US 20070293552A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0293552 A1 Gorczynski (43) Pub. Date: Dec. 20, 2007
(54) ANTIHYPERTENSIVE THERAPY METHOD Publication Classification (76) Inventor: Richard J. Gorczynski, Westminster, (51) Int. Cl. CO (US) A6II 3/42 (2006.01) (52) U.S. Cl...... S14/378 Correspondence Address: (57) ABSTRACT HARNESS, DICKEY, & PIERCE, P.L.C Methods and therapeutic combinations are provided for 7700 BONHOMME, STE 400 lowering blood pressure in a Subject exhibiting resistance to ST. LOUIS, MO 63105 (US) a baseline antihypertensive therapy with one or more drugs, or a subject having diabetes and/or chronic kidney disease. A method of the invention comprises administering, in some (21) Appl. No.: 11/761,499 embodiments adjunctively with a modified baseline therapy, a compound of formula (I) as defined herein. A therapeutic (22) Filed: Jun. 12, 2007 combination of the invention comprises a compound of formula (I); at least one diuretic; and at least one antihy pertensive drug selected from ACE inhibitors, angiotensin II Related U.S. Application Data receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers; wherein the at least one diuretic (60) Provisional application No. 60/813.966, filed on Jun. and/or the at least one antihypertensive drug are present at 15, 2006. substantially less than a full dose. US 2007/0293552 A1 Dec. 20, 2007
ANTHYPERTENSIVE THERAPY METHOD signaling pathways. While antagonism of the ETA receptor is known to reduce endothelin-mediated vasoconstriction, 0001. This application claims the benefit of U.S. provi antagonism of the endothelin-B (ET) receptor can block sional application Ser. No. 60/813,966, filed Jun. 15, 2006, clearance of ET-1 from the circulatory system, exacerbating incorporated in its entirety herein by reference. its hypertensive effect. FIELD OF THE INVENTION 0007 Wu et al. (2004) J. Med. Chem. 47, 1969-1986 presented comparative information on a range of compounds 0002 The present invention relates to methods and thera having varying degrees of affinity and selectivity for ETA peutic combinations useful for lowering blood pressure. and having a general formula (I) that can be represented: BACKGROUND OF THE INVENTION (I) 0003 Blood pressure control can often be achieved by HC RI antihypertensive therapy with one or more drugs. Despite a wide range of drugs available for antihypertensive therapy, a segment of the patient population continues to exhibit ( \ resistance to a baseline antihypertensive therapy with one or Yo NH more drugs. A particularly challenging patient population SO has resistant hypertension. Resistant hypertension is defined 7 R2 by the Seventh Report of the Joint National Committee on Z R3 Prevention, Detection, Evaluation, and Treatment of High S Blood Pressure (JNC 7: Chobanian et al. (2003) Hyperten Sion 42:1206-1252) as a failure to achieve goal blood O pressure in patients who are adhering to full doses of an H3C R4 appropriate three-drug regimen that includes a diuretic. Further, resistant hypertension is diagnosed by many phy sicians on the basis of a patient's resistance to adequate, but where, in certain of the compounds listed: less than full, doses of an appropriate three-drug regimen because of the risk or occurrence of adverse events associ 0008) R' is halo or C alkyl: ated with full doses. The terms "adequate” and “full in the 0009 R is hydrogen, C alkyl, (C. alkyl)carbonyl, present context are defined below. (C. cycloalkyl)carbonyl, cyano, halo, aminocarbonyl, di(C. alkyl)aminocarbonyl, (C- alkyl)sulfonyl, 0004. According to JNC 7, a goal of systolic blood oxazol-2-yl or benzoyl: pressure (SBP) <140 mmHg and diastolic blood pressure (DBP) <90 mmHg is recommended for patients with hyper 0010 R and R are independently hydrogen or C. tension and no other serious conditions. For patients with alkyl, or together form a methylenedioxy bridge; and serious or compelling conditions such as diabetes and chronic kidney disease, JNC 7 recommends a goal of SBP 0011 Z is CH, or NH. <130 mmHg and DBP <80 mmHg. Despite intensive, multi Among the compounds mentioned by Wu et al. are: drug therapy, only about 50% of patients with diabetes or chronic kidney disease reach traditional blood pressure 0012 sitaxsentan (N-(4-chloro-3-methylisoxazol-5- goals, with even fewer reaching the more stringent goals yl)-2-(2-(6-methyl-3,4-methylenedioxy-1-yl)acetyl)th now recommended by JNC 7. Thus, resistant hypertension is iophen-3-sulfonamide), in which R" is chloro, R is particularly acute for segments of the population which hydrogen, R and R form a methylenedioxy bridge, exhibit diabetes or chronic kidney disease. and Z is CH, and 0005. It should be noted that the British Hypertensive 0013 TBC37.11 (N-(2-acetyl-4,6-dimethylphenyl)-3- Society (BHD-IV: J. Human Hypertens. (2004) 18:139 (3,4-dimethylisoxazol-5-ylsulfamoyl)-thiophene-2- 185), the European Society of Hypertension/European Soci carboxamide), in which R" is methyl, R is acetyl, R is ety of Cardiology (ESH/ESC; J. Hypertens. (2003) 21:1011 hydrogen, R is methyl, and Z is NH. 1053), and the World Health Organization/International Wu et al. reported an ETA binding affinity (ICs) of Society of Hypertension (WHO/ISH: J. Hypertens. (2003) 1.4-0.5 nM for sitaxsentan and 0.08-0.02 nM for 21:1983-1992) guidelines propose similar but not identical TBC3711, and an ETAVET selectivity factor of 6.5x blood pressure goals for non-diabetic and diabetic patients. 10 for sitaxsentan and 441x10 for TBC37.11. 0006 Use of various selective endothelin-A (ETA) recep 0014) A clinical trial to test a selective ETA receptor tor antagonists to treat moderate hypertension has been antagonist of a different chemical class, namely darusentan, proposed or tested in clinical trials. Endothelin (more par for treatment of resistant hypertension was proposed in a ticularly the ET-1 isoform thereof) is a small peptide hor Myogen, Inc. news release dated Jul. 15, 2004 (http:// mone that is believed to play a critical role in control of investormyogen.com/phoenix.Zhtml?c=135160&p=iro1 blood flow and cell growth. Elevated endothelin blood levels are associated with several cardiovascular disease condi newsArticle&ID=759464&highlight=), later reported in tions, including pulmonary arterial hypertension, chronic Heart Disease Weekly, Aug. 15, 2004, p. 113. renal disease, coronary artery disease, hypertension, and 0015 New methods for lowering blood pressure continue chronic heart failure. Endothelin is a potent vasoconstrictor, to be much needed in the art. Such new methods would be triggering contraction through endothelin-receptor mediated of value if they afford one or more benefits over existing US 2007/0293552 A1 Dec. 20, 2007 therapies, for example one or more benefits as mentioned below, it being understood that recitation of any particular benefit sought does not limit the present invention to (I) embodiments exhibiting that benefit. HC RI 0016. Improved drug therapies for treatment of patients ( \ exhibiting resistance to a baseline antihypertensive therapy Yo NH with one or more drugs, and especially patients having SO resistant hypertension, would be highly desirable. Resistant 7 R2 hypertension is increasing in prevalence due to a variety of Z R3 contributing factors including an aging population, obesity, S patient noncompliance, and the effects of target-organ dis ease. Thus, a focus of current treatment of resistant hyper O tension is to identify and eliminate contributing factors. Despite reducing contributing factors, a Substantial propor tion of patients with resistant hypertension fail to achieve or a pharmaceutically acceptable salt thereof, where: blood pressure goals. 