); imidazole acetate derivatives Compositions Comprising Nebivolol including 2-N-butyl-4-chloro-1-(2-chlorobenzile) imida 0063. In part, the present invention features compositions Zole-5-acetic acid (see Long et al., J. Pharmacol. Exp. Ther. comprising a nebivolol metabolite and at least one other car 247(1), 1-7 (1988)); 4,5,6,7-tetrahydro-1H-imidazo[4,5-c. diovascular agent. In addition, the present invention features pyridine-6-carboxylic acid and analog derivatives (U.S. Pat. compositions comprising a nebivolol metabolite and at least No. 4,816.463): N2-tetrazole beta-glucuronide analogs (U.S. one other active agent. The amount of each cardiovascular Pat. No. 5,085.992); substituted pyrroles, pyrazoles, and trya agent and/or other active agent present in the compositions Zoles (U.S. Pat. No. 5,081,127); phenol and heterocyclic may vary depending on a number of variables Such as age, derivatives such as 1,3-imidazoles (U.S. Pat. No. 5,073,566); weight, gender, and health related issues. In general, the dos imidazo-fused 7-member ring heterocycles (U.S. Pat. No. age of the cardiovascular agents will generally be in the range 5,064,825); peptides (e.g., U.S. Pat. No. 4,772,684); antibod of about 0.01 ng to about 10g per kg body weight, specifically ies to angiotensin II (e.g., U.S. Pat. No. 4.302.386); and in the range of about 1 ng to about 0.1 g per kg, and more aralkyl imidazole compounds such as biphenyl-methyl Sub specifically in the range of about 100 ng to about 10 mg per stituted imidazoles (e.g., EP253,310, Jan. 20, 1988); ES8891 kg. In another embodiment, the amount of nebivolol in the (N-morpholinoacetyl-(-1-naphthyl)-L-alanyl-(4, thiazolyl)- compositions of the present invention may be anywhere from L-alanyl (35, 45)-4-amino-3-hydroxy-5-cyclo-hexapen about 0.125 mg to about 40 mg. When the other cardiovas tanoyl-N-hexylamide, Sankyo Company, Ltd., Tokyo, cular agent is an ACE inhibitor, the amount of the ACE Japan); SKF 108566 (E-alpha-2-2-butyl-1-(carboxyphenyl) inhibitor may be anywhere from 0.5 mg to about 80 mg. When methyl 1H-imidazole-5-ylmethylane-2-thiophenepro US 2011/0065783 A1 Mar. 17, 2011

panoic acid, Smith Kline Beecham Pharmaceuticals, Pa.); clonidine, cyclopentamine, denopamine, detomidine, Losartan (DUP753/MK954, DuPont Merck Pharmaceutical dimetofrine, dioxethedrine, diplivefrin, dopexamine, ephe Company); Remikirin (RO42-5892. F. Hoffman LaRoche A drine, epinephrine, etafedrine, ethylnorepinephrine, fenot G); A. Sub.2 agonists (Marion Merrill Dow) and certain non erol, fenoxazoline, formoterol, guanabenz, guanfacine, hexo peptide heterocycles (G. D. Searle and Company). Other prenaline, hydroxyamphetamine, ibopamine, indanazoline, non-limiting examples of ARBs include candesartan, eprosa isoetharine, isometheptene, isoproterenol, mabuterol, rtan, irbesartan, losartan, and Valsartan. Other ARBs may be mephentermine, metaproterenol, metaraminol, metizoline, identified using standard assaying techniques known to one methoxamine, methylhexaneamine, methoxyphenamine, of ordinary skill in the art. midodrine, modafinil, moXonidine, naphazoline, norepineph 0068 Angiotensin converting enzyme” (ACE) is an rine norfenefrine, octodrine, octopamine, oxyfedrine, enzyme which catalyzes the conversion of angiotensin Ito oxymetazoline, phenylephrine hydrochloride, phenylpro angiotensin II. ACE inhibitors include amino acids and panolamine hydrochloride, phenylpropylmethylamine, derivatives thereof, peptides, including di- and tri-peptides pholedrine, pirbuterol prenalterol, procaterol, propyl and antibodies to ACE which intervene in the renin-angio hexedrine, protokylol, pseudoephedrine, reproterol, rillmeni tensin system by inhibiting the activity of ACEthereby reduc dine, rimiterol, ritodrine, salmeterol, Solterenol, Synephrine, ing or eliminating the formation of pressor Substance angio talipexole, terbutaline, tetrahydrozoline, tiamenidine, trama tensin II. ACE inhibitors have been used medically to treat Zoline, tretoquinol, tuaminoheptane, tulobuterol, tymazoline, hypertension, congestive heart failure, myocardial infarction tyramine, Xamoterol, Xylometazoline, and mixtures thereof. and renal disease. Classes of compounds known to be useful as ACE inhibitors include acylmercapto and mercaptoal Agents for Pheochromocytoma kanoyl prolines such as captopril (U.S. Pat. No. 4,105,776) and Zofenopril (U.S. Pat. No. 4.316,906), carboxyalkyl 0071 Include but are not limited to chemotherapeutics. dipeptides such as enalapril (U.S. Pat. No. 4.374,829), lisi Antianginal Agents nopril (U.S. Pat. No. 4.374,829), quinapril (U.S. Pat. No. 4,344.949), ramipril (U.S. Pat. No. 4,587.258), and perin 0072 Include but are not limited to amlodipine besylate, dopril (U.S. Pat. No. 4,508,729), carboxyalkyl dipeptide amlodipine maleate, betaxolol hydrochloride, bevantolol mimics such as cilazapril (U.S. Pat. No. 4,512.924) and hydrochloride, butoprozine hydrochloride, carvedilol, benazepril (U.S. Pat. No. 4.410,520), phosphinylalkanoyl cinepazet maleate, metoprolol Succinate, molsidomine, prolines such as fosinopril (U.S. Pat. No. 4.337.201) and monatepil maleate, nitrates (including but not limited to glyc trandolapril. Other non-limiting examples of ACE inhibitors eryl trinitrate (GTN, nitroglycerin, Nitro-Bid), isosorbide-5- include, but are not limited to, alacepril, benazepril, captopril, mononitrate (5-ISMN, Ismo), amyl nitrate and nicorandil ceronapril, cilaZapril, delapril, enalapril, enalaprilat, fosino (Icorel)), primidolol, ranolazine hydrochloride, tosifen, Vera pril, imidapril, lisinopril, perindopril, quinapril, ramipril, pamil hydrochloride). ramiprilat, spirapril, temocapril, trandolapril. Antiarrhythmics Other Active Agents Also Include the Following: 0073. Non-limiting examples of antiarrhythmics that may Adrenergic Blockers be used in the compositions of the present invention include acebutolol, acecamide, adenosine, ajmaline, alprenolol. 0069. Non-limiting examples of adrenergic blockers, both amiodarone, amoproxan, aprindine, aprotinolol, atenolol. C- and B-adrenergic blockers, that may be used in the com azimilide, bevantolol, bidisomide, bretylium tosylate, bucu positions of the present invention include Beta-adrenergic molol, butetolol, bunaftine, bunitrolol, bupranolol, butidrine receptor blockers include, but are not limited to, atenolol. hydrochloride, butobendine, capobenic acid, carazolol, car acebutolol, alprenolol, befunolol, betaxolol, bunitrolol, car teolol, cifenline, cloranolol, disopyramide, dolfetilide, enca teolol, celiprolol, hydroxalol, indenolol, labetalol, mide, esmolol, flecainide, hydroquinidine, ibutilide, indeca levobunolol, mepindolol, methypranol, metindol, meto mide, indenolol, ipratropium bromide, lidocaine, lorajmine, prolol, metrizoranolol, Oxprenolol, pindolol, propranolol. lorcamide, meobentine, mexiletine, moricizine, nadoxolol. practolol, Sotalolnadolol, tiprenolol, tolamolol, timolol. nifenaolol, Oxprenolol, penbutolol, pentisomide, pilsicainide, bupranolol, penbutolol, trimepranol, yohimbine, 2-(3-(1,1- pindolol, pirmenol, practolol, prajmaline, procainamide dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecar hydrochloride, pronethalol, propafenone, propranolol. bonitrilHCl, 1-butylamino-3-(2,5-dichlorophenoxy)-2-pro panol. 1-isopropylamino-3-(4-(2-cyclopropylmethoxyethyl) pyrinoline, quinidine, sematilide, Sotalol, talinolol, tilisolol. phenoxy)-2-propanol, 3-isopropylamino-1-(7-methylindan timolol, tocainide, Verapamil, Vicquidil, Xibenolol, and mix 4-yloxy)-2-butanol, 2-(3-t-butylamino-2-hydroxy tures thereof. propylthio)-4-(5-carbamoyl-2-thienyl)thiazole, 7-(2- Antiplatelet Agents hydroxy-3-t-butylaminpropoxy)phthalide. The above identified compounds can be used as isomeric mixtures, or in 0074 Non-limiting examples of antiplatelet agents that their respective levorotating or dextrorotating form. may be used in the compositions of the present invention include clopidogrel, dipyridamole, abciximab, and ticlopi Adrenergic Agonists dine. 0070. Non-limiting examples of adrenergic agonists, both Anticoagulants C- and B-adrenergic agonists, that may be used in the com positions of the present invention include adrafinil, adrena 0075 Anti-coagulant agents are agents which inhibit the lone, albuterol, amidephrine, apraclonidine, bitolterol, coagulation pathway by impacting negatively upon the pro budralazine, carbuterol, clenbuterol, clonidine, clorprenaline, duction, deposition, cleavage and/or activation of factors US 2011/0065783 A1 Mar. 17, 2011

essential in the formation of a blood clot. Non-limiting Such as picotamide and Sulotroban, ticlopidine, tirofiban, tra examples of anticoagulants (i.e. coagulation-related therapy) pidil and ticlopidine, trifenagrel, trilinolein, 3-substituted that may be used in the compositions of the present invention 5,6-bis(4-methoxyphenyl)-1,2,4-triazines, and antibodies to include Aggrenox, Agrylin, Amicar, Anturane, Arixtra, Cou glycoprotein IIb/IIIa as well as those disclosed in U.S. Pat. madin, Fragmin, Heparin Sodium, Lovenox, Mephyton, No. 5,440,020, and anti-serotonin drugs, Clopidogrel; Sulfin Miradon, Persantine, Plavix, Pletal, Ticlid, Trental, Warfarin. pyrazone: Aspirin; Dipyridamole; Clofibrate: Pyridinol Car Other “anti-coagulant and/or “fibrinolytic' agents include bamate; PGE: Glucagon; Antiserotonin drugs; Caffeine; Plasminogen (to plasmin via interactions of prekallikrein, Theophylline Pentoxifylline: Ticlopidine. kininogens, Factors XII, XIIIa, plasminogen proactivator, and tissue plasminogen activatorTPA) Streptokinase; Antihypertensives Urokinase: Anisoylated Plasminogen-Streptokinase Activa 0079 Non-limiting examples of antihypertensives that tor Complex: Pro-Urokinase; (Pro-UK); rTPA (alteplase or may be used in the compositions of the present invention activase: r denotes recombinant); rPro-UK; Abbokinase; include amlodipine, benidipine, benazepril, candesartan, Eminase; Streptase Anagrelide Hydrochloride; Bivalirudin; captopril, darodipine, diltiazem HCl, diazoxide, doxazosin Dalteparin Sodium; Danaparoid Sodium; Dazoxiben Hydro HCl, enalapril, eprosartan, losartan mesylate, felodipine, chloride: Efegatran Sulfate; Enoxaparin Sodium: Ifetroban: fenoldopam, fosinopril, guanabenz, acetate, irbesartan, israd Ifetroban Sodium; Tinzaparin Sodium; reteplase; ipine, lisinopril, mecamylamine, minoxidil, nicardipine HCl, Trifenagrel; Warfarin: Dextrans. nifedipine, nimodipine, nisoldipine, phenoxybenzamine 0076 Still other anti-coagulantagents include, but are not HCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telm limited to, Ancrod; Anticoagulant Citrate Dextrose Solution; isartan, and Valsartan. Anticoagulant Citrate Phosphate Dextrose Adenine Solution; Anticoagulant Citrate Phosphate Dextrose Solution; Antico Antilipemic Agents agulant Heparin Solution; Anticoagulant Sodium Citrate Solution: Ardeparin Sodium; Bivalirudin; Bromindione: 0080. Non-limiting examples of antilipemic agents that Dalteparin Sodium; Desirudin; Dicumarol; Heparin Cal may be used in the compositions of the present invention cium; Heparin Sodium; Lyapolate Sodium; Nafamostat include acipimox, aluminum nicotinate, atorvastatin, Mesylate; Phenprocoumon; Tinzaparin Sodium. cholestyramine resin, colestipol, polidexide, beclobrate, flu vastatin, gemfibrozil, lovastatin, lysosomal acid lipase, icofi 0077. Inhibitors of platelet function are agents that impair brate, niacin; PPARC agonist such as fibrates, which include, the ability of mature platelets to perform their normal physi but are not limited to fenofibrate, clofibrate, pirifibrate, ological roles (i.e., their normal function). Platelets are nor ciprofibrate, bezafibrate, clinofibrate, ronifibrate, theofibrate, mally involved in a number of physiological processes Such clofibric acid, etofibrate, and gemfibrozil; pravastatin as adhesion, for example, to cellular and non-cellular entities, Sodium, Simfibrate, simvastatin, niceritrol, nicoclonate, nico aggregation, for example, for the purpose of forming a blood mol. Oxiniacic acid, etiroXate, thyropropic acid, thyroxine, clot, and release of factors such as growth factors (e.g., plate acifran, azacosterol, benfluorex, beta-benzalbutyramide, car let-derived growth factor (PDGF)) and platelet granular com nitine, chondroitin Sulfate clomestrone, detaXtran, dextran ponents. One Subcategory of platelet function inhibitors are Sulfate Sodium, 5, 8, 11, 14, 17-eicosapentaenoic acid, erita inhibitors of platelet aggregation which are compounds denine, furazabol, meglutol, melinamide, mytatrienediol. which reduce or halt the ability of platelets to associate physi ornithine, gamma-ory Zanol, pantethine, pentaerythritol tet cally with themselves or with other cellular and non-cellular raacetate, alpha-phenylbutyramide, pirozadil, probucol, beta components, thereby precluding the ability of a platelet to sitosterol, Sultosilic acid (piperazine salt), tiadenol, tripara form a thrombus. nol, xenbucin, and mixtures thereof. 0078 Examples of useful inhibitors of platelet function includebut are not limited to acadesine, anagrelide (if given at Antidiabetics doses exceeding 10 mg/day), anipamil, argatroban, aspirin, clopidogrel, cyclooxygenase inhibitors such as nonsteroidal I0081. Non-limiting examples of antidiabetics that may be anti-inflammatory drugs and the synthetic compound used in the compositions of the present invention include FR-122047, danaparoid sodium, dazoxiben hydrochloride, biguanides Such as buformin, metformin, and phenformin; diadenosine 5'5"-P1-P4-tetraphosphate (Ap4A) analogs, hormones such as insulin; Sulfonylurea derivatives such as difibrotide, dilazep dihydrochloride, 1.2- and 1,3-glyceryl acetohexamide, 1-butyl-3-metanily lurea, carbutamide, chlo dinitrate, dipyridamole, dopamine and 3-methoxytyramine, rpropamide, glibomuride, gliclazide, glimepiride, glipizide, efegatran Sulfate, enoxaparin sodium, glucagon, glycoprotein gliquidone, glisoxepid, glyburide, glybuthiazole, glybuzole, IIb/IIIa antagonists such as Ro-43-8857 and L-700.462, glyhexamide, glymidine, glypinamide, phenbutamide, ifetroban, ifetroban sodium, iloprost, Integrilin (eptifibatide), tolaZamide, tolbutamide, tolcyclamide; HDL agonists; isocarbacyclin methyl ester, isosorbide-5-mononitrate, itazi PPARY agonists Such as thiazolidinediones Such as pioglita grel, ketanserin and BM-13.177, lamifiban, lifarizine, molsi Zone, rosiglitaZone, and troglitaZone; and others including domine, nifedipine, oxagrelate, PGE, platelet activating fac acarbose, calcium mesoxalate, miglitol, and repaglinide. tor antagonists such as lexipafant, prostacyclin (PGI), pyrazines, pyridinol carbamate, ReoPro (i.e., abciximab), Antiinflammatory Agents sulfinpyrazone, synthetic compounds BN-50727, BN-52021, I0082) Non-limiting examples of antiinflammatory agents CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, that may be used in the compositions of the present invention KC-404, KF-4939, OP-41483, TRK-100, TA-3090, TFC-612 include Alclofenac; Alclometasone Dipropionate; Algestone and ZK-36374,2,4,5,7-tetrathiaoctane, 2,4,5,7-tetrathiaoc Acetonide; Alpha Amylase; Amcinafal; Amcinafide; tane 2,2-dioxide, 2,4,5-trithiahexane, theophylline, pentoxi Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; fylline, thromboxane and thromboxane synthetase inhibitors Anirolac, AnitraZafen; Apazone; Balsalazide Disodium; US 2011/0065783 A1 Mar. 17, 2011