0024) R' is halo or Cs alkyl: 0017 Furthermore, a baseline antihypertensive therapy, 0025 R is hydrogen, C alkyl, (C. alkyl)carbonyl, whether or not a patient exhibits resistance thereto, can have (C. cycloalkyl)carbonyl, cyano, halo, aminocarbonyl, undesirable, in Some cases clinically unacceptable or even di(C. alkyl)aminocarbonyl, (C- alkyl)sulfonyl, dangerous, adverse side effects, especially when adminis oxazol-2-yl or benzoyl: tered at a full dose of each constituent drug in the therapy. 0026 R and R are independently hydrogen or C. 0018 Thus of particular benefit would be an effective alkyl, or together form a methylenedioxy bridge; and drug therapy for treatment of patients exhibiting resistance 0027 Z is CH or NH; to a baseline antihypertensive therapy with one or more drugs, and especially patients having resistant hypertension, wherein wherein the baseline therapy can be modified in a manner 0028 (a) the baseline therapy is modified by dose that results in a reduced risk or incidence of adverse events. reduction or elimination of at least one of said drugs; 0.019 Ambulatory blood pressure in most patients exhib 0029 (b) the baseline therapy is modified in a manner its a 24-hour cycle wherein both systolic and diastolic blood that results in a reduced risk or incidence of adverse pressures are typically higher during the day than at night. events; and/or Any beneficial change in a patient's 24-hour pattern of 0030) (c) a beneficial change in the subjects 24-hour ambulatory systolic and/or diastolic blood pressure would be pattern of systolic and/or diastolic blood pressure is desirable where the patient exhibits resistance to a baseline obtained. antihypertensive therapy with one or more drugs, and espe A closely related embodiment provides use of a com cially where the patient has resistant hypertension. pound of formula (I) in preparation of a medicament for adjunctive administration to lower blood pressure in a 0020. In patients having resistant hypertension, improved Subject exhibiting resistance to a baseline antihyper renal and/or cardiovascular function, including prevention tensive therapy with one or more drugs; said adjunctive of cardiovascular adverse events, would be of great benefit. administration being with the baseline therapy, which is modified (a) by dose reduction or elimination of at least 0021. As mentioned above, control of hypertension is one of said drugs and/or (b) in a manner that results in especially critical for patients having compelling conditions a reduced risk or incidence of adverse events. Such as diabetes and/or chronic kidney disease. A new drug therapy for lowering blood pressure in Such patients is 0031. There is further provided a method for lowering blood pressure in a Subject having diabetes and/or chronic therefore another important desideratum. kidney disease. The method comprises administering a com pound of formula (I) above or a pharmaceutically acceptable SUMMARY OF THE INVENTION salt thereof to the subject. A closely related embodiment 0022. In various embodiments of the present invention, provides use of a compound of formula (I) in preparation of one or more of the benefits sought above, and/or further a medicament for lowering blood pressure in a subject benefits that will become apparent on reading the detailed having diabetes and/or chronic kidney disease. description that follows, can be realized. 0032. There is still further provided a method for pro viding a beneficial effect on renal and/or cardiovascular 0023. Accordingly, there is now provided a method for function in a subject having resistant hypertension. The lowering blood pressure in a Subject exhibiting resistance to method comprises administering a compound of formula (I) a baseline antihypertensive therapy with one or more drugs. above or a pharmaceutically acceptable salt thereof to the The method comprises administering to the Subject, adjunc subject. A closely related embodiment provides use of a tively with the baseline therapy, a compound of formula (I) compound of formula (I) in preparation of a medicament for US 2007/0293552 A1 Dec. 20, 2007
providing a beneficial effect on renal and/or cardiovascular to measure trough sitting SBP or DBP at around the same function in a Subject having resistant hypertension. time of day for each such measurement, to minimize varia 0033. There is still further provided a therapeutic com tion due to the natural 24-hour blood pressure cycle. bination comprising a compound of formula (I) above or a pharmaceutically acceptable salt thereof, at least one 0040. The course of the 24-hour blood pressure cycle is diuretic, and at least one antihypertensive drug selected from most conveniently tracked by ambulatory blood pressure ACE inhibitors, angiotensin II receptor blockers, beta-adr (ABP) monitoring. energic receptor blockers and calcium channel blockers, wherein the at least one diuretic and/or the at least one 0041 A“24-hour ambulatory” SBP or DBP is an average antihypertensive drug are present at Substantially less than a of measurements taken repeatedly in the course of a 24-hour full dose. period, in an ambulatory Subject. 0034. In the above combination and in all the above 0.042 A“maximum diurnal” SBP or DBP is a measure of methods, the compound of formula (I) is, in a first embodi highest SBP or DBP recorded in a 24-hour period, for ment, sitaxsentan (N-(4-chloro-3-methylisoxazol-5-yl)-2- example by ABP monitoring, and often reflects the peak of (2-(6-methyl-3,4-methylenedioxy-1-yl)acetyl)thiophen-3- the natural 24-hour blood pressure cycle, typically occurring sulfonamide), or, in a second embodiment, TBC3711 (N-(2- in the morning, for example between about 5 am and about acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5- 11 am. Commonly, a second peak occurs in the evening, for ylsulfamoyl)-thiophene-2-carboxamide). example between about 5 pm and 10 pm. Such a bimodal 0035) Other embodiments, including particular aspects of waveform 24-hour ABP pattern may be especially charac the embodiments summarized above, will be evident from teristic of resistant hypertension. the detailed description that follows. 0043. A common feature of resistant hypertension is a DETAILED DESCRIPTION night-time (defined herein as 2200 (10 pm) to 0600 (6 am)) mean systolic ABP that is no lower, or lower by a margin of 0036) Initiation of patient enrollment in a study to evalu less than about 10%, than the daytime (defined herein as ate once-daily oral administration of TBC3711 in patients 0600 to 2200) mean systolic ABP. The parameter herein with resistant hypertension was announced in an Encysive termed “day/night ABP ratio’ expressed as a percentage is Pharmaceuticals news release dated Jan. 9, 2006 (http:// ir.encysive.com/ireye?ir site.Zhtml?ticker=ency&script= calculated from daytime and night-time mean systolic ABP 410&layout=6&item id=801805). More details of this pro using the formula posed study, including inclusion and exclusion criteria, have (daytime mean-night-time mean), daytime meanx100. been posted (http://www.clinicaltrials.gov/ct/show/ NCT00272961?order=1). These disclosures are incorpo A 24-hour ABP pattern having a day/night ABP ratio of less rated herein by reference but no admission is made as to than about 10% is sometimes referred to as a “non-dipping their status as prior art or otherwise with respect to the ABP. present invention. 