Bendazac. Benoxaprofen; Benzydamine Hydrochloride: cilnidipine, efonidipine, elgodipine, felodipine, isradipine, Bromelains; Broperamole; Budesonide; Carprofen; Ciclo lacidipine, lercanidipine, manidipine, nicardipine, nife profen; Cintazone; Cliprofen; Clobetasol Propionate; Clobe dipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, tasone Butyrate; Clopirac; Cloticasone Propionate; cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, Cormethasone Acetate; Cortodoxone; Deflazacort; Des etafenone, fantofarone, perhexyline, and mixtures thereof. onide; DeSoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone CETP Inhibitors Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate: Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone: I0084. A non-limiting example of a CETP inhibitor that Enlimomab: Enolicam Sodium; Epirizole; Etodolac.; Etofe may be used in the compositions of the present invention namate; Felbinac; Fenamole: Fenbufen, Fenclofenac; Fen includes torcetrapib and JT7-705. clorac; Fendosal: Fenpipalone: Fentiazac.; Flazalone: Fluaza cort; Flufenamic Acid, Flumizole; Flunisolide Acetate; COX-2 Inhibitors Flunixin: Flunixin Meglumine: Fluocortin Butyl; Fluo rometholone Acetate; FluguaZone: Flurbiprofen; Fluretofen; I0085. Non-limiting examples of COX-2 inhibitors that Fluticasone Propionate; Furaprofen; Furobufen; Halcinon may be used in the compositions of the present invention ide; Halobetasol Propionate; Halopredone Acetate; Ibufenac: include compounds according to the following: all of the Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol: compounds and Substances beginning on page 8 of Winokur Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; WO99/20110 as members of three distinct structural classes Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxi of selective COX-2 inhibitor compounds, and the compounds cam; Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; and substances which are selective COX-2 inhibitors in Nich Loteprednol Etabonate; Meclofenamate Sodium; Meclofe therger, U.S. Pat. No. 6,136,804, Oct. 24, 2000, entitled namic Acid; Meclorisone Dibutyrate; Mefenamic Acid; "Combination therapy for treating, preventing, or reducing Mesalamine: MeseclaZone; Methylprednisolone Suleptan the risks associated with acute coronary ischemic syndrome ate; Morniflumate; Nabumetone; Naproxen; Naproxen and related conditions', and the compounds and Substances Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgot which are selective COX-2 inhibitors in Isakson et al., PCT ein; Orpanoxin: Oxaprozin: Oxyphenbutazone; Paranyline application WO/09641645 published Dec. 27, 1996, filed as Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone PCT/US 9509905 on Jun. 12, 1995, entitled “Combination of Sodium Glycerate; Pirfenidone: Piroxicam; Piroxicam Cin a Cyclooxygenase-2 Inhibitor and a Leukotriene B4 Receptor namate; Piroxicam Olamine; Pirprofen; Prednazate: Prife Antagonist for the Treatment of Inflammations.” The mean lone: Prodolic Acid; ProquaZone: Proxazole; Proxazole Cit ing of COX-2 inhibitor in this invention shall include the rate; Rimexolone; Romazarit; Salcolex; Salnacedin; compounds and Substances referenced and incorporated into Salsalate: Salicylates; Sanguinarium Chloride: SeclaZone: Winokur WO99/20110 by reference to art therein, the com Sermetacin; Sudoxicam, Sulindac: Suprofen; Talmetacin; pounds and Substances referenced and incorporated into Talniflumate; Talosalate; Tebufelone; Tenidap: Tenidap Nichtberger, U.S. Pat. No. 6,136,804, Oct. 24, 2000, by ref Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine: erence to art therein, and the compounds and Substances Tiopinac; Tixocortol Pivalate: Tolimetin: Tolimetin Sodium; which are COX-2 inhibitors referenced and incorporated into Triclonide; Triflumidate; Zidometacin; Glucocorticoids; Isakson etal, PCT application WO/09641645 published Dec. Zomepirac Sodium. One preferred antiinflammatory agent is 27, 1996, filed as PCT/US 9509905 on Jun. 12, 1995, entitled aspirin. “Combination of a Cyclooxygenase-2 Inhibitor and a Leu kotriene B4 Receptor Antagonist for the Treatment of Inflam Calcium Channel Blockers mations.” The meaning of COX-2 inhibitor in this invention also includes rofecoxib, and celecoxib, marketed as VIOXX 0083 Calcium channel blockers are a chemically diverse and CELEBREX by Merck and Searle/Pfizer respectively. class of compounds having important therapeutic value in the Rofecoxib is discussed in Winokur, WO99/20110 as com control of a variety of diseases including several cardiovas pound 3, on p. 9. Celecoxib is discussed as SC-58635 in the cular disorders, such as hypertension, angina, and cardiac same reference, and in T. Penning, Synthesis and biological arrhythmias (Fleckenstein, Cir. Res. V. 52, (suppl. 1), p. 13-16 evaluation of the 1.5-diarylpyrazole class of cyclooxyge (1983); Fleckenstein, Experimental Facts and Therapeutic nase-2 inhibitors: identification of 4-5-(4-methylphenyl)-3- Prospects, John Wiley, New York (1983); McCall, D., Curr (trifluoromethyl)-1H-pyrozol-1-ylbenzenesulfonami de Pract Cardiol. v. 10, p. 1-11 (1985)). Calcium channel block (SC-58635, celecoxib), J. Med. Chem. Apr. 25, 1997: 40(9): ers are a heterogeneous group of drugs that prevent or slow 1347-56. The meaning of COX-2 inhibitor in this invention the entry of calcium into cells by regulating cellular calcium also includes SC299 referred to as a fluorescent diarylox channels. (Remington, The Science and Practice of Phar azole. C. Lanzo et al., “Fluorescence quenching analysis of the macy, Nineteenth Edition, Mack Publishing Company, association and dissociation of a diarylheterocycle to Eaton, Pa., p. 963 (1995)). Most of the currently available cyclooxygenasel-1 and cyclooxygenase-2: dynamic basis of calcium channel blockers, and useful according to the present cycloxygenase-2 selectivity”. Biochemistry May 23, 2000, invention, belong to one of three major chemical groups of vol.39(20):6228-34, and in J. Talley et al. “4,5-Diaryloxazole drugs, the dihydropyridines, such as nifedipine, the phenyl inhibitors of cyclooxygenase-2 (COX-2), Med. Res. Rev. alkyl amines. Such as Verapamil, and the benzothiazepines, May 1999; 19(3): 199-208. The meaning of COX-2 inhibitor Such as diltiazem. Non-limiting examples of calcium channel in this invention also includes Valdecoxib. See, “4-5-Methyl blockers that may be used in the compositions of the present 3-phenylisoxazol-1-ylbenzenesulfonamide, Valdecoxib: A invention include bepridil, clentiazem, diltiazem, fendiline, Potent and Selective Inhibitor of COX-2, J. Med. Chem. gallopamil, mibefradil, prenylamine, Semotiadil, terodiline, 2000, Vol. 43: 775-777, and parecoxib, sodium salt or pare Verapamil, amlodipine, aranidipine, barnidipine, benidipine, coxib sodium, See, N-(5-methyl-3-phenylixoxazol-4-yl)- US 2011/0065783 A1 Mar. 17, 2011

phenylsulfonylpropanimide, Sodium Salt, Parecoxib Bioorg. Med. Chem. Lett. 11 (8): 1059-62 (Apr. 23, 2001). Sodium: A Potent and Selective Inhibitor of COX-2 for Another selective COX-2 inhibitor is DFU 5,5-dimethyl-3- Parenteral Administration, J. Med. Chem. 2000, Vol. 43: (3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-fura 1661-1663. The meaning of COX-2 inhibitor in this invention none referenced in Yergey et al. Drug Metab. Dispos. 29(5): also includes the Substitution of the Sulfonamide moiety as a 638-44 (May 2001). The inventors also include as a selective suitable replacement for the methylsulfonyl moiety. See, J. COX-2 inhibitor the flavonoid antioxidant silymarin, and an Carteretal, Synthesis and activity of sulfonamide-substituted active ingredient in silymarin, Silybinin, which demonstrated 4.5-diaryl thiazoles as selective cyclooxygenase-2 inhibi significant COX-2 inhibition relative to COX-1 inhibition. tors.” Bioorg. Med. Chem. Lett Apr. 19, 1999: Vol. 9(8): The silymarin also showed protection against depletion of 1171-74, and compounds referenced in the article “Design glutathione peroxidase. Zhao et al. “Significant Inhibition by and synthesis of sulfonyl-substituted 4,5-diarylthiazoles as the Flavonoid Antioxidant Silymarin against 12-O-tetrace selective cyclooxygenase-2 inhibitors’, Bioorg. Med. Chem. canoylphorbol 13-acetate-caused modulation of antioxidant Lett Apr. 19, 1999: Vol. 9(8): 1167-70. The meaning of this and inflammatory enzymes, and cyclooxygenase 2 and inter invention includes a COX-2 inhibitor, NS398 referenced in leukin-1 alpha expression in SENCAR mouse epidermis: two articles: Attiga et al., “Inhibitors of Prostaglandin Synthe implications in the prevention of stage I tumor promotion.” sis Inhibit Human Prostate Tumor Cell Invasiveness and Mol. Carcinog. December 1999, Vol 26(4):321-33 PMID Reduce the Release of Matrix Metalloproteinases’, 60 Can 10569809. Silymarin has been used to treat liver diseases in cer Research 4629-4637, Aug. 15, 2000, and in “The Europe. cyclooxygenase-2 inhibitor celecoxib induces apoptosis by 0086 A number of the above-identified COX-2 inhibitors blocking Akt activation in human prostate cancer cells inde are prodrugs of selective COX-2 inhibitors, and exert their pendently of Bcl-2. Hsu et al., 275(15) J. Biol. Chem. 11397 action by conversion in vivo to the active and selective COX-2 11403 (2000). The meaning of COX-2 inhibitor in this inven inhibitors. The active and selective COX-2 inhibitors formed tion includes the cyclo-oxygenase-2 selective compounds from the above-identified COX-2 inhibitor prodrugs are referenced in Mitchell et al., “Cyclo-oxygenase-2: pharma described in detail in WO95/00501, published Jan. 5, 1995, cology, physiology, biochemistry and relevance to NSAID WO95/18799, published Jul 13, 1995 and U.S. Pat. No. therapy”, Brit. J. of Pharmacology (1999) vol. 128: 1121 5,474,995, issued Dec. 12, 1995. Given the teachings of U.S. 1132, see especially p. 1126. The meaning of COX-2 inhibi Pat. No. 5,543,297, entitled: “Human cyclooxygenase-2 tor in this invention includes so-called NO-NSAIDs or nitric cDNA and assays for evaluating cyclooxygenase-2 activity.” oxide-releasing-NSAIDs referred to in L. Jackson et al. a person of ordinary skill in the art would be able to determine “COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs: whether an agent is a selective COX-2 inhibitor or a precursor Do They Really Offer Any Advantages?, Drugs, June, 2000 of a COX-2 inhibitor, and therefore part of the present inven vol. 59(6): 1207-1216 and the articles at footnotes 27, and 28. tion. Also included in the meaning of COX-2 inhibitor in this invention includes any substance that selectively inhibits the COX-2 isoenzyme over the COX-1 isoenzyme in a ratio of “Direct Thrombin Inhibitors’ greater than 10 to 1 and preferably in ratio of at least 40 to 1 I0087. Nonlimiting examples of direct thrombin inhibitors as referenced in Winokur WO99/20110, and has one sub include hirudin, hirugen, Hirulog, argatroban, PPACK, and stituent having both atoms with free electrons under tradi thrombinaptamers. tional Valence-shell-electron-pair-repulsion theory located on a cyclic ring (as in the Sulfylamine portion of celecoxib), Diuretics and a second Substituent located on a different ring suffi ciently far from said first Substituent to have no significant I0088. Non-limiting examples of diuretics that may be used electron interaction with the first substituent. The second in the compositions of the present invention include althiaz substituent should have an electronegativity within such sub ide, bendroflumethiazide, benzthiazide, buthiazide, chlortha stituent greater than 0.5, or the second substituent should be lidone, cyclopenthiazide, cyclothiazide, epithiazide, ethiaz an atom located on the periphery of the compound selected ide, fenduizone, indapamide, hydroflumethiazide, from the group of a halogen F, Cl, Br or I, or a group VI methyclothiazide, meticrane, metolaZone, paraflutizide, element, S or O. Thus for purposes of this last included polythiazide, quinethaZone, teclothiazide, trichloromethiaz meaning of a COX-2 inhibitor, one portion of the COX-2 ide, chlormerodrin, meralluride, mercamphamide, mercap inhibitor should be hydrophilic and the other portion lipo tomerin Sodium, mercumatilin Sodium, mercurous chloride, philic. Also included as a COX-2 inhibitor are compounds mersalyl, acefylline, 7-morpholinomethyl-theophylline, listed at page 553 in Pharmacotherapy: A Pathophysiologic pamabrom, protheobromine, theobromine, canrenone, olean Approach, Depiro et al (McGraw Hill 1999) including nabu drin, spironolactone, acetazolamide, ambuside, azosemide, metone and etodolac. Recognizing that there is overlap bumetanide, butazolamide, clopamide, clorexolone, disulfa among the selective COX-2 inhibitors set out in this para mide, ethoXZolamide, furosemide, mefruside, methaZola graph, the intent of the term COX-2 inhibitor is to compre mide, piretanide, torsemide, tripamide, Xipamide, aminome hensively include all selective COX-2 inhibitors, selective in tradine, amisometradine, amanozine, amiloride, arbutin, the sense of inhibiting COX-2 over COX-1. The inventors add chlorazanil, ethacrynic acid, etoZolin, hydracarbazine, isos to the class of COX-2 inhibitors useful in the invention the orbide, mannitol, metochalcone, muZolimine, perhexyline, drug bearing the name etoricoxib referenced in the Wall ticrynafen, triamterene, urea, and mixtures thereof. Depend Street Journal, Dec. 13, 2000, manufactured by Merck. See, ing on the diuretic employed, potassium may also be admin also, Chauret et al., “In vitro metabolism considerations, istered to the patient in order to optimize the fluid balance including activity testing of metabolites, in the discovery and while avoiding hypokalemic alkalosis. The administration of selection of the COX-2 inhibitor etoricoxib (MK-0663).” potassium can be in the form of potassium chloride or by the US 2011/0065783 A1 Mar. 17, 2011