0044) The term “subject” refers to a warm-blooded ani 0037. In various aspects of the invention, methods are mal, generally a mammal such as, for example, a primate, provided for lowering blood pressure in subjects exhibiting including a human. In one embodiment the Subject is a resistance to a baseline antihypertensive therapy with one or human, for example a patient having clinically diagnosed more drugs, including Subjects having resistant hypertension hypertension. as in the proposed TBC37.11 study referenced above. “Resis tant hypertension' is to be understood herein as resistance at 0045. As indicated above, the subject receiving blood least to adequate doses of an appropriate three-drug antihy pressure lowering (antihypertensive) therapy according to a pertensive regimen that includes a diuretic. Typically resis method of the invention can be a subject exhibiting resis tant hypertension is diagnosed clinically. According to some tance to a baseline antihypertensive therapy with one or of these methods, any one or more measures of blood more drugs. A “baseline antihypertensive therapy' herein pressure can be lowered, including SBP and/or DBP as means a therapeutic regimen comprising administration of determined, for example, by sphygmomanometry. Accord one or more drugs, with an objective (which can be the ing to certain embodiments, as indicated with particularity primary objective or a secondary objective of the regimen) hereinbelow, one or more particular measures of blood of lowering blood pressure in a hypertensive Subject. Each pressure are specified. drug according to the regimen is administered at least at a 0038 SBP and/or DBP can be measured, for example, in dose considered by an attending physician to be adequate for a sitting or ambulatory Subject. treatment of hypertension, taking into account the particular 0039. A “trough sitting SBP or DBP is measured at a Subject's medical condition and tolerance for the drug time point when serum concentration of a drug or drugs without unacceptable adverse side-effects. An "adequate’ administered according to a method of the invention is dose as prescribed by the physician can be less than or equal expected to be at or close to its lowest in a treatment cycle, to a full dose of the drug. A “full dose is the lowest of (a) typically just before administration of a further dose. Illus the highest dose of the drug labeled for a hypertension tratively, where the drug or drugs are administered once a indication; (b) the highest usual dose of the drug prescribed day at a particular time, for example around 8 am, trough according to JNC 7, BHD-IV, ESH/ESC or WHO/ISH sitting SBP or DBP can be measured at that time, immedi guidelines; or (c) the highest tolerated dose of the drug in the ately before the daily administration. It is generally preferred particular Subject. US 2007/0293552 A1 Dec. 20, 2007
0046) A baseline antihypertensive therapy illustratively (CH)"(CH=CH)(CH), comprises administering one or more diuretics and/or one or (CH),C(O)(CH), NH(CH), C=N(OH)(CH), more antihypertensive drugs selected from (a) angiotensin (CH),C(O)(CH=CH)NH(CH), converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers, (c) CH(CH)C(O)(CH), calcium channel blockers, (d) direct vasodilators, (e) alpha CH(CH)C(O)(CH), (CH=CH)(CH), (CH), 1-adrenergic receptor blockers, (f) central alpha-2-adrener (CH),(O) or C(O)O, in which m, s, and rare each gic receptor agonists and other centrally acting antihyper independently an integer from Zero to 6; tensive drugs, (g) aldosterone receptor antagonists, (h) vasopeptidase inhibitors, (i) neutral endopeptidase (NEP) 0.053 R', R. R. R'' and R' are independently inhibitors, () prostanoids, (k) phosphodiesterase type 5 selected from hydrogen, hydroxy, NHR, CONRR, (PDE5) inhibitors, (1) nitrosylated compounds, (m) oral nitro, cyano, halo, alkyl, alkenyl, alkynyl, aryl, ary nitrates and (n) inhibitors of renin activity or release. lalkyl, heteroaryl, alkoxy, alkenyloxy, alkylamino, Optionally drugs of still further classes can be included in alkenylamino, alkylthio, alkenylthio, haloalkyl, the baseline therapy, for example to address secondary alkylsulfinyl, alkenylsulfinyl, alkylsulfonyl, alkenyl conditions occurring in a hypertensive subject or side-effects Sulfonyl, alkylcarbonyl, alkoxycarbonyl, alkylami of one or more of the diuretic or antihypertensive drugs. nocarbonyl, arylaminocarbonyl, aminocarbonyl, 0047 A subject who is “resistant to a baseline antihy (alkylaminocarbonyl)alkyl, carboxyl, carboxyalkyl, pertensive therapy is one in whom hypertension is failing to carboxyalkenyl, alkylsulfonylaminoalkyl, respond adequately or at all to the baseline therapy. Typi cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, cally, the Subject receiving the baseline therapy is failing to alkoxyalkoxy, acetoxyalkoxy, hydroxyalkoxy and reach an established blood pressure goal, as set forth for U.S. formyl groups; or at least two of R', R', R', R'' patients, for example, in JNC 7 or comparable standards in and R', which substitute adjacent carbons on the other countries (e.g., BHD-IV. ESH/ESC or WHO/ISH ring, together form an alkylenedioxy, alkyleneth guidelines). Illustratively, the JNC 7 goal for SBP is <140 ioxyoxy or alkylenedithioxybridge, which is option mmHg and for DBP <90 mmHg, or for a subject having a ally substituted with halo, alkyl, alkoxy or haloalkyl complicating condition Such as diabetes and/or chronic groups, and the others of R'', R. R. R'' and R' kidney disease, <130 mmHg SBP and <80 mmHg DBP. are independently selected as above; where, in NHR 0.048. The compound administered according to the and CONRR groups, Rand Rare independently methods of the present invention is an endothelin receptor selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, antagonist, preferably a selective ETA receptor antagonist, haloalkyl, alkylaryl, heterocyclyl, arylalkyl, aryla for example one having an ICso for ETA not greater than lkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and about 10 nM, e.g., not greater than about 5 nM or not greater cycloalkynyl; and than about 2 nM, and/or an ETAVET selectivity factor of at least about 100, e.g., at least about 500 or at least about 0054 X is O, N or S; 1OOO. in which alkyl or acyl portions comprise 1 to about 12, 0049. The compound is a member of a class of endothelin for example 1 to about 6, carbon atoms and alkenyl receptor antagonists having the formula (II) or alkynyl portions comprise 2 to about 12, for example 2 to about 6, carbon atoms, and can form Ar’ SO. NH-Air' (II) straight or branched chains; and cycloalkyl, or a pharmaceutically acceptable salt thereof, where: cycloalkenyl and cycloalkynyl portions comprise 3 0050 Ar' is a monocyclic or polycyclic heteroaryl to about 12, for example 3 to about 6, carbon atoms. moiety, unsubstituted or substituted with one or more Substituents independently selected from amino, halo, 0055. In a compound of formula (II) where Z is alkyl, acyl, aryl, heteroaryl, alkoxyalkyl, alkylamino, (CH),C(O)NH(CH), at least two of R'', R', R', R' alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio. and R' are other than hydrogen. haloalkyl, haloaryl and carbonyl groups; 0056 Illustratively, the compound administered can have 0051) Ar is a moiety formula (II) where 0057) Ar' is a monocyclic 5-membered ring having 1 to 3 heteroatoms in the ring, at least one of which is N. and is unsubstituted or substituted with one or more halo or alkyl, (e.g., C alkyl) substituents; 0058 Z' is (CH),C(O)(CH), for example where m is zero and r is 1, C(O)CH; or (CH),C(O)NH(CH), R 14 for example where m and rare each Zero, C(O)NH; and 0059) X is S. where: 0060 Such compounds and processes for their prepara 0052 Z' is a linking group (CH),C(O)(CH), tion are disclosed, for example in U.S. Pat. No. 6,248,767 to (CH),C(O)NH(CH), CH(OH)(CH), Blok et al., incorporated herein by reference. US 2007/0293552 A1 Dec. 20, 2007