daily ingestion of foods with high potassium content Such as, thereof, and antibodies to renin. Examples of renin inhibitors for example, bananas or orange juice. that are the subject of United States patents are as follows: urea derivatives of peptides (U.S. Pat. No. 5,116,835); amino Endothelin Receptor Antagonists acids connected by nonpeptide bonds (U.S. Pat. No. 5,114, 0089. Non-limiting examples of an endothelin receptor 937); di- and tri-peptide derivatives (U.S. Pat. No. 5,106, antagonist that may be used in the compositions of the present 835); amino acids and derivatives thereof (U.S. Pat. Nos. 5,104,869 and 5,095,119); diol sulfonamides and sulfinyls invention include bosentan, Sulfonamide endothelin antago (U.S. Pat. No. 5,098,924); modified peptides (U.S. Pat. No. nists, BQ-123, SQ28.608, and the like); and mixtures thereof. 5,095,006); peptidyl beta-aminoacyl aminodiol carbamates HMG-CoA Reductase Inhibitor (Statins) (U.S. Pat. No. 5,089.471); pyrolimidazolones (U.S. Pat. No. 5,075,451); fluorine and chlorine statine or statone containing 0090 HMG-CoA (3-hydroxy-3-methylglutaryl-coen peptides (U.S. Pat. No. 5,066,643); peptidyl amino diols Zyme A) reductase is the microsomal enzyme that catalyzes (U.S. Pat. Nos. 5,063,208 and 4,845,079); N-morpholino the rate limiting reaction in cholesterol biosynthesis (HMG derivatives (U.S. Pat. No. 5,055.466); pepstatin derivatives CoA6Mevalonate). An HMG-CoA reductase inhibitor inhib (U.S. Pat. No. 4,980,283); N-heterocyclic alcohols (U.S. Pat. its HMG-CoA reductase, and as a result inhibits the synthesis No. 4,885.292); monoclonal antibodies to renin (U.S. Pat. of cholesterol. A number of HMG-CoA reductase inhibitors No. 4,780.401); and a variety of other peptides and analogs have been used to treat individuals with hypercholester thereof (U.S. Pat. Nos. 5,071,837, 5,064,965, 5,063,207, olemia. More recently, HMG-CoA reductase inhibitors have 5,036,054, 5,036,053, 5,034,512, and 4,894.437). been shown to be beneficial in the treatment of stroke (Endres M, et al., Proc Natl AcadSci USA, 1998, 95:8880-5). Vasodilators 0091 HMG-CoA reductase inhibitors useful for co-ad ministration with the agents of the invention include, but are 0.095 Non-limiting examples of vasodilators that may be not limited to, simvastatin (U.S. Pat. No. 4,444,784), lovas used in the compositions of the present invention include tatin (U.S. Pat. No. 4,231.938), pravastatin sodium (U.S. Pat. bencyclane, cinnarizine, citicoline, cyclandelate, ciclonicate, No. 4,346.227), fluvastatin (U.S. Pat. No. 4,739,073), atorv diisopropylamine dichloroacetate, eburnamonine, fasudil, astatin (U.S. Pat. No. 5.273.995), cerivastatin, and numerous fenoxedil, flunarizine, ibudilast, ifenprodil, isosorbide dini others described in U.S. Pat. Nos. 5,622,985; 5,135,935; trate, isosorbide mononitrate, lomerixine, nafronyl, nica 5,356,896; 4,920,109; 5,286,895; 5,262,435: 5,260,332; metate, nicergoline, nimodipine, papaverine, pentifylline, 5,317,031: 5,283.256; 5,256,689; 5,182,298; 5,369,125; tinofedrine, Vancamine, vinpocetine, Viduidil, amotriphene, 5,302,604; 5,166,171: 5,202,327: 5,276,021; 5,196,440; bendazol, benfurodil hemisuccinate, benziodarone, chlo 5,091,386; 5,091,378; 4,904,646; 5,385,932; 5,250,435: racizine, chromonar, clobenfurol, clonitrate, cloricromen, 5,132,312; 5,130,306; 5,116,870; 5,112,857; 5,102,911; dilaZep, dipyridamole, droprenilamine, efloxate, erythrityl 5,098,931; 5,081,136; 5,025,000; 5,021,453: 5,017,716; tetranitrate, etafenone, fendiline, floredil, ganglefence, heart 5,001,144; 5,001,128: 4,997,837; 4,996,234: 4,994,494; muscle extract, hexestrol bis(alpha-diethylaminoethyl ether), 4,992,429: 4,970,231: 4,968,693: 4,963,538; 4,957,940; hexobendine, hydralazine compound, itramin tosylate 4,950,675; 4,946,864; 4,946,860: 4,940,800; 4,940,727: khellin, lidoflazine, mannitol hexanitrate, medibazine, nitro 4,939,143: 4,929,620: 4,923,861; 4,906,657; 4,906,624 and glycerin, isosorbide mononitrate, isosorbide dinitrate, and 4,897,402, the disclosures of which patents are incorporated other nitrates, pentaerythritol tetranitrate, pentrinitrol, per herein by reference. hexyline, pimethylline, prenylamine, propatyl nitrate, pyrid 0092. Other non-limiting examples of HMG-CoA reduc ofylline, trapidil, tricromyl, trimetazidine, trolnitrate phos tase inhibitors that may be used in the compositions of the phate, Visnadine, aluminum nicotinate, bamethan, present invention include mevastatin, pitavastatin, rosuvasta bencyclane, betahistine, bradykinin, brovincamine, bufe tin, gemcabene, and probucol. niode, buflomedil, butalamine, cetiedil, ciclonicate, cinepazide, cinnarizine, cyclandelate, diisopropylamine Inotropic Agents dichloroacetate, eledoisin, fenoxedil, flunazine, hepronicate, ifenprodil, iloprost, inositol niacinate, isoXSuprine, kallidin, 0093. Non-limiting examples of inotropic agents that may kallikrein, moxisylyte, nafronyl, nicametate nicergoline, be used in the compositions of the present invention include nicofuranose, nicotinyl alcohol, nylidrin, pentifylline, pen acefylline, acetyldigitoxins, 2-amino-4-picoline, amrinone, toxifylline, piribedil, prostaglandin E1, Suloctidil, tolazoline, benfurodil hemisuccinate, bucladesine, camphotamide, con Vallatoxin, cymarin, denopamine, deslanoside, digitalin, Xanthinol niacinate, and mixtures thereof. digitalis, digitoxin, digoxin, dobutamine, docarpamine, 0096. Note that “hydralazine compound” refers to a com dopamine, dopexamine, enoXimone, erythrophleine, fenal pound having the formula: Somine, gitalin, gitoxin, glycocyamine, heptaminol, hydras tinine, ibopamine, lanatosides, loprinine, milrinone, nerifo R lin, oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, 8. b . proscillaridin, resibufogenin, Scillaren, Scillarenin, strophan RN FN FR2 thin, Sulmazole, theobromine, Vesnarinone, Xamoterol, and mixtures thereof. 0097 whereina, b and care each independently a single or a double bond; R and R are each independently a hydrogen, “Renin Inhibitors’ an alkyl, an ester or a heterocyclic ring; R and Ra are each 0094 Renin inhibitors are compounds which interfere independently alone pair of electrons or a hydrogen, with the with the activity of renin. Renin inhibitors include amino proviso that at least one of R. R. RandR is not a hydrogen. acids and derivatives thereof, peptides and derivatives Examples of hydralazine compounds include, but are not US 2011/0065783 A1 Mar. 17, 2011

limited to budralazine, cadralazine, dihydralazine, endrala 0.108 anti-epileptics, such as beclamide, carbamazepine, Zine, hydralazine, pildralazine, todralazine and the like. clonazepam, ethotoin, felbamate, fosphenyloin Sodium, lam otrigine, methoin, methSuximide, methylphenobarbitone, Vasopressors oXcarbazepine, paramethadione, phenacemide, phenobarbi 0098. Non-limiting examples of vasopressors that may be tone, phenyloin, phensuximide, primidone, Sulthiame, tiaga used in the compositions of the present invention include bine HCl, topiramate, Valproic acid, and vigabatrin; amezinium methyl sulfate, angiotensin amide, dimetofrine, 0109 anti-fungal agents, such as amphotericin, butenafine dopamine, etifelmin, etillefrin, gepefrine, metaraminol, meth HCl, butoconazole nitrate, clotrimazole, econazole nitrate, oxamine, midodrine, norepinephrine, pholedrine, Syneph fluconazole, flucytosine, griseofulvin, itraconazole, keto rine, and mixtures thereof. conazole, miconazole, natamycin, nystatin, Sulconazole nitrate, oxiconazole, erbinafine HCl, terconazole, tiocona AGE Crosslink Breakers (Advanced Glycosylation End Zole and undecenoic acid; Product Crosslink Breakers) 0110 anti-gout agents. Such as allopurinol, probenecid and Sulphinpyrazone; 0099 Non-limiting examples of AGE crosslink breakers 0111 anti-malarials, such as amodiaquine, chloroquine, that may be used in the compositions of the present invention chlorproguanil HCl, halofantrine HCl, mefloquine HCl, include Alagebrium. proguanil HCl, pyrimethamine and quinine Sulfate; 0112 anti-migraine agents, such as dihydroergotamine AGE Formation Inhibitors (Advanced Glycosylation End mesylate, ergotamine tartrate, froVatriptan, methysergide Product Formation Inhibitors) maleate, naratriptan HCl, pizotifen maleate, rizatriptan ben 0100. Non-limiting examples of AGE formation inhibitors Zoate, Sumatriptan Succinate, and Zolmitriptan; that may be used in the compositions of the present invention 0113 anti-muscarinic agents, such as atropine, benzhexol include Pimagedine. HCl, biperiden, ethopropazine HCl, hyoscyamine, mepen Zolate bromide, oxyphencyclimine HCl and tropicamide; Other Actives: 0114 anti-neoplastic agents and immunosuppressants, 0101. Non-limiting examples of other active ingredients Such as aminoglutethimide, amsacrine, azathioprine, that may be combined with these nebivolol compositions bicalutamide, bisantrene, buSulfan, camptothecin, capecitab include, but are not limited to, the following representative ine, chlorambucil, cyclosporin, dacarbazine, ellipticine, classes of compounds, as well as their pharmaceutically estramustine, etoposide, irinotecan, lomustine, melphalan, acceptable salts, isomers, esters, ethers and other derivatives: mercaptopurine, methotrexate, mitomycin, mitotane, mitox 0102 Analgesics and anti-inflammatory agents, such as antrone, mofetil mycophenolate, nilutamide, paclitaxel, pro aloxiprin, auranofin, azapropaZone, benorylate, capsaicin, carbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teni celecoxib, diclofenac, diflunisal, etodolac, fenbufen, feno poside, testolactone, topotecan HCl, and toremifene citrate; profen calcium, flurbiprofen, ibuprofen, indomethacin, keto 0115 anti protozoal agents, such as atovaquone, ben profen, ketorolac, leflunomide, meclofenamic acid, mefe Znidazole, clioquinol, decoquinate, diiodohydroxyquinoline, namic acid, nabumetone, naproxen, oxaprozin, diloxanide furoate, dinitolmide, furazolidone, metronida oxyphenbutaZone, phenylbutaZone, piroxicam, rofecoxib, Zole, nimorazole, nitrofuraZone, omidazole and timidazole; Sulindac, tetrahydrocannabinol, tramadol and tromethamine; 0116 anti-psychotics, such as aripiprazole, clozapine, 0103 antihelminthics, such as albendazole, bephenium Ziprasidone, haloperidol, molindone, loxapine, thioridazine, hydroxynaphthoate, cambendazole, dichlorophen, ivermec molindone, thiothixene, pimozide, fluphenazine, risperidone tin, mebendazole, oxaminiquine, Oxfendazole, oxantel mesoridazine, quetiapine, trifluoperazine, chlorprothixene, embonate, praziquantel, pyrantel embonate and thiabenda chlorpromazine, perphenazine, trifluopromazine, olanzap Zole; ine; 0104 anti-asthma agents, such as Zileuton, Zafirlukast, 0117 anti-thyroid agents, such as carbimazole, paricalci terbutaline sulfate, montelukast, and albuterol; tol, and propylthiouracil; 0105 anti-bacterial agents, such as alatrofloxacin, 0118 anti-tussives, such as benzonatate; azithromycin, baclofen, benzathine penicillin, cinoxacin, 0119 anxiolytics, sedatives, hypnotics and neuroleptics, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, Such as alprazolam, amylobarbitone, barbitone, bentazepam, demeclocycline, dirithromycin, doxycycline, erythromycin, bromazepam, bromperidol, brotizolam, butobarbitone, car ethionamide, furazolidone, grepafloxacin, imipenem, levof bromal, chlordiazepoxide, chlormethiazole, chlorpromazine, loxacin, lorefloxacin, moxifloxacin HCl, nalidixic acid, nitro chlorprothixene, clonazepam, clobazam, clotiazepam, cloza furantoin, norfloxacin, ofloxacin, rifampicin, rifabutin, rifap pine, diazepam, droperidol, ethinamate, fluianisone, fluni entine, sparfloxacin, spiramycin, Sulphabenzamide, trazepam, triflupromazine, flupenthixol decanoate, Sulphadoxine, Sulphamerazine, ulphacetamide, Sulphadiaz fluphenthixol decanoate, flurazepam, gabapentin, haloperi ine, Sulphafurazole, Sulphamethoxazole, Sulphapyridine, tet dol, lorazepam, lormetazepam, medazepam, meprobamate, racycline, trimethoprim, trovafloxacin, and Vancomycin; mesoridazine, methaqualone, methylphenidate, midazolam, 0106 anti-viral agents, such as abacavir, amprenavir, molindone, nitrazepam, olanzapine, oxazepam, pentobarbi delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevi tone, perphenazine pimozide, prochlorperazine, pseudoephe rapine, ritonavir, saquinavir, and stavudine; drine, quetiapine, risperidone, sertindole, Sulpiride, 0107 anti-depressants, such as amoxapine, bupropion, temazepam, thioridazine, triazolam, Zolpidem, and Zopi citalopram, clomipramine, fluoxetine HCl, maprotiline HCl, clone; mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline 0120 corticosteroids, such as beclomethasone, HCl, trazodone HCl, trimipramine maleate, and Venlafaxine betamethasone, budesonide, cortisone acetate, desoxymetha HC1; Sone, dexamethasone, fludrocortisone acetate, flunisolide, US 2011/0065783 A1 Mar. 17, 2011 fluocortolone, fluticasone propionate, hydrocortisone, meth ment may be, but are not limited to, (-)-epictechin, (+)- ylprednisolone, prednisolone, prednisone and triamcinolone; catechin, procyanidin B2, quercetin dehydrate, taxifolin, res 0121 anti-parkinsonian agents, such as apomorphine, Veratrol, and the like. bromocriptine mesylate, lisuride maleate, pramipexole, rop 0.136 Carotenoids, which are generally are tetraterpenes inirole HCl, and tolcapone: originating from the mevalonate and deoxyxylulose phos 0122 gastrointestinal agents, such as bisacodyl, cimeti phate pathways (older Sources sometimes refer to their source dine, cisapride, diphenoxylate HCl, domperidone, famoti as the isoprenoid pathway). Two molecules of the Co com dine, lanSoprazole, loperamide, mesalazine, nizatidine, ome pound geranylgeranyldiphosphate (GGDP) condense to form prazole, ondansetron HCL, rabeprazole Sodium, ranitidine the symmetrical carotenoid skeleton. HCl and sulphasalazine; 0.137 Carotenoids are divided into two subclasses, i.e., 0123 keratolytics, such as acitretin, calcipotriene, calcife more polar compounds called Xanthophylls, or oxycaro diol, calcitriol, cholecalciferol, ergocalciferol, etretinate, ret tenoids, and the nonpolar hydrocarbon carotenes. inoids, Targretin, and tazarotene; 0.138 Terms such as carotenoid analog and carotenoid 0124 lipid regulating agents, such as atorvastatin, beZafi derivative may generally refer to in Some embodiments brate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluv chemical compounds or compositions derived from a natu astatin, gemfibrozil, pravastatin, probucol, and simvastatin: rally occurring carotenoid or simply to synthetic carotenoids. 0125 muscle relaxants, such as dantrolene sodium and In some embodiments, terms such as carotenoid analog and tizanidine HCl; carotenoid derivative may generally refer to chemical com 0126 nutritional agents, such as calcitriol, carotenes, pounds or compositions which are synthetically derived from dihydrotachysterol, essential fatty acids, non-essential fatty non-carotenoid based parent compounds; however, which acids, phytonadiol, Vitamin A, vitamin B. Sub.2, vitamin D, ultimately substantially resemble a carotenoid derived ana vitamin E and vitamin K; log. In certain embodiments, terms such as carotenoid analog 0127 opioid analgesics, such as codeine, dextropro and carotenoid derivative may generally refer to a synthetic poxyphene, diamorphine, dihydrocodeine, fentanyl. derivative of a naturally occurring carotenoid. Examples of meptazinol, methadone, morphine, nalbuphine and pentaZo carotenoids are provided in the book “Carotenoids Hand cine; book.” edited by G. Britton et al., 2004, which is herein incor 0128 sex hormones, such as clomiphene citrate, cortisone porated by reference. acetate, danazol, dehydroepiandrosterone, ethynyl estradiol. 0.139. It will be evident to any skilled person how to choose finasteride, fludrocortisone, fluoxymesterone, medroX the Suitable carotenoid compound for the purpose of the yprogesterone acetate, megestrol acetate, mestranol, methylt present development. estosterone, norethisterone, norgestrel, oestradiol, conju 0140. Examples of carotenoids include astaxanthin, zeax gated estrogens, progesterone, rimexolone, Stanozolol. anthin, lutein, lycopene, beta-carotene. stilbestrol, testosterone and tibolone; 0.141. Other non-limiting examples of naturally occurring 0129 stimulants, such as amphetamine, dexamphetamine, carotenoids include: Aaptopurpurin; Actinioerythrin; Actin dexfenfluramine, fenfluramine and mazindol; ioerythrol; Adonirubin; Adonixanthin; A.g.470; A.g.471; 0130 drugs for rheumatoid arthritis such as methotrexate, Agelaxanthin C; AleuriaXanthin; Alloxanthin; Amarouciax auranofin, aurothioglucose and gold sodium thiomalate; anthin A; Amarouciaxanthin B; Anchovy Xanthin; 3',4'-Anhy 0131 drugs for osteoporosis such as alendronate and ral drodiatoxanthin; Anhydrodeoxyflexixanthin; Anhydroe oxifene; schscholtZXanthin; Anhydrolutein; Anhydroperidinin; 0132 local anesthetics; Anhydrorhodovibrin; Anhydrosaproxanthin; Anhydrowarm 0.133 anti-herpes drugs such as acyclovir, Valacyclovir ingol; Anhydrowarmingone; Antheraxanthin; Aphanicin; and famciclovir, Aphanicol; Aphanin; Aphanol: Aphanizophyll, 8-Apo-beta 0134 anti-emetics Such as ondansetron and granisetron; carotein-8-al; 10'-Apo-beta-caroten-10'-al; 12-Apo-beta 0135 Flavonoids and Isoflavonoids which include the caroten-12'al; 14'-Apo-beta-caroten-14'-al; 6'-Apo-psi-caro anthocyanidins and anthocyanins; proanthocyanidins; fla ten-6'-al; 8-Apo-psi-caroten-8-al; beta-Apo-2-carotenal; van-3-ols; flavonols; flavones; flavanones; isoflavanones; beta-Apo-3-carotenal; beta-Apo-4-carotenal; beta-Apo-2'- salts and esters thereof. This development is however, not carotenal; beta-Apo-8-carotenal; beta-Apo-10'-carotenal; limited to flavonoid compounds isolated from plant, part of beta-Apo-12-carotenal; beta-Apo-1,4-carotenal: Apo-8.8- plant or extracts of Astragalus Membranaceus, but encom carotenedial; 8-Apo-beta-carotene-3,8-diol; 4'-Apo-beta passes any Suitable flavonoid compound isolated from differ caroten-4-oic acid; 8-Apo-beta-caroten-8-oic acid; 10'- ent Sources or chemically synthesized. In addition, any Suit Apo-beta-caroten-10'-oic acid; 12-Apo-beta-caroten-12'-oic able known or not yet discovered flavonoid compound, and acid; beta-Apo-2'-carotenoic acid; beta-Apo-2'-carotenoic isoflavonoid compound, is within the scope of the present acid methylester; beta-Apo-8-carotenoic acid; beta-Apo-10'- technology. A number of flavonoids and isoflavonoids are carotenoic acid; beta-Apo-12-carotenoic acid, 8-Apo-beta described in USDA-Iowa State University Database on the caroten-3-ol; beta-Apo-2-carotenol; Apo-7-fucoxanthinol; Isoflavone Content of Foods, Release 1.3-2002, and in USDA Apo-2-lycopenal; Apo-3-lycopenal: Apo-6' lycopenal; Apo Database for the Flavonoid Content of Selected Foods 2003 8'-lycopenal: Apo-10'-violaxanthal: Apo-12-violaxanthal; (http://www.nal.usda. gov/fnic/foodcomp/Data/isoflav/ Apoviolaxanthinal; Apo-2-zeaxanthinal: Apo-3-zeaxanthi isoflav.html) and (http://www.nal.usda.gov/fnic/foodcomp/ nal; Apo-4-zeaxanthinal; Astacein; Astacene; AStacene Data/Flav/flav.html) (both of them herewith incorporated by dipalmitate; Astaxanthin; Asterinic acid; Asteroidenone; reference). It will be evident to any skilled person how to Asym. Zeta-carotene; Aurochrome; Auroxanthin; AZafirin; choose the suitable flavonoid and/or isoflavonoid compound AZafrinaldehyde; for the purpose of the present development. For example, 0.142 Bacterial phytoene: Bacterioerythrin alpha; Bacte flavonoid compounds for the purpose of the present develop rioerythrin beta; Bacteriopurpurin alpha; Bacterioruberin;

US 2011/0065783 A1 Mar. 17, 2011

0156 Tangeraxanthin; Taraxanthin; Taraxanthin dipalmi 8-dihydro-8-oxo-alpha-carotene: 3.3',6'-Trihydroxy-5.8- tate; Taraxien, Tareoxanthin; Tedaniaxanthin; Tedanin; Tern epoxy-alpha-carotene; 3.4,4'-Trihydroxypirardixanthin; 1,1'. stroemiaxanthin; Tethyatene; 7,8,7,8-Tetradehydroastaxan 2'-Trihydroxy-3,4,3',4'-tetradehydro-1,2,1,2-tetrahydro-psi, thin; 34.3',4'-Tetradehydro-beta.beta-carotene; 3.4.3',4'- psi-caroten-2-one: 3,4,4'-Trihydroxy-5.6.5',6'-tetrahydro Tetradehydro-psi.psi-carotene; 7,8,7,8-Tetradehydro-beta, beta,beta-carotene; Trikentriorhodin; 3,4,4-Triketo-beta beta-carotene-3,3'-diol; 34.3',4'-Tetradehydro-beta.beta carotene; 3,1'2'-Trimethoxy-3',4'-didehydro-1'.2" dihydro carotene-2,2'-dione; 3',4',7,8-Tetradehydro-beta.beta beta.psi-caroten-4-one; Triophaxanthin; Triphasiaxanthin; caroten-3-ol: 34.3'4"Tetradehydrolycopene: 6,7,6,7- Trisanhydrobacterioruberin; Trollein; Trollichrome; Trol Tetradehydro-5.6.5',6'-tetrahydro-beta.beta-carotene-3,3'- liflavin; Trolliflor; Trollixanthin; Tunaxanthin; Uriolide; diol; 6.7.6'7"-Tetradehydro-5.6.5',6'-tetrahydro-beta.beta Vaucheriaxanthin; Violaxanthin; Violeoxanthin; Violeryth carotene-3.5.3',5'-tetrol; 7.8.7,8-Tetradehydrozeaxanthin; rin; Warmingol; Warmingone; Webbiaxanthin; Xanthophyll; 34.3',4'-Tetradehydrobisanhydrobacterioruberin; 5.6.5',6'- Xanthophyll K (1): Xanthophyll K (1)S: Xanthophyll Tetrahydrocanthaxanthin; 7,8,7,8-Tetrahydrocapsorubin; dipalmitate; Xanthophyll epoxide; alpha-Zeacarotene; beta Tetrahydro-beta-carotene; 7.8.7,8-Tetrahydro-beta.beta Zeacarotene; beta (1)-Zeacarotene; alpha-Zeacarotene-3,17 carotene; 7.8'11", 12'-Tetrahydro-beta.psi-carotene; 7.8'11", diol; beta-Zeacarotene-3,17-diol; beta-Zeacaroten-3-ol; 12-Tetrahydro-gamma-carotene: 7",8,11,12'-Tetrahydro Zeaxanthene; Zeaxanthin: Zeaxanthin diepoxide; Zeaxanthin gamma,psi-carotene; 1,2,7,8-Tetrahydro-psi.psi-carotene; dimethyl ether: Zeaxanthin dirhamnoside; Zeaxanthin 1.2.1'2'-Tetrahydro-psipsi-carotene; 7.8,11,12-Tetrahydro dipalmitate; Zeaxanthin 5,6-epoxide: Zeaxanthin 5.8-ep psi.psi-carotene; 7,8,7,8-Tetrahydro-psi.psi-carotene: oxide: Zeaxanthin furanoxide; Zeaxanthin monomethyl 5.6.5", 6"-Tetrahydro-beta.beta-carotene-4,4'-diol; 7,8,7,8'- ether; Zeaxanthin monorhamnoside; Zeaxanthol; and Zei Tetrahydro-beta.beta-carotene-3,3'-diol; 7.8'9", 10'-Tetrahy noxanthin. dro-beta.psi-carotene-3,17-diol; 1,2,1',2'-Tetrahydro-psi, 0157. The above list of naturally occurring carotenoids is psi-carotene-1,1'-diol; 5.6.5',6'-Tetrahydro-beta.beta meant to be a non-limiting example of naturally occurring carotene-4,4'-dione; 5.6.5',6'-Tetrahydro-beta.beta-carotene carotenoids. This list is not comprehensive as more naturally 3,5,6,3',5',6'-hexyl: 1,2,7,8-Tetrahydro-psi.psi-caroten-1-ol; occurring molecules are being discovered which will fall 1,2,7,8-Tetrahydro-psipsi-caroten-1-ol; 7.8,11,12-Tetrahy within the category of carotenoids. dro-4,4'-diapocarotene; 7,8,7,8-Tetrahydro-4,4'-diapocaro tene; Tetrahydrolycopene; 1.2.1',2'-Tetrahydrolycopene; 5.6, Sulfonylureas 5',6'-Tetrahydrolycopene; 7,8,11,12-Tetrahydrolycopene: 0158. Non-limiting examples of sulfonylureas include, 7,8,7,8-Tetrahydrolycopene; 7",8,11,12'-Tetrahydrolyco but are not limited to acetohexamide, DiaBeta, glibencla pene; 1.2.1.2'-Tetrahydrolycopene-1,1'-diol: 1,2,1',2'-Tet mide, gliclazide, glipizide (Glucotrol), glyclopyramide, chlo rahydroneurosporene; 3.4.11", 12'-Tetrahydrospheroidene: rpropamide, tolaZamide, tolbutamide, glimepiride (Amaryl), 3,4,7,8-Tetrahydrospirilloxanthin; 3.4.3',4'-Tetrahydrospiril tolbutamide and meglitinide analogues (for example, repa loxanthin; 34.3',4'-Tetrahydrospirilloxanthin-20-al; 5.6.5". glinide, nateglinide, meglitinide and mitiglinide (KAD 6'-Tetrahydro-3,4,3',4'-tetrol 4,4'-disulfate; 2.3,2',3'-Tetrahy 1229)) and the like. droxy-beta.beta-caroteine-4,4'-dione; 2.3.2',3'-Tetrahydroxy beta.beta-caroten-4-one; 3.19.3", 17'-Tetrahydroxy-beta,chi Niacin and Related Derivatives caroten-6'-one 3-sulfate; 3.5.3',5'-Tetrahydroxy-6,7- didehydro-5,8.5',6'-tetrahydro-beta.beta-caroten-8-one; 3,3', 0159. The term niacin is the generic descriptor for nico 5.5'-Tetrahydroxy-6'-hydro-7-dehydro-beta-carotene; 34.3', tinic acid (pyridine-3-carboxylic acid) and its derivatives. 4'-Tetrahydroxypirardixanthin; 34.3',4'-Tetrahydroxy-5.6, Non-limiting examples of nicotinic acid derivatives include 5",6'-tetrahydro-beta.beta-carotene: (3,4,3'4")-Tetraketo nicofuranose, AcipimoX (5-methylpyrazine-2-carboxylic beta-carotene; 4,5,4',5'-Tetraketo-beta-carotene; Thiothece acid 4-oxide), niceritrol, probucol, isonicotinic acid, Cholex 425; Thiothece-460; Thiothece-474; Thiothece-478: amin, oxiniacic acid, nicoclonate, nicomol, NIASPAN, nic Thiothece-484; Thiothece-OH-484; TilefishXanthin I; Tile erikol and tocopherol nicotinate. fishXanthin II; TilefishXanthin III; TilefishXanthin IV: Toru 0.160) Further examples of other active agents which may larhodin; Torularhodinaldehyde; Torularhodin methyl ester; be suitable for this invention include, without limitation, AGI Torulenal; Torulene; Torulenecarboxylic acid; 2.3,2'-Trihy 1067, abecarnil, acamprostate, acavir, acebutolol, ace droxy-beta,beta-caroten-4-one; 3.3',4'-Trihydroxy-beta, clofenac, acemetacin, acetaminophen, acetaminoSalol, aceta beta-caroten-4-one; 34.3'-Trihydroxy-beta, chi-caroten-6'- nilide, acetohexamide, acetophenazine maleate, one; 3,3',5'-Trihydroxy-6',7'-dehydro-alpha-carotene; 3,3'.8- acetophenazine, acetoXolone, acetoxypregnenolone, acetre Trihydroxy-7,8-didehydro-beta.chi-caroteine-4,6'-dione: tin, acrisorcin, acrivastine, acyclovir, adinazolam, adiphenine 3.3', 8-Trihydroxy-7,8-didehydro-beta.chi-caroten-6'-one: hydrochloride, adrafinil, adrenolone, agatroban, ahnitrine, 3.19.3'-Trihydroxy-7,8-didehydro-beta.chi-caroten-6'-one akatinol, alatrofloxacin, albendazole, albuterol, aldioxa, allen 3-sulfate; 3,1',2'-Trihydroxy-3',4'-didehydro-1,2-dihydro dronate, alfentanil, alibendol, alitretinoin, allopurinol, ally beta.psi-caroten-4-one; 3,5,19-Trihydroxy-6,7-didehydro-5, lamines, allylestrenol, alminoprofen, almotriptan, alosetron, 6,7,8-tetrahydro-7'-apo-beta-caroten-8-one 3-acetate aloxiprin, alprazolam, alprenolol, amantadine, ambuceta 19-hexanoate; 3,5,6'-Trihydroxy-6,7-didehydro-5,6,7,8-tet mide, amidephrine, amidinomycin, amiloride, aminoarylcar rahydro-beta.epsi-carotene-3',8-dione; 3.5.3'-Trihydroxy boxylic acid derivatives, aminoglutethimide, aminoglyco 5,6-dihydro-beta-carotene; 3,3',5'-Trihydroxy-5',6'-dihydro sides, aminopentamide, aminopromazine, aminorex, beta-caroteine 5',6'-epoxide; 3.19.3'-Trihydroxy-7,8-dihydro amiodarone, amiphenazole, amiprilose, amisulpride, ami beta, epsi-caroten-8-one; 3.19.3'-Trihydroxy-7,8-dihydro triptyline, amlexanoX, amlodipine, amodiaquine, amoSulalol, beta.beta-caroten-8-one 19-laurate; 3,6,3'-Trihydroxy-7,8- amotriphene, amoxapine, amoxicillin, amphecloral, amphet dihydro-gamma.epsi-carotein-8-one; 3,3',19-Trihydroxy-7, amine, amphomycin, amphotericin, amplicillin, ampiroxi US 2011/0065783 A1 Mar. 17, 2011 20 cam, amprenavir, aminone, amsacrine, amyl nitrate, amylo fiban, cromolyn, cropropamide, crotethamide, curcumin, barbitone, anagestone acetate, anastroZole, andinocillin, cyclandelate, cyclarbamate, cyclazocine, cyclexedrine, androstenediol, androstenediol-17-acetate, androstenediol cyclizine, cyclobenzaprine, cyclodrine, cyclonium iodide, 17-benzoate, androstenediol-3-acetate, androstenediol-3-ac cyclopentamine, cyclosporin, cypionate, cyproheptadine, etate-17-benzoate, androstenedione, androsterone acetate, cyproterone acetate, cytarabine, dacarbazine, dalfopristine, androsterone benzoate, androsterone propionate, androster dantrolene Sodium, dapiprazole, darodipine, decanoate, one, angiotensin, anidulatungin, aniracetam, apaZone, apicy decitabine, decoquinate, dehydroemetine, delavirdine, cline, apoatropine, apomorphine, apraclonidine, aprepitant, delaviridine, demeclo cycline, denopamine, deramciclone, aprotinin, arbaprostil, ardeparin, aripiprazole, amikacin, aro descitalopram, desipramine, desloratadine, 3-ke tinolol, arstiinol, arylacetic acid derivatives, arylalkylamines, todesogeskel, desomorphine, desoxymethasone, detomidine, arylbutyric acid derivatives, arylcarboxylic acids, arylpipera dexamphetamine, dexanabinol, dexchlorpheniramine, Zines, arylpropionic acid derivatives, aspirin, astemizole, dexfenfluramine, dexmethylphenidate, dexraZoxane, dextro atenolol, atomoxetine, atorvastatin, atovaquone, atropine, amphetamine Sulfate, dextroamphetamine, dextropro auranofin, azapropaZone, azathioprine, azelastine, azetazola poxyphene, DHEA, diacetate, diamorphine, diazemine, diaz mide, azithromycin, baclofen, bambuterol, bamethan, barbi epam, diaziquinone, diazoxide, dibromopropamidine, tone, barnidipine, basalazide, beclamide, beclobrate, befi dichlorophen, diclofenac, dicoumarol, didanosine, dideoxy molol, bemegride, benazepril, bencyclane, bendazac, adenosine, diethylpropion, difemerine, difenamizole, bendazol, bendroflumethiazide, benethamine penicillin, ben diflunisal, digitoxin, digoxin, dihydroergotamine, dihydroco exate hydrochloride, benfurodil hemisuccinate, benidipine, deine, dihydrocodeinone enol acetate, dihydroergotamine benorylate, bentazepam, benzhexol, benziodarone, ben mesylate, dihydroergotamine, dihydrogesterone, dihydro Znidazole, benzoctamine, benzodiazepine derivatives, benzo morphine, dihydropyridine derivatives, dihydrostreptomy diazepine, benzonatate, benzphetamine, benzylmorphine, cin, dihydrotachysterol, dihydroxyaluminum acetylsalicy beperiden, bephenium hydroxynaphthoate, bepridil, betahis late, diiodohydroxyquinoline, diisopromine, dilazep. tine, betamethasone, betaxolol, bevantolol, bevonium methyl dilevalol, diltiazem, diloxanide furoate, diloxanide, dilt sulfate, bexarotene, bezadoxifine, bezafibrate, bialamicol, iazem, dimefline, dimenhydrinate, dimethisterone, dimetot biapenem, bicalutamide, bietamiverine, bifonazole, bineda rine, dimorpholamine, dinitolmide, dioxaphetyl butyrate, line, binifibrate, biricodar, bisacodyl, bisantrene, bisoprolol, dioxethedrine, diphemethoxidine, diphenhydramine, diphe bitolterol, bopindolol, boswellic acid, bradykinin, bretylium, noxylate, diphetarSone, diplivefrin, diponium bromide, dipy bromazepam, bromocriptine, bromperidol, brotizolam, ridamole, dirithromycin, disopyramide, divalproex sodium, brovincamine, buciclate, bucloxic acid, bucumolol, budrala dofetilide, domperidone, donepezil, dopexamine, dopradil, Zine, buieniode, bufetolol, buflomedil, bufuralol, bumet doSmalfate, doxapram, doxazosin, doxefazepam, doxepin, anide, bunitrolol, bupranolol, buprenorphine, bupropion, doxycycline, drofenine, dromostanolone propionate, dromo buspirone, buSulfan, butalamine, butorphanol, butaverine, stanolone, dronabinol, droperidol, droprenilamine, d-threo butenatime, butidrine hydrochloride, butobarbitone, buto methylphenidate, duloxetine, ebrotidine, eburnamonine, eca conazole nitrate, butoconazole, butofilol, butropium bro bet, ecenofloxacin, econazole nitrate, edavarone, edoxudine, mide, cabergoline, calcifediol, calcipotriene, calcitriol, efavirenz, effivarenZ, efloxate, eledoisin, eletriptan, elgo caldibine, cambendazole, camioxirole, camo.stat, campes dipine, ellipticine, emepronium bromide, emetine, enalapril, terol, camptothecin, candesartan, candoXatril, capecitabine, enanthate, encamide, enlopitat, enoXimone, enprostil, enta caprate, capsaicin, captopril, carazolol, carbacephems, car capone, epanolol, ephedrine, epinastine, epinephrine, epiru bamates, carbamazepine, carbapenems, carbarsone, Carba bicin, eplerenone, eprosartan, ergocalciferol, ergoloid mesy trol, carbenoXolone, carbimazole, carbromal, carbuterol, lates, ergotamine, ertapenum, erythromycin, erytlirityl carisoprodol, carotenes, caroverine, carteolol, carvedilol. tetranitrate, esaprazole, escitalopram, esmolol, esomepra cefaclor, cefazolin, cefbuperaZone, cefepime, cefoselis, cef Zole, esonarimod, estazolam, estradiol benzoate, estramus tibuten, celecoxib, celiprolol, cephaeline, cephalosporin C, tine, eskiol Succinate, estrone acetate, estrone Sulfate, cephalosporins, cephamycins, cerivastatin, certoparin, ceta etafedrine, etafenone, ethacrynic acid, ethamivan, ethi molol, cetiedil, cetirizine, cetraxate, chloracizine, chloram namate, ethinyleskadiol 3-acetate, ethinyleskadiol 3-ben bucil, chlorbetamide, chlordantoin, chlordiazepoxide, chlor Zoate, ethinylestradiol, ethionamide, ethisterone (17a-ethi madinone acetate, chlormethiazole, chloroquine, nyltestosterone), ethopropazine, ethotoin, ethoxyphenamine, chlorothiazide, chlorpheniramine, chlorphenoxamide, chlor ethylestrenol, ethylmorphine, ethylnorepinephrine, ethyno phentermine, chlorproguanil, chlorpromazine, chlorpropam diol diacetate, etodolac, etofibrate, etoposide, etoricoxib, ide, chlorprothixene, chlortetracycline, chlorthalidone, etretinate, everolimus, exalamide, examestane, examorelin, cholecalciferol, chromonar, ciclesonide, ciclonicate, cido eZemitibe, falecalcitriol, famciclovir, famotidine, fantofar fovir, ciglitaZone, cilansetron, cilostaZol, cimetidine, one, farapenum, fargilitazar, fasudil, felbamate, felodipine, cimetropium bromide, cinepazet maleate, cinnamedrine, cin femalamide, fenbuLen, fenbutrazate, fendiline, fenfluramine, narizine, cinolazepam, cinoxacin, ciprofibrate, ciprofloxacin, fenoldopam, fenoprofen, fenoterol, fenoverine, fenoxazo cisapride, cisplatin, citalopram, citicoline, clarithromycin, line, fenoxedil, fenpiprane, femproporex, fenspiride, fentanyl. clebopride, clemastine, clenbuterol, clidanac, clinofibrate, fexofenadine, flavoxate, flecamide, flopropione, floredil, clioquinol, clobazam, clobenfurol, clobenzorex, clofazimine, floxuridine, fluconazole, flucytosine, fludarabine, fludiaz clofibrate, clofibric acid, cloforex, clomipramine, clon epam, fludrocortisone, flulenamic acid, flunanisone, flunariz azepam, clonidine, clonitrate, clopidogrel, clopirac ine, flunisolide, flunitrazepam, fluocortolone, fluoxetine, flu indomethacin, cloranolol, cloricromen, clorprenaline, clor penthixol decanoate, fluiphenazine decanoate, fluphenazine termine, clotiazepam, clotrimazole, cloxacillin, clozapine, enanthate, fluphenazine, fluproduaZone, flurazepam, flurbi cmepazide, codeine methyl bromide, codeine phosphate, profen, fluorogestone acetate, fluticasone propionate, fluvas codeine Sulfate, codeine, colloidal bismuth Subcitrate, croma tatin, fluvoxamine, fominoben, formoterol, foScarnet, foscar US 2011/0065783 A1 Mar. 17, 2011 net, fosinopril, fosphenyloin, froVatriptan, fudosteine, Monteplase, moprolol, moricizine, morphine hydrochloride, fumagillin, furazolidone, furazolidone, furfurylmethyl