0061 The invention is described herein with particular reference to a compound of formula (I) HC CH3 (I) O a f H3C RI Osilsy- - HN O-N ( \ Yo NH W \ N CH3 SO S / R2 O S Z R3 H3C CH3. O HC R4 0068 Processes for preparing the above compounds are found, for example, in Wu et al. (2004) J. Med. Chem. 47. or a pharmaceutically acceptable salt thereof, where: 1969-1986, incorporated by reference herein. 0069. The invention is not limited to any route of admin 0062) R' is halo or C alkyl: istration of the compound of formula (I), so long as the route 0063 R’ is hydrogen, C, alkyl, (C- alkyl)carbonyl, selected results in effective delivery of the drug so that a (C. cycloalkyl)carbonyl, cyano, halo, aminocarbonyl, benefit is obtainable. Thus administration of the compound di(C. alkyl)aminocarbonyl, (C. alkyl)sulfonyl, of formula (I) can illustratively be parenteral (e.g., intrave nous, intraperitoneal, Subcutaneous or intradermal), trans oxazol-2-yl or benzoyl; dermal, transmucosal (e.g., buccal, Sublingual or intranasal), 0064) R and R are independently hydrogen or Cs intraocular, intrapulmonary (e.g., by inhalation) or rectal. alkyl, or together form a methylenedioxy bridge; and Most conveniently for the majority of subjects, however, the compound of formula (I) is administered orally, i.e., per os 0065 Z is CH, or NH. (p.o.). Any Suitable orally deliverable dosage form can be used for the compound of formula (I), including without 0066. In one embodiment, in the compound of formula limitation tablets, capsules (solid- or liquid-filled), powders, (I), R is C alkyl; R is hydrogen or C alkyl; R and R' granules, syrups and other liquids, etc. are independently hydrogen or C alkyl, or together form 0070 For oral administration, any dose of the compound a methylenedioxy bridge; and Z is CH or NH. of formula (I) that is therapeutically effective, up to a maximum that is tolerated by the Subject without unaccept 0067. According to this embodiment, the compound can able adverse side effects, can be administered. Illustratively, illustratively be sitaxsentan or TBC37.11. Sitaxsentan (N-(4- in the case of TBC3711, such a dose for most subjects is chloro-3-methylisoxazol-5-yl)-2-(2-(6-methyl-3,4-methyl likely to be about 1 to about 600 mg/day, for example about enedioxy-1-yl)acetyl)thiophen-3-sulfonamide) has formula 10 to about 200 mg/day. Higher or lower doses can be useful (I) where R' is chloro, R is hydrogen, R and R form a in specific circumstances. methylenedioxy bridge, and Z is CH, and can be repre 0071. The prescribed daily dosage amount can be admin sented as istered in any suitable number of individual doses, for example four times, three times, twice or once a day. With
a dosage form having appropriate controlled release prop erties, a lower frequency of administration may be possible, for example once every two days, once a week, etc. 0072 Most antihypertensive medicines are suitable for once a day administration, and, where the compound of formula (I) is likewise suitable for once a day administra tion, it is generally most convenient to administer the compound of formula (I) once a day, for example orally in a dose as indicated above for TBC37.11 or, for another compound, a dose providing equivalent therapeutic efficacy. This is particularly true in those embodiments of the inven tion wherein the compound of formula (I) is administered and TBC3711 (N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4- adjunctively with other antihypertensive drugs, for example dimethylisoxazol-5-ylsulfamoyl)-thiophene-2-carboxam in a modified baseline therapy. ide) has formula (I) where R is methyl, R is acetyl, R is 0073 Subjects resistant to a baseline antihypertensive hydrogen, R is methyl, and Z is NH, and can be represented therapy, especially such a therapy involving a plurality of aS drugs, clearly represent a very challenging population for US 2007/0293552 A1 Dec. 20, 2007
treatment. Typically in Such subjects, increasing dosages of blockers are associated with increased risk of broncho the baseline therapy are not an option because of resulting spasm, bradycardia, heart block, excess negative inotropic adverse side effects; furthermore this approach is often effect, peripheral arterial insufficiency and sometimes male ineffective in providing a desired lowering of blood pres impotence. Calcium channel blockers are associated with Sure. Accordingly, in various embodiments of the present increased risk of lower limb edema. Aldosterone receptor invention, a method for lowering blood pressure in a subject antagonists can cause gynecomastia. Further information on exhibiting resistance to a baseline antihypertensive therapy adverse events associated with antihypertensive drugs can with one or more drugs comprises administering to the be found, for example, in standard reference works such as Subject, adjunctively with the baseline therapy, a compound Goodman & Gilman's The Pharmaceutical Basis of Thera of formula (I) above or a pharmaceutically acceptable salt peutics, 13th ed. (Brunton et al., eds. (2006), New York: thereof, wherein the baseline therapy is modified (a) by dose McGraw Hill). reduction or elimination of at least one of said drugs; and/or 0079. In the method of the present embodiment, the (b) in a manner that results in a reduced risk or incidence of compound of formula (I) is illustratively administered adverse events. “Modified herein means by comparison adjunctively with a modified baseline therapy that comprises with the baseline therapy to which the subject has exhibited administration of one or more diuretics and/or one or more resistance. antihypertensive drugs selected from (a) ACE inhibitors and 0074. In one such embodiment, the adjunctively admin angiotensin II receptor blockers, (b) beta-adrenergic recep istered baseline therapy is modified by dose reduction or tor blockers, (c) calcium channel blockers, (d) direct vasodi elimination of at least one of said drugs. lators, (e) alpha-1-adrenergic receptor blockers, (f) central 0075 Dose reduction according to the present embodi alpha-2-adrenergic receptor agonists and other centrally ment can comprise any degree of dose reduction resulting in acting antihypertensive drugs, (g) aldosterone receptor a dose that is substantially less than a full dose as defined antagonists, (h) vasopeptidase inhibitors, (i) NEP inhibitors, above. In many situations the reduced dose can be substan () prostanoids, (k) PDE5 inhibitors, (1) nitrosylated com tially less than the dose of the drug previously used in the pounds, (m) oral nitrates and (n) inhibitors of renin activity baseline therapy to which the subject has exhibited resis and release. tance, even where such dose was less than a full dose. For 0080) “Adjunctive' administration of a compound of example, without limitation, a dose of one or more drugs in formula (I) herein means that the compound of formula (I) the baseline therapy can be reduced by at least about 10%, is administered concomitantly with one or more additional at least about 25%, or at least about 50%, and can be reduced drugs, in the present instance one or more drugs constituting by as much as about 75% or more, by comparison with a full a modified baseline therapy. For example, a compound of dose. Alternatively or in addition, at least one drug in the formula (I) can be administered adjunctively with an baseline therapy can be eliminated in its entirety. adequate to full dose of one or more of the drugs in the 0.076 Dose reduction or elimination of a baseline therapy baseline therapy, while the other one or more drugs in the drug permitted by use of a compound of formula (I) can baseline therapy are administered at reduced dose or elimi result in a reduced risk or incidence of adverse events by nated. comparison with the baseline therapy alone without Such 0081. The method of the present embodiment, in com dose reduction or elimination. Accordingly, in one aspect of mon with methods of other embodiments described herein, the present method, a reduced risk or incidence of adverse can be especially beneficial where the subject has resistant events is obtained by comparison with the baseline therapy hypertension. By definition herein, in general accordance alone without said dose reduction or elimination. with JNC 7, such a subject exhibits resistance to an antihy 0.077 Particularly when used at a full dose, many base pertensive regimen of at least three drugs including a line antihypertensive therapy drugs can have undesirable, in diuretic. In one embodiment, the Subject having resistant Some cases clinically unacceptable or even dangerous, hypertension exhibits resistance to a baseline antihyperten adverse side effects. For example, especially at full doses, sive therapy that comprises at least the following: potassium-sparing diuretic drugs can be associated with increased risk of hyperkalemia and related disorders. Over 0082 (1) one or more diuretics; and use of loop diuretics can cause depletion of sodium resulting in hyponatremia and/or extracellular fluid volume depletion 0083 (2) two or more antihypertensive drugs, selected associated with hypotension, reduced GFR (glomerular fil from at least two of the following classes: tration rate), circulatory collapse, and thromboembolic epi 0084 (a) ACE inhibitors and angiotensin II receptor sodes. Further, loop diuretics can cause ototoxicity that blockers; results in tinnitus, hearing impairment, deafness and/or vertigo. Thiazide diuretics, similarly to loop diuretics, can 0085 (b) beta-adrenergic receptor blockers; and have adverse effects related to abnormalities of fluid and electrolyte balance. Such adverse events include extracellu 0086) (c) calcium channel blockers. lar Volume depletion, hypotension, hypokalemia, hyponatre 0087. In some cases, the subject is resistant to an even mia, hypochloremia, metabolic alkalosis, hypomagnesemia, more comprehensive baseline therapy, further comprising, hypercalcemia and hyperuricemia. Thiazide diuretics can for example, one or more direct vasodilators, alpha-1- also decrease glucose tolerance, and increase plasma levels adrenergic blockers, central alpha-2-adrenergic agonists or of LDL (low density lipoprotein) cholesterol, total choles other centrally acting antihypertensive drugs, aldosterone terol, and total triglycerides. receptor antagonists, vasopeptidase inhibitors, NEP inhibi 0078 ACE inhibitors are associated with cough and tors, prostanoids, PDE5 inhibitors, nitrosylated compounds, increased risk of angioedema. Beta-adrenergic receptor oral nitrates and/or inhibitors of renin activity or release. US 2007/0293552 A1 Dec. 20, 2007
0088. In one aspect of the present embodiment, the levels consistent with good management of these conditions, compound of formula (I) is administered at a dose and the method of the present embodiment can be especially frequency effective, in combination with the modified base beneficial for such subjects. line therapy, to provide a reduction of at least about 3 mmHg 0097. In another embodiment of the invention, a method in one or more blood pressure parameters selected from for lowering blood pressure in a Subject exhibiting resistance trough sitting SBP trough sitting DBP. 24-hour ambulatory to a baseline antihypertensive therapy with one or more SBP. 24-hour ambulatory DBP, maximum diurnal SBP and drugs comprises administering to the Subject, adjunctively maximum diurnal DBP. with the baseline therapy, a compound of formula (I) above 0089. In a particular aspect, the subject has resistant or a pharmaceutically acceptable salt thereof, wherein the systolic hypertension, and the dose and frequency of admin baseline therapy is modified in a manner that results in a istration of the compound of formula (I) is effective in reduced risk or incidence of adverse events. combination with the modified baseline therapy to provide a 0098. Examples of modifications of the baseline therapy reduction of at least about 3 mmHg in one or more of trough which can result in a reduced risk or incidence of adverse sitting, 24-hour ambulatory and maximum diurnal SBP. events include, without limitation, dose reduction, elimina 0090. In a further particular aspect, the at least about 3 tion, split-dose administration, controlled release formula mmHg reduction is observed in trough sitting SBP and at tion, and/or selection of a non-peroral route of administra least comparable reductions can be, but are not necessarily, tion of at least one of the drugs in the baseline therapy. observable in 24-hour ambulatory and/or maximum diurnal Another Such modification comprises administering differ SBP. In some cases the method is effective to provide a ent drugs in the baseline therapy at different times of day greater reduction in trough sitting SBP, for example at least instead of all at about the same time, a mode of adminis about 5 mmHg, at least about 7 mmHg or at least about 10 tration termed “non-simultaneous' herein. The term “split mmHg. dose administration' means increasing the frequency of administration of a drug, for example from once to twice a 0.091 The present method can increase the likelihood of day, without increasing the total daily dose of the drug. a subject achieving SBP goal, for example a JNC 7, BHD 0099 Variants and illustrative modalities of the method IV, ESH/ESC or WHO/ISH goal for SBP. Thus in a still of this embodiment, for example selection of a compound of further particular aspect, a JNC 7 goal for SBP is achieved, formula (I), the baseline therapy employed, routes of admin for example a trough sitting or 24-hour ambulatory SBP of istration, dosages, durations of treatment, frequency of <140 mmHg or, in the case of a subject with diabetes or administration, formulations of the compound of formula (I) chronic kidney disease, <130 mmHg. and particular blood pressure benefits provided, are as 0092. In another particular aspect, the subject has resis described hereinabove. tant diastolic hypertension, and the dose and frequency of 0100. In yet another embodiment of the invention, a administration of the compound of formula (I) is effective in method for lowering blood pressure in a subject exhibiting combination with the modified baseline therapy to provide a resistance to a baseline antihypertensive therapy with one or reduction of at least about 3 mmHg in one or more of trough more drugs comprises administering to the Subject, adjunc sitting, 24-hour ambulatory and maximum diurnal DBP. tively with the baseline therapy, a compound of formula (I), 0093. In a further particular aspect, the at least about 3 wherein a beneficial change in the Subject's 24-hour pattern mmHg reduction is observed in trough sitting DBP, and at of SBP and/or DBP is obtained. According to this embodi least comparable reductions can be, but are not necessarily, ment, the adjunctively administered baseline therapy can be observable in 24-hour ambulatory and/or maximum diurnal unmodified but is optionally modified (a) by dose reduction DBP. In some cases the method is effective to provide a or elimination of at least one of said drugs and/or (b) in a greater reduction in trough sitting DBP. for example at least manner that results in a reduced risk or incidence of adverse about 5 mmHg, at least about 7 mmHg or at least about 10 eVentS. mmHg. 0101 The term “24-hour pattern” in relation to a blood pressure parameter such as SBP or DBP refers to a cycle in 0094. The present method can increase the likelihood of that parameter that recurs approximately daily, for example a subject achieving DBP goal, for example a JNC 7, BHD reflecting underlying endogenous circadian rhythms and/or IV, ESH/ESC or WHO/ISH goal for DBP. Thus in a still blood levels of one or more drugs administered in an further particular aspect, a JNC 7 goal for DBP is achieved, antihypertensive regimen. For example, increases, for example a trough sitting or 24-hour ambulatory DBP of decreases, maxima and minima of blood pressure that typi <90 mmHg or, in the case of a subject with diabetes or cally occur each day or night around the same time or times chronic kidney disease, <80 mmHg. are aspects of the 24-hour pattern. Further aspects include 0.095. In yet another aspect, the method of the present SBP or DBP measured at a specific time in relation to the embodiment is effective to provide a beneficial change in the timing of administration of an antihypertensive drug, for subject's 24-hour pattern of SBP and/or DBP. The kinds of example a compound of formula (I). Illustratively, SBP or beneficial change that can be provided are more fully DBP measured shortly before the regular time of adminis described hereinbelow. tration is referred to as “trough' SBP or DBP, being mea Sured at a time when levels of the drug circulating in the 0096. Because of the particular criticality of controlling bloodstream are assumed to be at their lowest. Thus, as blood pressure in Subjects with complicating conditions explained above, where the drug is administered once daily Such as diabetes and/or chronic kidney disease, and the at around 8 am, the trough SBP or DBP relates to a blood greater difficulty of lowering blood pressure to the lower pressure measurement taken shortly before 8 am on any day. US 2007/0293552 A1 Dec. 20, 2007