morphine Sulfate, morphine, morpholine Salicylate, amphetamine, furosemide, gabapentin, gabexate, gaboxadol, mosapramine, moxifloxacin, moxisylyte, moxonidine, galanthamine, gallopamil, gammaparin, ganciclovir, gan mycophenolate, nabumetone, nadolol, nadoxolol, nadro glefene, gefarnate, gemcitabine, gemfibrozil, gepirone, ges parin, nafamo.stat, nafronyl, naftopidil, nalbuphine, nalidixic tadene, ghrelin, glatiramer, glaucarubin, glibenclamide, gli acid, nalmefene, nalorphine, naloxone, naltrexone, nan clazide, glimepiride, glipizide, gluconic acid, glutamic acid, drolone benzoate, nandrolone cyclohexanecarboxylate, nan glyburide, glyceryl trinitrate, glimepiride, granisetron, grepa drolone cyclohexane-propionate, nandrolone decanoate, floxacin, griseofulvin, guaiaZulene, guanabenz, guanfacine, nandrolone furylpropionate, nandrolone phenpropionate, halofankine, haloperidol decanoate, haloperidol, halox naphazoline, naproxen, naratriptan, natamycin, nateglinide, aZolam, hepronicate, heptanoate, hexobendine, hexoprena nedocromil, nefazodone, nefopam, nelfinavir, nemonapride, line, hydramitrazine, hydrazides, hydrocodone, hydrocorti neomycin undecylenate, neomycin, neokofin, nesiritide, SOne, hydromorphone, hydroxyamphetamine, n-ethylamphetamine, nevirapine, nexopamil, nicametate, hydroxymethylprogesterone acetate, hydroxymethylproges nicardipine, nicergoline, nicofibrate, nicofuranose, nicomor terone, hydroxyprogesterone acetate, hydroxyprogesterone phine, nicorandil, nicotinyl alcohol, nicoumalone, nifedipine, caproate, hydroxyprogesterone, hymecromone, hyos nifenalol, nikethamide, nilutamide, nilvadipine, nimodipine, cyamine, ibopamine, ibudilast, ibutenac, ibuprofen, ibutilide, nimorazole, nipradillol, nisoldipine, nitisonone, nitrazepam, idoxuridine, ifenprodil, igmesine, iloprost, imatinib, imi nitrofurantoin, nitrofuraZone, nitroglycerin, nizatidine, dapril, imidazoles, imipenem, imipramine, imolamine, norastemizole, norepinephrine, norethynodrel, norfenefrine, incadronic acid pergolide, indanazoline, indenolol, indinavir, norfloxacin, norgestimate, norgeskel, norgestrienone, indomethacin, indoramin, inosine pranobex, inositol niaci normethadone, normethisterone, normorphine, norpseu nate, iodoquinol, ipidracine, iproniazid, irbesartan, irinote doephedrine, nortriptyline, novantrone, nylidrin, nystatin, can, irsogladine, isobutyrate, isocaprate esters, isoetharine, octamylamine, octodrine, octopamine, ofloxacin, olanzap isometheptene, isoproterenol, isosorbide dinitrate, isosorbide ine, olanzapine, olapatadine, olmesartan, Olapatadine, mononitrate, isosorbide dinitrate, isoxSuprine, isradipine, olsalazine, omapatrilat, omeprazole, ondansetron, opium, itasetron, itraconazole, itramintosylate, ivermectin, kallidin, oprevelkin, orlistat, ornidazole, ornoprostil, oseltamivir, kallikrein, kanamycin, ketamine, ketoconazole, ketoprofen, oxaliplatin, oxamniquine, Oxandrolone, Oxantel embonate, ketorolac, ketotifen, labetalol, lafutidine, lamifiban, lamivu oxaprozin, oxatomide pemirolast, oxatomide, oxazepam, dine, lamotrigine, lanatoside c. lansoprazole, lasofoxifene, oxcarbazepine, oxfendazole, oxiconazole, oxiracetam, oxo leflunomide, leminoprazole, lercanidipine, lesopitron, letro linic acid, oXprenolol, oxycodone, oxyfedrine, oxymetazo Zole, leucovorin, levalbuterol, levallorphan, levetiracetam, line, oxymorphone, oxyphenbutaZone, oxyphencyclimine, levetriacetam, levobunolol, levodopa, levofloxacin, oZagrel, paclitaxel, palonosetron, pantoprazole, papaverine, levophacetoperane, levorphanol, lidocaine, lidoflazine, lifi paricalcitol, paramethadione, parecoxib, pariprazole, paro brol, limaprost, lineZolid, lintitript, liranaftate, lisinopril, momycin, paroxetine, parsalmide, paZinaclone, pemoline, lisuride, lobeline, lobucavir, lodoxamide, lomefloxacin, lom penbutolol, penciclovir, penicillin G benzathine, penicillin G erizine, lomustine, loperamide, lopinavir, loprazolam, lora procaine, penicillin V, penicillins, pentaerythritol tetranitrate, carbef, loratadine, lorazepam, lorefloxacin, lormetazepam, pentaerythritol tetranitrate, pentapiperide, pentazocine, pen losartan, lovastatin, lovastatin, loxapine Succinate, loxapine, tifylline, pentigetide, pentobarbitone, pentorex, pentoxifyl 1-threo methylphenidate, lumiracoxib, lysine acetylsalicy line, pentrinitrol, pirbuterol, pirenzepine, pergolide, perhexy late, lysozyme, lisuride, mabuterol, mafenide, magnesium line, perindopril erbumine, peroSpone, perphenazine acetylsalicylate, malgramostin, mannitol hexanitrate, mapro pimozide, perphenazine, phanquinone, phenacemide, phen tiline, mazindol, mebendazole, meclizine, meclofenamic acetin, phenazopyridine, phencarbamide, phendimetrazine, acid, mecloxaminepentapiperide, medazepam, medibazine, phenelZine, phenindione, phenmetrazine, phenobarbitone, medigoxin, medrogestone, medroxyprogesterone acetate, phenoperidine, phenothiazines, phenoxybenzamine, phen mefenamic acid, mefenorex, mefloquin, mefloquine, mege Suximide, phentermine, phentolamine, phenylsalicylate, phe strol acetate, melengestrol acetate, melphalan, memantine, nylacetate, phenylbutaZone, phenylephrine hydrochloride, mepenZolate bromide, meperidine, mephenoxalone, phenylpropanolamine hydrochloride, phenylpropanolamine mephentermine, mepindolol, mepixanox, meprobamate, hydrochloride, phenylpropyl-methylamine, phenyloin, phlo meptazinol, mercaptopurine, meropenum, mesalamine, roglucinol, pholedrine, physostigmine Salicylate, physostig mesalazine, mesoridazine besylate, mesoridazine, meta mine, phytonadiol, phytosterols, piapenum, picilorex, clazepam, metamfepramone, metampicillin, metaproterenol, piclaimilast, picrotoxin, picumast, pifarnine, pilsicainide, metaraminol, methacycline, methadone hydrochloride, pimagedine, pimeclone, pimecrolimus, pimethylline, methadone, methamphetamine, methaqualone, metharnphet pimozide, pinaverium bromide, pindolol, pioglitaZone, pip amine, methoin, methotrexate, methoxamine, methSuximide, eracillin, piperazine estrone sulfate, piperazine derivatives, methylhexaneamine, methylphenidate d-threo-methylpheni piperilate, piracetam, piribedil, pirifibrate, piroXicam, pitav date, methylphenidate, methylphenobarbitone, methylpred astatin, pizotyline, plaunotol, polaprezinc, polybenzarsol, nisolone, methysergide, metiazinic acid, metizoline, meto polyestrol phosphate, practolol, pralnacasan, pramipexole, clopramide, metolaZone, metoprolol, metoxalone, pranlukast, pravastatin, prazepam, praziquantel, praZosin, metripranolol, metronidazole, mexiletine, metaxalone, pregabalin, prenalterol, prenylamine, pridinol, pri?inium bro mianserin, mibefradil, miconazole, midazolam, midodrine, mide, primidone, primipramine, probenecid, probucol, miglitol, milnacipran, milrinone, minoxidil, mirtazapine, procainamide, procarbazine, procaterol, prochlorperazine, misoprostol, mitomycin, mitotane, mitoxantrone, mizolas proguanil, pronethalol, propafenone, propamidine, propatyl tine, modafinil, mofebutaZone, mofetil, molindone hydro nitrate, propentoffyline, propionate, propiram, pro chloride, molindone, molsidomine, monatepil, montelukast, poxyphene, propranolol, propylhexedrine, propylthiouracil, US 2011/0065783 A1 Mar. 17, 2011 22 protokylol, protriptyline, proxazole, pseudoephedrine, Xibenolol, Ximelagatran, Xylometazoline, yohimbine, purines, pyrantel embonate, pyrazoles, pyrazolones, pyrid Zacopride, Zafirlukast, Zalcitabine, Zaleplon, Zanamivir, Zate ofylline, pyrimethamine, pyrimidines, pyrrolidones, bradine, Ziconotide, Zidovudine, Zileuton, Zimeldine, Zinc quaZepam, quetiapine, quetuapine, quinagolide, quinapril, propionate, Ziprasidone, Zolimidine, Zolmitriptan, Zolpidem, quinestrol, quinfamide, quinidine, quinine Sulfate, quinolo Zonisamide, Zopiclone, and mixtures thereof. nes, quinupritin, rabalzotan, rabeprazole sodium, rabepra 0.161 The compounds according to the invention may be Zole, racefimine, ramahroban, ramipril, ranitidine, ranola formulated as pharmaceutical compositions Suitable for oral, Zine, ransoprazole, rasagiline, rebamipide, refludan, buccal, parenteral, transdermal or rectal administration or in a repaglinide, repinotan, repirinast, reproterol, reserpine, retin form suitable for administration by inhalation or insufflation. oids, ribavirin, rifabutine, rifampicin, rifapentine, rillmeni Parenteral administration includes Subcutaneous injections, dine, riluzole, rimantadine, rimiterol, rioprostil, risperidone, intravenous, intramuscular, intrasternal injection, or infusion ritanovir, ritapentine, ritipenem, ritodrine, ritonavir, rivasti techniques. grnine, rizatriptan, rociverine, rofecoxib, rohypnol, rolipram, 0162 The pharmaceutical compositions may also be for remoxipride, ronifibrate, ropinirole, ropivacaine, rosaprostol, mulated as a therapeutically effective amount in a dosage unit rosiglitaZone, rosuvastatin, rotinolol, rotraxate, roXatidine form for ease of administration and uniformity of dosage. acetate, roXindole, rubitecan, salacetamide, Salicin, salicyla Dosage unit form as used in the specification and claims mide, salicylic acid derivatives, salmeterol, saquinavir, herein refers to physically discrete units suitable as unitary saquinavir, Scopolamine, secnidazole, selegiline, semotiadil, dosages, each unit containing a predetermined quantity of sertindole, Sertraline, Sibutramine, sildenafil. Simvastatin, sir active ingredient calculated to produce the desired therapeu amesine, sirolimus, sitaxsentan, Sofalcone. Somotiadil, tic effect in association with the required pharmaceutical Sorivudine, Sotalol, Soterenol, sparfloxacin, spasmolytol, carrier. Examples of Such dosage unit forms are tablets (in spectinomycin, spiramycin, Spizofurone, stavudine, Strepto cluding scored or coated tablets), capsules, pills, powder mycin, Succinylsulfathiazole, Sucralfate, Sufentanil, Sulcona packets, wafers, injectable solutions or Suspensions, tea Zole nitrate, Sulfacetamide, Sulfadiazine, Sulfaloxicacid, Sul spoonfuls, tablespoonfuls and the like, and segregated mul farside, Sulfmalol, Sulindac, Suloctidil, Sulphabenzamide, tiples thereof. Such dosage forms can also comprise, as in Sulphacetamide, Sulphadiazine, Sulphadoxine, Sulphafura conventional practice, additional Substances other than inert Zole, Sulphamerazine, Sulphamethoxazole, Sulphapyridine, diluents, e.g., lubricating agents such as magnesium Stearate. SulphaSalazine, Sulphinpyrazone, Sulpiride, Sulthiame, Sulto In the case of capsules, tablets, effervescent tablets, and pills, pride, sulbroponium, Sumanirole, Sumahriptan, sunepihon, the dosage forms can also comprise buffering agents. Soft Superoxide dismutase, Suplatast, Suramin Sodium, Syneph gelatin capsules can be prepared to contain a mixture of the rine, tacrine, tacrolimus, tacrolimus, tadalafil, talinolol, tal active compounds or compositions of the invention and Veg ipexole, tamoxifen, tamsulosin, targretin, tazanolast, tazaro etable oil. Hard gelatin capsules can contain granules of the tene, taZobactam, tecastimezole, teclozan, tedisamil, active compound in combination with a solid, pulverulent tegaserod, telenzepine, telmisartan, temazepam, teniposide, carrier Such as lactose, Saccharose, Sorbitol, mannitol, potato teprenone, teraZosin, terbinafine, terbinafine, terbutaline Sul starch, corn starch, amylopectin, cellulose derivatives of gela fate, terbutaline, terconazole, terfenadine, terodiline, terofe tin. Tablets and pills can be prepared with enteric coatings. namate, tertatolol, testolactone, 4-dihydrotestosterone, tetra 0163 Liquid dosage forms for oral administration can cyclics, tetracycline, tetrahydrocannabinol, tetrahydrozoline, include pharmaceutically acceptable emulsions, Solutions, thalidomide, theofibrate, thiabendazole, thiazinecarboxam Suspensions, syrups, and elixirs containing inert diluents ides, thiocarbamates, thiocarbamizine, thiocarbarsone, thior commonly used in the art, Such as water. Such compositions idazine, thiothixene, tiagabine, tiamenidine, tianeptine, can also comprise adjuvants, such as wetting agents, emulsi tiaprofenic acid, tiaramide, ticlopidine, tigloidine, tilisolol. fying and Suspending agents, and Sweetening, flavoring, and timolol, timidazole, tinofedrine, tinzaparin, tioconazole, perfuming agents. tipranavir, tirapazamine, tirofiban, tiropramide, titanicene, 0164 Suppositories for vaginal or rectal administration of tizanadine, tizanidine, tizinadine, tocainide, tolaZamide, tola the compounds and compositions of the invention can be Zoline, tolbutamide, tolcapone, tolciclate, tolfenamic acid, prepared by mixing the compounds or compositions with a toliprolol, tolteridine, tolterodine, tonaberstat, topiramate, Suitable nonirritating excipient such as cocoa butter and poly topotecan, torsemide, toremifene cibrate, toremifene, to Su ethylene glycols which are solid at room temperature but floxacin, tramadol, tramaZoline, trandolapril, tranilast, tra liquid at body temperature, such that they will melt and nylcypromine, trapidil, traxanox, traZodone, tretoquinol, tri release the drug. acetin, triamcinolone, triamterine, triamterene, triazolam, 0.165 Injectable preparations, for example, sterile inject trifluoperazine hydrochloride, trifluoperazine, triflupro able aqueous or oleaginous Suspensions can be formulated mazine, trihexyphenidyl, trimaZosin, trimebutine, trimetazi according to the known art using Suitable dispersing agents, dine, trimethoprim, trimgestone, trimipramine, trimoprostil, wetting agents and/or Suspending agents. The sterile inject trithiozine, troglitaZone, trolnibrate phosphate, able preparation can also be a sterile injectable solution or tromethamine, tropicamide, trovafloxacin, troXipide, tuami Suspension in a nontoxic parenterally acceptable diluent or noheptane, tulobuterol, tymazoline, tyramine, undecanoate, Solvent, for example, as a solution in 1,3-butanediol. Among undecenoic acid, urinastatin, Valacyclovir, Valdecoxib, Valer the acceptable vehicles and solvents that can be used are ate, Valganciclovir, Valproic acid, Valsartan, Vancomycin, water, Ringer's Solution, and isotonic sodium chloride solu Vardenafil. Venlafaxine, venorelbine, Verapamil, Vidarabine, tion. Sterile fixed oils are also conventionally used as a sol vigabakin, Vincamine, Vinpocetine, viomycin, Vicquidil, vis vent or Suspending medium. nadine, Vitamin a derivatives, vitamina, Vitamin b, Vitamin 0166 The compositions of this invention can further d, Vitamine, Vitamink, Voglibose, Voriconazole, Xaliproden, include conventional excipients, i.e., pharmaceutically Xamoterol, Xanthinol niacinate, Xeny tropium bromide, acceptable organic or inorganic carrier Substances Suitable for US 2011/0065783 A1 Mar. 17, 2011