Blood pressure measurements can be recorded in a sitting or stood, except where the context demands otherwise, to reclining Subject. In one embodiment, however, 24-hour include pharmaceutically acceptable salts, esters, prodrugs, pattern and effects of an antihypertensive regimen thereon metabolites, racemates and enantiomers of the drug, to the are established for an ambulatory subject by ABP monitor extent that Such salts, esters, prodrugs, metabolites, race 1ng. mates or enantiomers exist and are therapeutically effective. 0102) Examples of beneficial changes in aspects of the 0116 Examples of drugs useful in combination or 24-hour blood pressure pattern include without limitation adjunctive therapy with a compound of formula (I) or as a component of a baseline antihypertensive therapy are clas 0.103 (a) lowering of 24-hour mean ABP: sified and presented in several lists below. Some drugs are 0.104 (b) lowering of trough sitting SBP: active at more than one target; accordingly certain drugs may appear in more than one list. Use of any listed drug in 0105 (c) lowering of trough sitting DBP: a combination or adjunctive therapy of the invention is 0106 (d) lowering of diurnal maximum ABP; contemplated herein, independently of its mode of action. 0.107 (e) trend away from a bimodal waveform pattern 0.117) A suitable diuretic can illustratively be selected towards a unimodal or less pronouncedly bimodal from the following list. pattern consistent with normotensive Subjects; 0118 Organomercurials 0.108 (f) increase in day/night ABP ratio; and 0119) chlormerodrin 0.109 (g) at least about 10% nocturnal dipping of ABP. 0120 meralluride 0110. In one such aspect, the method of the present 0121 mercaptomerin sodium embodiment is effective to increase day/night ABP ratio, for example from a baseline below about 10% to greater than 0.122 mercumatilin sodium 10%. Day/night ABP ratio can illustratively be increased by 0123 mercurous chloride at least about 2, for example at least about 3 or at least about 5 percentage points. 0.124 mersalyl 0111. In another aspect, the method of the present 0.125 Purines embodiment is effective to lower blood pressure in all phases 0126 pamabrom of a 24-hour blood pressure cycle, for example as measured 0127 protheobromine by ABP monitoring at a suitable interval, e.g., hourly. According to this aspect, the 24-hour blood pressure cycle 0128 theobromine can exhibit a bimodal waveform pattern both at baseline and when treated with a compound of formula (I) according to 0129. Steroids the present method, but treatment with the compound of 0130 canrenone formula (I) in combination with the baseline therapy shifts 0131 eplerenone the waveform pattern downward. 0112 The method of the present embodiment optionally 0132) oleandrin permits dose reduction or elimination of at least one of the 0.133 spironolactone drugs in the baseline therapy, and/or optionally results in a reduced risk or incidence of adverse events when the base 0134) Sulfonamide Derivatives line therapy is modified as described above, by comparison 0135) acetazolamide with the unmodified baseline therapy alone. 0.136 ambuside 0113 Variants and illustrative modalities of the method of this embodiment, for example selection of a compound of 0137) azosemide formula (I), the baseline therapy employed, routes of admin 0138 bumetanide istration, dosages, durations of treatment, frequency of administration, and formulations of the compound of for 0139 butazolamide mula (I) are as described hereinabove. 0140 chloraminophenamide 0114. In the embodiments described above, the com 0.141 clofenamide pound of formula (I) is administered adjunctively with a baseline antihypertensive therapy comprising administration 0.142 clopamide of one or more additional drugs. Each of these additional 0143 clorexolone drugs can be administered at a full, adequate or reduced dose. One of skill in the art can readily identify a suitable full 0.144 disulfamide dose for any particular drug mentioned here from publicly 0145 ethoxzolamide available information in printed or electronic form, for example on the internet, and can, if desired, reduce the dose 0146 furosemide in accordance with certain embodiments of the present invention based on the disclosure herein. 0147 mefruside 0115 Mention of a particular diuretic or antihypertensive 0.148 methazolamide drug in the present specification and claims will be under 0149 piretamide US 2007/0293552 A1 Dec. 20, 2007
O150 torsemide 0.192 In some embodiments, the diuretic comprises a thiazide or loop diuretic. Thiazide diuretics are generally not 0151) tripamide preferred where the Subject has a complicating condition 0152) Xipamide Such as diabetes or chronic kidney disease, and in Such 0153. Thiazides and Analogs situations a loop diuretic can be a better choice. 0193 Particularly suitable thiazide diuretics include 0154) althiazide chlorothiazide, chlorthalidone, hydrochlorothiazide, indapa O155) bendroflumethiazide mide, metolaZone, polythiazide and combinations thereof. Particularly suitable loop diuretics include bumetanide, 0156) benzthiazide furosemide, torsemide and combinations thereof. O157) benzylhydrochlorothiazide 0.194. A suitable ACE inhibitor can illustratively be 0158 buthiazide selected from the following list: 0159) chlorothiazide 0.195 alacepril 0160 chlorthalidone 0196) benazepril 0161) cyclopenthiazide 0197) captopril 0162 cyclothiazide 0198 ceronapril 0163) ethiazide 0199 cilazapril 0164) fenduizone 0200 delapril 01.65 hydrochlorothiazide 0201 enalapril 0166) hydroflumethiazide 0202) enalaprilat 0167) indapamide 0203 eosinopril 01.68 methyclothiazide 0204 fosinopril 0169 metolaZone 0205) imidapril 0170) paraflutizide 0206 lisinopril 0171 polythiazide 0207 moexipril 0172 quinethaZone 0208 moveltipril 0173 teclothiazide 0209 omapatrilat 0174) trichlormethiazide 0210 perindopril 0175 Uracils 0211 quinapril 0176) aminometradine 0212 ramipril 0177 Unclassified 0213 sampatrilat 0178) amiloride 0214 spirapril 0179 Biogen BG 9719 0215 temocapril 0180 chlorazanil 0216 trandolapril 0181 ethacrynic acid 0217 Particularly suitable ACE inhibitors include 0182 etozolin benazepril, captopril, enalapril, fosinopril, lisinopril, moex ipril, perindopril, quinapril, ramipril, trandolapril and com 0183) isosorbide binations thereof. 0184 Kiowa Hakko KW 3902 0218. A suitable angiotensin II receptor blocker can illus 0185 mannitol tratively be selected from the following list: 0186 muZolimine 0219 candesartan 0187) perhexiline 0220 eprosartan 0188) Sanofi-Aventis SR 121463 0221) irbesartan 0189) ticrynafen 0222 losartan 0.190) triamterene 0223) olmesartan 0191) la 0224 tasosartan US 2007/0293552 A1 Dec. 20, 2007 10