oral, buccal, parenteral, transdermal or rectal administration composition, physiological condition of the patient (includ or in a form suitable for administration by inhalation or insuf ing age, sex, disease type and stage, general physical condi flation, which do not deleteriously react with the active com tion, responsiveness to a given dosage and type of medica pounds. Suitable pharmaceutically acceptable carriers tion), route of administration, and the like. The guidelines include, for example, water, salt Solutions, alcohol, vegetable presented herein may be used to optimize the treatment, e.g., oils, polyethylene glycols, gelatin, lactose, amylose, magne determining the optimum time and/or amount of administra sium Stearate, talc, Surfactants, silicic acid, viscous paraffin, tion, which will require no more than routine experimentation perfume oil, fatty acid monoglycerides and diglycerides, consisting of monitoring the Subject and adjusting the dosage petroethral fatty acid esters, hydroxymethyl-cellulose, poly and/or timing. vinylpyrrolidone, and the like. The pharmaceutical prepara 0.174 While the subject is being treated, the health of the tions can be sterilized and if desired, mixed with auxiliary patient may be monitored by measuring one or more of the agents, e.g., lubricants, preservatives, stabilizers, wetting relevant indices at predetermined times during the treatment agents, emulsifiers, salts for influencing osmotic pressure, period. Treatment, including composition, amounts, times of buffers, colorings, flavoring and/or aromatic Substances and administration and formulation, may be optimized according the like which do not deleteriously react with the active com to the results of Such monitoring. The patient may be periodi pounds. For parenteral application, particularly suitable cally reevaluated to determine the extent of improvement by vehicles consist of solutions, preferably oily or aqueous solu measuring the same parameters. Adjustments to the amount tions, as well as Suspensions, emulsions, or implants. Aque (s) of Subject composition administered and possibly to the ous Suspensions may contain Substances that increase the time of administration may be made based on these reevalu Viscosity of the Suspension and include, for example, sodium ations. carboxymethyl cellulose, sorbitol and/or dextran. Optionally, 0.175 Treatment may be initiated with smaller dosages the Suspension may also contain stabilizers. which are less than the optimum dose of the compound. 0167 Both tablets and capsules may also be manufactured Thereafter, the dosage may be increased by Small increments in the form of sustained release formulations, such that they until the optimum therapeutic effect is attained. provide a controlled continuous release of the compounds 0176 The use of the subject compositions may reduce the according to the invention over a period of hours. required dosage for any individual agent contained in the 0168 Administration of the compositions of the present compositions (e.g., the steroidal anti inflammatory drug) invention will be in an amount sufficient to achieve a thera because the onset and duration of effect of the different agents peutic effect as recognized by one of ordinary skill in the art. may be complimentary. 0169. The dosage of any compositions of the present 0177 Toxicity and therapeutic efficacy of subject compo invention will vary depending on the symptoms, age and body sitions may be determined by standard pharmaceutical pro weight of the patient, the nature and severity of the disorder to cedures in cell cultures or experimental animals, e.g., for be treated or prevented, the route of administration, and the determining the LDs and the EDso. form of the subject composition. Any of the subject formula 0.178 The data obtained from the cell culture assays and tions may be administered in a single dose or individed doses. animal studies may be used in formulating a range of dosage Dosages for the compositions of the present invention may be for use in humans. The dosage of any Subject composition lies readily determined by techniques known to those of skill in preferably within a range of circulating concentrations that the art or as taught herein. include the EDs with little or no toxicity. The dosage may 0170 The dosage range for nebivolol ranges from about vary within this range depending upon the dosage form 0.1 mg to about 100 mg per day. In another embodiment, the employed and the route of administration utilized. For com dosage range may be from about 0.75 mg to about 50 mg per positions of the present invention, the therapeutically effec day. In yet another embodiment, the dosage range may be tive dose may be estimated initially from cell culture assays. from about 1.25 mg to about 10 mg per day. 0179. In general, the doses of an active agent will be cho 0171 In certain embodiments, the dosage of the co-active sen by a physician based on the age, physical condition, compounds will generally be in the range of about 0.01 ng to weight and other factors known in the medical arts. about 1 g per kg body weight, specifically in the range of 0180 Those of skill in treating subjects suffering from a about 1 ng to about 0.1 g per kg, and more specifically in the vascular disease, for instance, an increased blood pressure, range of about 100 ng to about 10 mg per kg body weight. could easily determine the therapeutically effective amount 0172 An effective dose or amount, and any possible from the test results presented hereinafter. In general it is affects on the timing of administration of the formulation, contemplated that an effective daily dose of the compounds of may need to be identified for any particular composition of formula (I) or their pharmaceutically acceptable acid-addi the present invention. This may be accomplished by routine tion salts would be from about 0.01 mg/kg to about 50 mg/kg experiment as described herein, using one or more groups of body weight, in particular from about 0.1 mg/kg to about 10 animals (preferably at least 5 animals per group), or in human mg/kg body weight, and preferably from about 0.1 mg/kg to trials if appropriate. The effectiveness of any Subject compo about 1 mg/kg body weight. sition and method of treatment or prevention may be assessed 0181. The invention also provides pharmaceutical kits by administering the composition and assessing the effect of comprising one or more containers filled with one or more of the administration by measuring one or more applicable indi the ingredients of the pharmaceutical compounds and/or ces, and comparing the post-treatment values of these indices compositions of the invention, including, hydroxylated to the values of the same indices prior to treatment. nebivolol metabolites. Such kits can also include, for 0173 The precise time of administration and amount of example, other compounds and/or compositions (e.g., diuret any particular Subject composition that will yield the most ics, digoxin, compounds used to treat cardiovascular dis effective treatment in a given patient will depend upon the eases, therapeutic agents, permeation enhancers, lubricants, activity, pharmacokinetics, and bioavailability of a subject and the like), a device(s) for administering the compounds US 2011/0065783 A1 Mar. 17, 2011 24 and/or compositions, and written instructions in a form pre The location of damaged arterial surfaces is determined by scribed by a governmental agency regulating the manufac conventional diagnostic methods, such as X-ray angiography, ture, use or sale of pharmaceuticals or biological products, performed using routine and well-known methods available which instructions can also reflects approval by the agency of to one skilled in the art. manufacture, use or sale for human administration. 0187. When administered in vivo, the compounds and 0182 Another embodiment of the invention relates to the compositions of the invention can be administered in combi local administration of at least one hydroxylated metabolite nation with pharmaceutically acceptable carriers and in a of nebivolol, and, optionally, at least one additional therapeu therapeutically effective dosage, as described herein. tic agent to treat injured tissue. Such as damaged blood ves 0188 When the compounds and compositions of the sels. present invention are administered as a mixture of at least one 0183 The compounds of the present invention and, hydroxylated nebivolol metabolite, they can also be used in optionally, other therapeutic agents, can be incorporated into combination with one or more additional therapeutic agents a natural or synthetic matrix which can then be applied with which are known to be effective against the specific disease specificity to a biological site of interest. Accordingly the state targeted for treatment, such as for example diuretics nebivolol metabolites are “bound to the matrix' which means and/or different antihypertensive agents such as beta-block that the nebivolol metabolite(s) along with other therapeutic ers, calcium channel blockers or ACE inhibitors. It is to be agents are physically and/or chemically associated with part understood that such combination therapy constitutes a fur of incorporated with, attached to, or contained within the ther aspect of the present invention. natural or synthetic matrix. 0189 "Concurrent administration' encompasses simulta 0184 Any of a wide variety of natural or synthetic poly neous or sequential treatment with the components of the mers can be used as the matrix in the context of the invention. combination, as well as regimens in which the drugs are It is only necessary for the matrix to be biologically accept alternated, or wherein one component is administered long able. Exemplary matrixes suitable for use in the invention are term and the other(s) are administered intermittently. Com polymers including, for example, polyolefins (such as poly ponents can be administered in the same or in separate com styrene, polypropylene, polyethylene, high density polyeth positions, and by the same or different routes of ylene, polytetrafluorethylene, polyvinylidene diflouride and administration. polyvinylchloride), polyethylenimine or derivatives thereof, 0190. The nebivolol metabolites of the present invention polyethers (such as polyethylene glycol), polyesters (such as may be used in combination with other drugs that are used in poly-L-lactic acid, poly-D, L-lactic, poly-D-lactic, polygly the treatment/prevention/suppression or amelioration of the colic, poly-(lactide/glycolide)), polyanhydrides, polyhy diseases or conditions for which the hydroxylated nebivolol droxybutyrates, polyamides (such as nylon), polyurethanes, metabolites are useful. Other drugs include, for example, an polyurethane copolymers (such as pellethane polymers), antithrombogenic agent, a thrombolytic agent, a fibrinolytic polyacrylates (such as polymethacrylate, poly (2-(methacry agent, a vasospasm inhibitor, a potassium channel activator, a loyloxyethyl)-2'-(trimethylammonium)ethyl phosphate calcium channel blocker, an antihypertensive agent, an anti inner salt-co-n-dodecyl methacrylate), mixtures of polymers microbial agent, an antibiotic, an antiplatelet agent, an anti (such as polylactic acid/polylysine copolymers, polyure mitotic agent, an antiproliferative agent, a microtubule inhibi thane/polyester copolymers, polyurethane/polyether copoly tor, an antisecretory agent, a remodelling inhibitor, an mers, nylon/polyether copolymers, such as Vestamid), antisense nucleotide, an anti-cancer chemotherapeutic agent, biopolymers (such as peptides, proteins, oligonucleotides, a steroid, a non-steroidal antiinflammatory agent, a selective antibodies, peptide hormones, glycoproteins, glycogen and COX-2 inhibitor, an immunosuppressive agent, a growth fac nucleic acids), starburst dendrimers, natural fibrous matrix tor antagonist or antibody, a dopamine agonist, a radiothera (such as filter paper), synthetic fibrous matrix materials (Such peutic agent, a biologic agent, an angiotensin converting as three-dimensional lattice of synthetic polymers and enzyme inhibitor, an angiotensin II receptor antagonist, a copolymers) and the like. Exemplary polymers are described renin inhbitior, a free radical Scavenger, an iron chelator, an in U.S. Pat. Nos. 5,705,583, 5,770,645 and 5,994,444, the antioxidant, a sex hormone, an antipolymerase, an antiviral disclosures of which are incorporated by reference herein in agent, a photodynamic therapy agent, an antibody targeted their entirety. therapy agent, a gene therapy agent, biphosphonates or other 0185. The physical and structural characteristics of the osteoporosis agents, cholesterol lowering agents, including matrixes suitable for use in the invention are not critical, but but not limited to statins, niacin, or gemfibrozil, or mixtures depend on the application. It will be appreciated by one thereof. skilled in theart that where the matrix-metabolite of nebivolol 0191 Such other drugs may be administered, by a route composition of the invention is intended for local, relatively and in an amount commonly used therefore, contemporane short term administration or similar administration they need ously or sequentially with a compound of the hydroxylated not be biodegradable. For Some uses, such as postangioplasty, nebivolol metabolites. When a nebivolol metabolite of the coronary bypass Surgery or intimal hyperplasia associated present invention is used contemporaneously with one or with vascular graft implants or the like, it may be desirable for more other drugs, a pharmaceutical composition containing the matrix to slowly dissolve in a physiological environment Such other drugs in addition to the compound of the present or to be biodegradable or bioresorbable. invention is preferred. Accordingly, the pharmaceutical com 0186. In preventing and/or treating cardiovascular dis positions of the present invention include those that also eases or disorders, the nebivolol metabolites of the present contain one or more other active ingredients, in addition to the invention and optionally at least one therapeutic agent can be nebivolol metabolite of the present invention. Examples of administered directly to the damaged vascular Surface intra other active ingredients that may be combined with a nebiv venously by using an intraarterial or intravenous catheter, olol metabolite of the present invention, either administered suitable for delivery of the compounds to the desired location. separately or in the same pharmaceutical compositions, US 2011/0065783 A1 Mar. 17, 2011

include, but are not limited to: (1) morphine and other opiate monoxide releasing, delivering or transferring compounds receptoragonists including propoxyphene (Darvon); (2) non have the structure F NO, wherein F is a nitrogen monoxide steroidal anti-inflammatory drugs (NSAIDs) including releasing, delivering or transferring moiety, and include any COX-2 inhibitors such as propionic acid derivatives (almino and all Such compounds which provide nitrogen monoxide to profen, benoxaprofen, bucloxic acid, carprofen, fenbufen, its intended site of action in a form active for its intended fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, purpose. ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pra Administration of a Nebivolol Metabolite with a Blood Pres noprofen, Suprofen, tiaprofenic acid, and tioxaprofen), acetic Sure Reducing Agent acid derivatives (indomethacin, acemetacin, alclofenac, clid 0193 The nebivolol metabolites of the present invention anac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furo and the acid addition salts thereof may be administered fenac, ibufenac, isoxepac, oXpinac, Sulindac, tiopinac, tol before, during or after the administration of a blood pressure metin, Zidometacin, and Zomepirac), fenamic acid derivatives reducing agent provided that the time of the administration of (flufenamic acid, meclofenamic acid, mefenamic acid, niflu the compounds of the present invention in relation to the mic acid and tolfenamic acid), biphenylcarboxylic acid administration of the blood pressure reducing agent allows derivatives (diflunisal and flufenisal), oxicams (isoxicam, the compound of the present invention to be effective in piroXicam, Sudoxicam and tenoxican), Salicylates (acetyl potentiating the effects of the blood pressure reducing agent. salicylic acid, SulfaSalazine) and the pyrazolones (apaZone, 0194 As blood pressure reducing agents of which the bezpiperylon, feprazone, mofebutaZone, oxyphenbutaZone, activity is potentiated there may be mentioned agents having phenylbutazone), and the coxibs (celecoxib, valecoxib, rofe adrenergic and/or vasodilating activity. In particular Such coxib and etoricoxib); (3) corticosteroids such as betametha agents may be the compounds mentioned in U.S. Pat. Nos. Sone, budesonide, cortisone, dexamethasone, hydrocorti 3,663,607 and 3,836,671, in particular atenolol; U.S. Pat. Sone, methylprednisolone, prednisolone, prednisone and Nos. 3,337,628 and 3,520,919, in particular propranolol; U.S. triamcinolone; (4) histamine H1 receptor antagonists such as Pat. No. 3,873,600, in particular metoprolol; U.S. Pat. No. bromopheniramine, chlorpheniramine, dexchlorphe 3.511,836, in particular prazosin; U.S. Pat. No. 2,484,029, in niramine, triprolidine, clemastine, diphenhydramine, diphe particular hydralazine; U.S. Pat. No. 2,928,829 in particular nylpyraline, tripelennamine, hydroxy Zine, methdilazine, guanethidine: U.S. Pat. No. 2,503,059, in particular phento promethazine, trimeprazine, azatadine, cyproheptadine, lamine: U.S. Pat. No. 3,261,859, in particular verapamil: U.S. antazoline, pheniramine pyrilamine, astemizole, terfenadine, Pat. No. 3,485,847 in particular nifedipine: U.S. Pat. No. loratadine, cetirizine, desloratadine, fexofenadine and levo 3,910,924, in particular carteolol; German Pat. Nos. 2,458, cetirizine; (5) histamine H2 receptor antagonists such as 624 and 2,458,625, in particular celiprolol. All cited patents cimetidine, famotidine and ranitidine; (6) proton pump are incorporated herein by reference. These groups of active inhibitors such as omeprazole, lanSoprazole, pantoprazole ingredients are listed with the purpose of providing represen and esomeprazole; (7) leukotriene antagonists and 5-lipoxy tative examples but not with the purpose of restricting the genase inhibitors such as Zafirlukast, montelukast, pranlukast Scope of the present invention. and Zileuton; (8) drugs used for angina, myocardial ischemia (0195 Preferably a nebivolol metabolite of the present including nitrates such as nitroglycerin and isosorbide invention and the blood pressure reducing agent are admin nitrates, beta blockers such as atenolol, metoprolol, propra istered in the form of Suitable compositions. Said composi nolol, acebutolol, betaxolol, bisoprolol, carteolol, labetalol, tions are meant to also comprise products containing a nebiv nadolol, oXprenolol, penbutolol, pindolol, Sotalol and olol metabolite as defined herein and a blood-pressure timolol, and calcium channel blockers such as diltiazam, reducing agent as a combined preparation for simultaneous, Verapamil, nifedipine, bepridil, felodipine, flunarizine, isra separate, timed-release of either or both components, or dipine, nicardipine and nimodipine; (9) incontinence medi sequential use in blood-pressure reducing therapy. Such prod cations such as antimuscarinics, (e.g., tolterodine and oxybu ucts may, for example, comprise a kit comprising a container tinin); (10) gastrointestinal antispasmodics (such as atropine, with a Suitable composition containing a nebivolol metabolite Scopolamine, dicyclomine, antimuscarinics, as well as diphe of the present invention and another container containing a noxylate); skeletal muscle relaxants (cyclobenzaprine, cari composition with a blood pressure reducing agent. Such a Soprodol, chlorphenesin, chlorZoxazone, metaxalone, metho product may have the advantage that the physician wishing to carbamol, baclofen, dantrolene, diazepam, or orphenadrine); administer blood pressure reducing therapy can select, based (11) gout medications such as allopurinol, probenicid and on the diagnosis of the patient to be treated, the appropriate colchicine; (12) drugs for rheumatoid arthritis Such as meth amounts of both components and the sequence of adminis otrexate, auranofin, aurothioglucose and gold sodium thi tration. omalate; (13) drugs for osteoporosis Such as alendronate and 0196. When administered during the administration of the raloxifene; decongestants such as pseudoephedrine and phe blood pressure reducing agent, a composition containing both nylpropanolamine; (14) local anesthetics; (15) anti-herpes the blood pressure reducing agent and the active ingredient of drugs such as acyclovir, Valacyclovir and famcyclovir, (16) a nebivolol metabolite of the present invention may particu anti-emetics Such as ondansetron and granisetron; (17) larly be convenient. advanced glycosylation end-product crosslink breakers 0.197 Inafurther aspect of the present invention there may (AGE crosslink breakers), for example, alagebrium; and (18) be provided a composition comprising an amount capable of advanced glycosylation end-product formation inhibitors potentiating the effects of blood pressure reducing agents of a (AGE formation inhibitors), for example, pimagebine. nebivolol metabolite of the present invention as defined 0.192 The term "nitric oxide encompasses uncharged herein and a blood pressure reducing agent. In the said com nitric oxide (NO) and charged nitrogen monoxide species, position, the molar ratio between the nebivolol metabolite preferably charged nitrogen monoxide species, such as and the blood pressure reducing agent may be other than nitrosonium ion (NO") and nitroxyl ion (NO). The nitrogen about 1:1, or may be about 1:1. The amount of the active US 2011/0065783 A1 Mar. 17, 2011 26 ingredient of the nebivolol metabolite in such a composition warm-blooded animals in need of blood pressure reducing will be such that a potentiation of the effects of the blood medication, said method comprising administering to said pressure reducing agent is obtained; the amount of the blood warm-blooded animals of an effective amount of a blood pressure reducing agent will be such that when potentiated, a pressure reducing agent and a nebivolol metabolite of the blood pressure reducing effect is obtained upon administra present invention, as defined hereinabove. tion. In particular, it is contemplated that the molar ratio of the 0201 Or alternatively, the present invention concerns a compound of formula (I) to the blood pressure reducing com method of lowering the blood pressure in warm-blooded ani pound may be situated between about 50:1 and about 1:50, in mals suffering therefrom, said method comprising adminis particular between about 20:1 and about 1:20, or between tering to said warm-blooded animals of an effective amount about 10:1 and about 1:10, or between about 5:1 and about of a blood pressure reducing agent and a nebivolol metabolite 1:5, more particularly between about 2:1 and about 1:2. Par as defined hereinabove. ticular such compositions are those wherein the blood pres 0202 Those of skill in treating subjects suffering from an Sure reducing agent is one of the agents pertaining to the increased blood pressure could easily determine the safe and patents cited hereinabove, and more particularly the agents effective amount from the test results presented hereinafter. In specifically mentioned herein. general it is contemplated that an effective daily dose of the 0198 The present invention also provides a composition nebivolol metabolites of the present invention or their phar comprising a pharmaceutically acceptable carrier and, as maceutically acceptable acid-addition salts would be from active ingredient, an amount capable of potentiating the 0.01 mg/kg to 50 mg/kg body weight, in particular from 0.1 effects of blood pressure reducing agents of a nebivolol mg/kg to 10 mg/kg body weight, and preferably from 0.1 metabolite of the present invention or a pharmaceutically mg/kg to 1 mg/kg body weight. acceptable acid-addition salt thereof, as defined herein. Nebivolol Metabolites and Nitric Oxide Release from Nor 0199 To prepare such pharmaceutical compositions, an motensive Black American and White Donors effective amount of the particular compound or compounds, 0203) A higher prevalence of cardiovascular risk factors, in base or acid-addition salt form, as the active ingredient or especially hypertension, has been observed among Black active ingredients is combined in intimate admixture with a Americans in the United States. The increased CVriskamong pharmaceutically acceptable carrier, which carrier may take a Black Americans may be attributed to differences in vascular wide variety of forms depending on the form of preparation physiology, including reduced NO bioavailability. In support desired for administration. These pharmaceutical composi of this concept, a clinical evaluation of brachial artery activity tions are desirably in unitary dosage form suitable, prefer demonstrates reduced responsiveness of conductance vessels ably, for administration orally, rectally or by parenteral injec to both endogenous and exogenous NO in healthy Black tion. For example, in preparing the compositions in oral Americans, as compared with age-matched Whites. The basis dosage form, any of the usual pharmaceutical media may be for this difference is due to the low bioavailability of NO from employed. Such as, for example, water, glycols, oils, alcohols endothelium of Black Americans, despite much higher levels and the like in the case of oral liquid preparations such as of endothelial-dependent NO synthase (eNOS). The cellular Suspensions, syrups, elixirs and solutions; or Solid carriers basis for this paradox is the finding that excessive OT gen Such as starches, Sugars, kaolin, lubricants, binders, disinte eration by NAD(P)H-oxidase and uncoupled eNOS resulted grating agents and the like in the case of powders, pills, in the loss of functional NO due to its reactivity with O. capsules and tablets. Because of their ease in administration, resulting in peroxynitrite (ONOO) formation, a potent oxi tablets and capsules represent the most advantageous oral dant. dosage unit form, in which case Solid pharmaceutical carriers 0204 Six stereoselective hydroxy metabolites signifi are obviously employed. For parenteral compositions, the cantly enhanced NO bioavailability in endothelial cells from carrier will usually comprise Sterile water, at least in large both white and black American donors (FIG. 7). Several part, though other ingredients, for example, to aid solubility, metabolites had NO release activity that was dramatically may be included. Injectable solutions, for example, may be greater than nebivolol, and even 1-nebivolol due to key place prepared in which the carrier comprises saline Solution, glu ments of hydroxyl substituents on the nebivolol molecule. cose solution or a mixture of saline and glucose solution. Thus, steoselective hydroxy metabolites of nebivolol are Injectable Suspensions may also be prepared in which case potent stimulants of NO release from human endothelial appropriate liquid carriers, Suspending agents and the like cells. Also, certain hydroxy metabolites have NO release may be employed. In the compositions suitable for percuta activity that is dramatically greater than nebivolol or 1-nebiv neous administration, the carrier optionally comprises a pen olol due to select hydroxyl substituents. etration enhancing agent and/or a Suitable wetting agent, 0205 Experimental details: Acute treatment with six ste optionally combined with suitable additives of any nature in reoselective hydroxy metabolites in endothelial cells from minor proportions, which additives do not cause a significant both white and black American donors shows that all six deleterious effect to the skin. Said additives may facilitate the hydroxy metabolites have activity that is much superior to administration to the skin and/or may be helpful for preparing d-nebivolol, and most are Superior to nebivolol racemate. As the desired compositions. These compositions may be admin compared to nebivolol, the 4(R)-hydroxy-7-fluoro-6-hy istered in various ways, e.g., as a transdermal patch, as a droxy-l-nebivolol metabolite causes a nearly two-fold spot-on, as an ointment. Acid addition salts of the nebivolol increase in NO release to 476-20 and 383-18 nmol/L, metabolites of the present invention, due to their increased respectively, from white and black donors. The 4(R)-hy water solubility over the corresponding base form, are obvi droxy-5-fluoro-1-nebivolol metabolite also exceeds the activ ously more Suitable in the preparation of aqueous composi ity of nebivolol and evenl-nebivolol by >50%. These findings tions. indicate that hydroxy metabolites of nebivolol have distinct 0200. The present invention also concerns a method of and highly reproducible effects on acute NO release in human potentiating the effects of blood pressure reducing agents in endothelial cells. US 2011/0065783 A1 Mar. 17, 2011 27