0225) telmisartan 0267 nifenalol 0226 Valsartan 0268) nipradillol 0227. A suitable beta-adrenergic receptor blocker can 0269 oxprenolol illustratively be selected from the following list: 0270 penbutolol 0228 AC 623 0271 pindolol 0229) acebutolol 0272 practolol 0230) alprenolol 0273 pronethalol 0231 atenolol 0274 propranolol 0232) amosulalol 0275 sotalol 0233) arotinolol 0276) sulfinalol 0234 atenolol 0277) talinolol 0235) befunolol 0278 tertatolol 0236 betaxolol 0279 tilisolol 0237) bevantolol 0280 timolol 0238 bisoprolol 0281 toliprolol bopindolol 0239) 0282 xibenolol 0240) bucindolol 0283 Particularly suitable beta-adrenergic receptor 0241) bucumolol blockers include acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, penbutolol, pin 0242 bufetolol dolol, propranolol, timolol and combinations thereof. 0243) bufuralol 0284. A suitable calcium channel blocker can illustra 0244) bunitrolol tively be selected from the following list: 0245) bupranolol 0285) Aryklalkylamines 0246 butidrine hydrochloride 0286 bepridil 0247 butofilolol 0287) clentiazem 0248 carazolol 0288 diltiazem 0249 carteolol 0289 fendiline 0250) carvedilol 0290 gallopamil 0251) celiprolol 0291 mibefradil 0252) cetamolol 0292 prenylamine 0253) cloranolol 0293 semotiadil 0254) dilevalol 0294 terodiline 0255 esmolol 0295 verapamil 0256 indenolol 0296) Dihydropyridine Derivatives 0257) labetalol 0297 amlodipine 0258 landiolol 0298 aranidipine 0259 levobunolol 0299 barnidipine 0260) mepindolol 0300 benidipine 0261) metipranolol 0301 cilnidipine 0262) metoprolol 0302) efonidipine 0263 moprolol 0303 elgodipine 0264) nadolol 0304 felodipine 0265 nadoxolol 0305) isradipine 0266 nebivolol 0306 lacidipine US 2007/0293552 A1 Dec. 20, 2007 11
0307 lercanidipine 0347 isosorbide dinitrate 0308 manidipine 0348 isosorbide mononitrate 0309 micardipine 0349 itramin tosylate 0310 nifedipine 0350 khellin 0311 nilvadipine 0351 lidoflazine 0312 nimodipine 0352 mannitol hexanitrate 0313 nisoldipine 0353 minoxidil 0314 nitrendipine 0354 nitroglycerin 0315) NZ 105 0355 pentaerythritol tetranitrate 0316 Piperazine Derivatives 0356 pentrinitrol 0317 cinnarizine 0357 perhexiline 0318 dotarizine 0358 pimefylline 0319 flunarizine 0359 prenylamine 0320 lidoflazine 0360 propatyl nitrate 0321) lomerizine 0361 trapidil 0322 Unclassified 0362 tricromyl 0323 bencyclane 0363 trimetazidine 0324) etafenone 0364 trolnitrate phosphate 0325 fantofarone 0365 visnadine 0326 monatepil 0366 Particularly suitable direct vasodilators include 0327 perhexiline hydralazine, minoxidil and combinations thereof. 0328 Particularly suitable calcium channel blockers (0367 A suitable alpha-1-adrenergic receptor blocker can include amlodipine, diltiazem, felodipine, isradipine, nicar- illustratively be selected from the following list: spinnifedipine nisoldipine, Verapamil and combinations 0368 amosulalol 0329. A suitable direct vasodilator can illustratively be 0369 arotinolol selected from the following list: 0370 carvedilol 0330 amotriphene 0371 dapiprazole 0331 benfurodil hemisuccinate 0372 doxazosin 0332 benziodarone 0373 ergoloid mesylates 0333) chloracizine 0374 fenspiride 0334 chromonar 0375) idazoxan 0335) clobenfurol 0376 indoramin 0336 clonitrate 0377 labetalol 0337 cloricromen 0378 methyldopa 0338 dilazep 0379 monatepil 0339) droprenilamine 0380 naftopidil 0340 efloxate 0381 nicergoline 0341 erythrity1 tetranitrate 0382 prazosin 0342 etafenone 0383 tamsulosin 0343 fendiline 0384 terazosin 0344 hexestrol bis(B-diethylaminoethyl ether) 0385) tolazoline 0345 hexobendine 0386 trimazosin 0346) hydralazine 0387 yohimbine US 2007/0293552 A1 Dec. 20, 2007
0388 Particularly suitable alpha-1-adrenergic receptor 0423 Illustrative PDE5 Inhibitors Include: blockers include carvedilol, doxazosin, labetalol, praZosin, teraZosin and combinations thereof. It is noted that, of these, 0424 sildenafil carvedilol and labetalol also function as beta-adrenergic 0425 tadalafil receptor blockers. 0426 vardenafil 0389. A suitable central alpha-2-adrenergic receptor ago nist or other centrally acting antihypertensive drug can 0427. Inhibitors of Renin Activity or Release Include illustratively be selected from the following list: Renin Inhibitors, Illustratively: aliskiren 0390) clonidine 0428 0429 ciprokiren 0391) guanabenz 0430) ditekiren 0392) guanadrel 0431 enalkiren guanfacine 0393) 0432) remikiren methyldopa 0394) 0433 terlakiren 0395) moXonidine 0434 Zankiren 0396) reserpine 0435 The term “renin inhibitor herein means an inhibi 0397 A suitable aldosterone receptor antagonist can tor of the enzymatic activity of renin. A particularly suitable illustratively be selected from the following list: renin inhibitor is aliskiren. 0436. Other drugs that can be useful in combination or 0398) CaO. adjunctive therapy with a compound of formula (I) or in a 0399) eplerenone baseline antihypertensive therapy can illustratively be selected from the following unclassified list: 04.00 spironolactone 0437 ajmaline Illustrative Vasopeptidase Inhibitors Include: 0401) 0438) alfuzosin 0402 fasidotril 0439) Alteon ALT 711 0403) omapatrilat 0440 y-aminobutyric acid 04.04 Sampatrilat 0441 atrial natriuretic peptide 04.05 Illustrative NEP Inhibitors, Some of which are Also 0442 aZelnidipine ACE Inhibitors, Include: 0443) bethanidine 0406) candoxatril 0444 bietaserpine 0407) CGS 26582 0445) bosentan 04.08 MDL 100173 0446 budralazine 04.09 omapatrilat 0447) bufeniode 0410 phosphoramidon 0448 bunaZosin 0411 sinorphan 0449) cadralazine carmoxirole 0412 thiorphan 0450 0451 CD 3400 0413 Z13752A 0452 chlorisondamine chloride 0414 Illustrative Prostanoids Include: 0453 cicletanine 0415) beraprost 0454) ciclosidomine cicaprost 0416) 0455) clevidipine epoprostenol 0417 0456) debrisoquin 0418) iloprost 0457) denitronipradillol 0419 PGE 0458 desacetylalacepril 0420 PGI2 (prostacyclin) 0459) deserpidine 0421) NS-304 0460) diazoxide 0422 treprostinil 0461) dihydralazine US 2007/0293552 A1 Dec. 20, 2007 13
0462 endralazine 0502 todralazine 0463 fenoldopam 0503 tolonidine 0464 flosequinan 0504 trimethaphan camsylate 0465 guanethidine 0505) tyrosinase 0466 guanidine, N-cyano-N'-4-pyridinyl-N'-(1.2.2- 0506 urapidil trimethylpropyl)-, monohydrate 0507 Zofenopril 0467 guanoxabenz 0508. In one embodiment, the compound of formula (I) is 0468 guanoxan administered concomitantly (e.g., in combination or adjunc 0469 hexamethonium tive therapy) with one or more of 0509 (a) a diuretic selected from the group consisting 0470 ketanserin of chlorothiazide, chlorthalidone, hydrochlorothiazide, 0471) LBI 45 indapamide, metolaZone, polythiazide, bumetanide, 0472 levcromakalim furosemide, torsemide and combinations thereof; 0510 (b) an ACE inhibitor selected from the group 0473 lofexidine consisting of benazepril, captopril, enalapril, fosinopril, 0474 magnesiocard lisinopril, moexipril, perindopril, quinapril, ramipril, 0475 mebutamate trandolapril and combinations thereof, and/or an angio tensin II receptor blocker selected from the group 0476 mecamylamine consisting of candesartan, eprosartan, irbesartan, losa 0477 normopresil rtan, olmesartan, tasosartan, telmisartan, Valsartan and combinations thereof; 0478) 2-oxazolamine, N-(dicyclopropylmethyl)-4,5- dihydro-, (2E)-2-butenedioate 0511 (c) a beta-adrenergic receptor blocker selected from the group consisting of acebutolol, atenolol, 0479 pargyline betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, 0480 pempidine nadolol, penbutolol, pindolol, propranolol, timolol and combinations thereof; 0481 pentamethonium bromide 0512 (d) a calcium channel blocker selected from the 0482 pentolinium tartrate group consisting of amlodipine, diltiazem, felodipine, 0483 pheniprazine isradipine, nicardipine, nifedipine, nisoldipine, Vera 0484 phentolamine pamil and combinations thereof; 0513 (e) a direct vasodilator selected from the group 0485 pildralazine consisting of hydralazine, minoxidil and combinations 0486 pinacidil thereof, 0487 piperoxan 0514 (f) an alpha-1-adrenergic receptor blocker Selected from the group consisting of carvedilol, dox 0488 protoveratrines aZosin, labetalol, praZosin, teraZosin and combinations 0489 3.5-pyridinedicarboxylic acid, 1,4-dihydro-2,6- thereof; dimethyl-4-(3-nitrophenyl)- 0515 (g) a central alpha-2-adrenergic receptor agonist 0490 methyl 1-(phenylmethyl)-3-pyrrolidinyl ester or other centrally acting drug selected from the group consisting of clonidine, guanabenz, guanadrel, guanfa 0491 raubasine cine, methyldopa, moXonidine, reserpine and combi 0492 rescimetol nations thereof; 0493 rescinnamine 0516 (h) an aldosterone receptor antagonist selected from the group consisting of canrenone, eplerenone, 0494 rillmenidine spironolactone and combinations thereof, and 0495) saralasin 0517 (i) the renin inhibitor aliskiren. 