electrode system: nanosensor (working electrode), Saturated TABLE 1. calomel electrode (reference electrode) and platinum wire (counter electrode, 0.5 mm diameter). The three electrodes Acute NO Release with Compounds are connected to a potentiostat/galvanostat PAR273. The White Donors Black Donors baseline is stabilized after about 20 seconds. The test com Name NO (nM) NO (nM) pounds are injected with a nanoinjector on to the Surface of 4'(R)-Hydroxy-7-fluoro-6-hydroxy-l- 476 20 383 - 18 the cells following solubilization in buffer. The current pro nebivolol portional to the NO concentration is measured with the sen 4'(R)-Hydroxy-5-fluoro-6-hydroxy-l- 407 - 27 316 - 17 Sor, which operates in amperometric mode at a constant nebivolol potential of 0.63V. Data are acquired with the use of an IBM 4 (S)-Hydroxy-7'-fluoro-6'-hydroxy-l- 272 12 242 - 12 computer with custom Software and amperograms (current nebivolol 5-fluoro-6-hydroxy-l-nebivolol 258. 20 2129 vs. time curves) and are recorded with a Guniry FAS 1 Fem 4'(R)-Hydroxy-l-nebivolol 237 11 194 - 10 tostat (Warminster, Pa.). 4(S)-Hydroxy-l-nebivolol 204 12 1518 0210 Nanosensors are prepared from carbon fibers. The I-nebivolol 268: 12 1929 nebivolol 218 11 148 - 10 size of the tip of carbon fiber is reduced from 6 um to less than d-nebivolol 127, 17 87 6 1 um by temperature controlled burning. The sensors are sensitized to NO by deposition of electrically conductive polymeric porphyrin and covered with a thin layer of Nafion. 0206. In Table 1 and FIG. 7, the comparative effects of The prophyrinic microsensor has a response time of 0.1 ms at nebivolol, d-nebivolol, 1-nebivolol and six stereoselective a micromolar NO concentration and 10 ms at the detection hydroxy metabolites on NO release are shown for cells har limit of 1 nM. vested from white (open bars) and black American (solid 0211. The nanosensor for NO is calibrated using saturated bars) donors. The release of the NO from these endothelial solution (concentration 1.82 mM verified with the coulomet cells was evaluated with electrochemical nanosensors placed ric method). Linear calibration curves are constructed for within close proximity to the cell surface. All six hydroxy each sensor from 5x to 3xNO before and after measurements metabolites have activity that is significantly greater than of cell activity. The data are presented as the mean-SEM for d-nebivolol, and four are superior to nebivolol racemate. As each of the triplicate measurements. The data (calculation and compared to nebivolol, the 4(R)-hydroxy-7-fluoro-6-hy plotting) are transferred to Microcal Origin Software (Orig droxy-l-nebivolol (1689-64A) metabolite causes a nearly inLab Corp., Northampton, Mass.). two-fold increase in NO release to 476-20 and 383-18 nmol/ 0212. The HUVEC preparation is stable over the course of L. respectively, from white and black donors. The 4(R)- these experiments with the cells remaining viable in culture hydroxy-5-fluoro-1-nebivolol metabolite (1689-64B) also for >24 hours. Under non-stimulating conditions, basal levels exceeds the activity of 1-nebivolol by >50%. The metabolite of NO release are very low (<30 nM). Measurement of NO with the least activity is similar to nebivolol. These findings release as a function of treatment is conducted in individual indicate that hydroxy metabolites of nebivolol have distinct endothelial cells. Multiple measurements of NO release can and highly reproducible effects on acute NO release inhuman be conducted on single cells following a brief refractory endothelial cells. period. For robust statistical analysis, separate cells are used Other Pharmacological Examples for each concentration and type of drug used in these analy SCS. 0207 Methods and Materials: Measurements of NO Comparative Effects of Acute Treatment with Nebivolol Release from Human Endothelium Metabolites on NO Release from Human Endothelial Cells 0208 All measurements presented are recorded in vitro 0213. The results of these analyses demonstrate that six using a sensitive porphyrinic probe. NO release is measured metabolites of the B-adrenoceptor-selective antagonist directly from human umbilical vein endothelial cells (HU nebivolol have different effects on NO release from human VEC). HUVEC cells were obtained from American Type endothelial cells over a range of concentrations. FIG. 3 com Culture Collection (Manassas, Va.) and grown in Ham's pares peak NO release from HUVEC preparations for the six F12K medium with 2 mM L-glutamine adjusted to contain metabolites following addition of the agents at a concentra 1.5 g/l sodium bicarbonate and supplemented with 0.1 mg/ml tion of 10 uM. It is apparent from this figure that the metabo heparin and 0.03-0.05 mg/ml endothelial cell growth supple lites have quantitatively different effects on NO release under ment (ECGS)=10% fetal bovine serum. The HUVEC cells identical experimental conditions. At a relatively high con were kept in an atmosphere of elevated CO concentration centration of 10 uM, only one metabolite (4-hydroxy nebiv (5%). Nebivolol, its enantiomers, and nebivolol metabolites olol) produced NO levels that exceed 40004 whereas three of including the nebivolol glucuronides, 4-hydroxy-5' phenol the metabolites (N-DAD, N-DACA and N-DAAA) stimulate metabolite, 4-hydroxy-8-phenol metabolite, 4-hydroxy, less than 90 nM peak NO levels, even at this relatively high 5-hydroxy, 8-hydroxy metabolites, N-DAD, N-DACA and concentration. The remaining two metabolites (5-hydroxy N-DAAA, are obtained from Mylan Laboratories (Morgan and 8-hydroxy nebivolol) have intermediate effects on NO town, W.Va.) release of approximately 220 nMNO at a concentration of 10 0209 All measurements of endothelial NO release are uM. The dihydroxy nebivolol metabolites, including the conducted in Hank's balance solution at 37° C. Cell wells are 4-hydroxy-5'-phenol and 4-hydroxy-8-phenol, as well as transferred to a Faraday cage and a porphyrinic sensor (diam glucuronidated metabolites, are all active in regards to NO eter 0.5 mm) is positioned at a distance of 5+2 um from the releasing capacity. Surface of the endothelial cells using an inverted microscope 0214. The NO releasing effects of certain nebivolol (Leica Microsystems, Wetzler, Germany) and a computer metabolites are then compared directly to acetylcholine, assisted micromanipulator. The sensor operates with a three nebivolol and the nebivolol enantiomers in FIG. 4. These data US 2011/0065783 A1 Mar. 17, 2011 28 show that the metabolite, 4-hydroxy nebivolol, has the great est NO releasing effects compared to nebivolol or its enanti -continued omers. At an identical concentration of 5uM, the release of (9)

NO by 4-hydroxy nebivolol exceeds 400 nM whereas nebiv olol produces approximately a 225 nm level of NO peak release. Interestingly, 4-hydroxy nebivolol demonstrates an NO releasing effect that approximates values measured with acetylcholine, the natural mediator for NO release from the endothelium. The release of endothelial NO following treat ment with either 5-hydroxy or 8-hydroxy nebivolol is similar to that for the parent nebivolol compound and its enantiomers, as shown in FIGS. 1-6. 84. The method of claim 83, wherein the method comprises 0215. In FIG. 6, the most efficacious metabolite, 4-hy administering one or both of the following hydroxylated droxy nebivolol, is compared to the parent nebivolol com metabolites of nebivolol: pound and its enantiomers. Consistent with the previous fig ures, there are significant differences in the relative potency and efficacy of the agents when administered under identical (5)

experimental conditions. Comparing nebivolol and the other metabolites, 4-hydroxy nebivolol exhibits the greatest NO releasing effects over a broad range of drug concentrations with an ECs of 500 nm. Comparing treatment with the parent compound or its enantiomers, significant differences in effi cacy are observed for 4-hydroxy nebivolol at concentrations as low as 500

(10) 1-82. (canceled) 83. A method for treating hypertension in a patient in need thereof, comprising administering to a target site affected by hypertension in said patient one or more of the following hydroxylated metabolites of nebivolol:

(5) 85. The method of claim 83, wherein the method comprises administering one or both of the following hydroxylated metabolites of nebivolol:

(4)

O

(9) US 2011/0065783 A1 Mar. 17, 2011 29

86. The method of claim 83, wherein the method comprises 90. A method for treating hypertension in a patient in need administering the following hydroxylated metabolite of thereof, wherein the method comprises using one or more of nebivolol: the following hydroxylated metabolites of nebivolol:

(5) (5)

87. The method of claim 83, wherein the method comprises administering the following hydroxylated metabolite of nebivolol:

88. The method of claim 83, wherein the method comprises (9) administering the following hydroxylated metabolite of nebivolol:

(4)

91. The method of claim 90, wherein the one or more hydroxylated metabolites of nebivolol includes:

(5) 89. The method of claim 83, wherein the method comprises administering the following hydroxylated metabolite of nebivolol:

(9) (10) US 2011/0065783 A1 Mar. 17, 2011 30

92. The method of claim 90, wherein the one or more 94. The method of claim 90, wherein the one or more hydroxylated metabolites of nebivolol includes: hydroxylated metabolites of nebivolol includes:

(10) (4)

O

95. The method of claim 90, wherein the one or more hydroxylated metabolites of nebivolol includes: (9) (4)

96. The method of claim 90, wherein the one or more 93. Th e meunodthod ofOT claimcla1m 90,9U, Where1nwherein lineth one or more hydroxylated metabolites of nebivolol includes: hydroxylated metabolites of nebivolol includes:

(9)

(5)