0496 sodium nitroprusside 0518 More particularly, the compound of formula (I) can 0497 syrosingopine be administered in combination or adjunctive therapy with one or more of (a), (b), (c) and (d) above, optionally further 0498 Takeda TAK 536 with one or more of (e), (f), (g), (h) and (i). 0499 tetrahydrolipstatin 0519 Still more particularly, the compound of formula 0500 1,4-thiazepine-4(5H)-acetic acid, 6-1-(ethoxy (I) can be administered in combination or adjunctive therapy carbonyl)-3-phenylpropyl-aminoltetrahydro-5-oxo-2- with at least (a) and any two of (b), (c) and (d). (2-thienyl) 0520. The compound of formula (I), and the one or more 0501) tiamenidine drugs constituting the baseline antihypertensive therapy and US 2007/0293552 A1 Dec. 20, 2007 optionally administered in combination with the compound 0546 reserpine--hydrochlorothiazide; of formula (I) can be delivered by any suitable route of administration. Orally bioavailable drugs are particularly 0547 spironolactone--hydrochlorothiazide: Suitable, in particular those that are Suitable for once a day 0548 telmisartan+hydrochlorothiazide: oral administration. Thus in one embodiment at least one of the diuretic or antihypertensive drugs in the baseline therapy 0549 timolol--hydrochlorothiazide: is orally administered once a day. In a particular embodi 0550 trandolapril--Verapamil: ment, all drugs in the baseline therapy are orally adminis tered once a day. According to this embodiment, it will 0551 triamterene--hydrochlorothiazide; and generally be found convenient to administer all drugs in the 0552) Valsartan+hydrochlorothiazide. regimen, i.e., the compound of formula (I) as well as the 0553 Separate dosage forms can optionally be co-pack baseline therapy drugs, orally once a day. aged, for example in a single container or in a plurality of 0521. When a compound of formula (I) is used in adjunc containers within a single outer package, or co-presented in tive therapy with one or more baseline drugs, the compound separate packaging ("common presentation'). As an of formula (I) and at least one baseline drug can be admin example of co-packaging or common presentation, a kit is istered at different times or at about the same time (at exactly contemplated comprising, in separate containers, a com the same time or directly one after the other in any order). pound of formula (I) and at least one drug useful in com The compound of formula (I) and the at least one baseline bination or adjunctive therapy with the compound of for drug can be formulated in one dosage form as a fixed-dose mula (I). In another example, the compound of formula (I) combination for administration at the same time, or in two and the at least one drug useful in combination or adjunctive or more separate dosage forms for administration at the therapy with the compound of formula (I) are separately same or different times. packaged and available for sale independently of one 0522 Fixed-dose combinations of two or more drugs can another, but are co-marketed or co-promoted for use accord be achieved in many cases by coformulation of the drugs in ing to the invention. The separate dosage forms can also be a single dosage unit Such as a tablet or capsule. For example, presented to a Subject separately and independently, for use coformulations of various drugs useful in a baseline anti according to the invention. hypertensive therapy as defined herein are available, includ 0554. In an embodiment of the invention, a method is 1ng: provided for treating a hypertensive disorder, comprising 0523 amiloride+hydrochlorothiazide: administering in combination therapy a compound of for mula (I), more particularly TBC3711, and at least one 0524 amlodipine--benazepril; inhibitor of renin activity or release, for example a renin inhibitor Such as aliskiren, ciprokiren, ditekiren, enalkiren, 0525) atenolol--chlorthalidone: remikiren, terlakiren or Zankiren. 0526 benazepril--hydrochlorothiazide; 0555 Examples of hypertensive disorders that can be 0527 bisoprolol--hydrochlorothiazide; treated by the method of this embodiment include conditions marked by Systolic hypertension, diastolic hypertension or 0528 candesartan+hydrochlorothiazide; both, including isolated systolic hypertension and hyperten 0529 captopril--hydrochlorothiazide: sion in the elderly; Such conditions can be primary (essential hypertension) or secondary to other conditions including 0530 enalapril--felodipine; obesity, diabetes, renal disorders (e.g., chronic renal failure, 0531 enalapril--hydrochlorothiazide: renovascular disease, diabetic nephropathy, etc.), adrenal disorders (e.g., adrenocortical and mineralocorticoid hyper 0532 eprosartan+hydrochlorothiazide; tension, pheochromocytoma, primary aldosteronism, Cush ing's syndrome, etc.), insulin resistance, salt-sensitivity, 0533 fosinopril--hydrochlorothiazide: polycystic ovary syndrome, sleep apnea, preeclampsia, thy 0534 irbesartan+hydrochlorothiazide; roid and parathyroid diseases, and transplantation. Whether primary or secondary, such hypertension can be, as 0535 lisinopril--hydrochlorothiazide: described above, resistant to baseline antihypertensive thera 0536 losartan+hydrochlorothiazide: pies, including resistant hypertension as clinically defined or diagnosed. Hypertensive disorders also include pulmonary 0537 methyldopa+hydrochlorothiazide; arterial hypertension, which likewise can be primary or 0538 metoprolol--hydrochlorothiazide: secondary to various conditions including diseases of the Scleroderma spectrum (e.g., mixed connective tissue dis 0539 moexipril--hydrochlorothiazide: ease, Raynaud's disease, CREST syndrome, systemic scle 0540 nadolol--hydrochlorothiazide: rosis, or overlap syndrome); rheumatoid arthritis; chronic hepatitis; systemic lupus erythematosus; anorexigen use: 0541) olmesartan+hydrochlorothiazide: human immunodeficiency virus (HIV) infection; chronic 0542 propranolol--hydrochlorothiazide; hypoxemia resulting from conditions such as chronic bron chitis, emphysema, sleep apnea, interstitial lung disease, or 0543 quinapril--hydrochlorothiazide; pulmonary fibrosis; thromboembolic diseases such as in situ 0544 reserpine--chlorothiazide; thrombosis, tumors, or sickle cell disease; Volume and pressure overloads induced primarily from disorders of the 0545 reserpine--chlorthalidone: left heart (for example, chronic heart failure, septal defects, US 2007/0293552 A1 Dec. 20, 2007 mitral valve disease, and left atrial myxoma); and disorders 0562. In one aspect of this embodiment, a method for directly affecting the pulmonary vasculature Such as Schis preventing one or more cardiovascular adverse events in a tosomiasis, Sarcoidosis and pulmonary capillary hemangi Subject having resistant hypertension comprises administer omatosis. ing a compound of formula (I) to the Subject. Examples of 0556. The method can be used, for example, to lower cardiovascular adverse effects include without limitation blood pressure in a subject exhibiting resistance to a baseline acute coronary syndrome (including unstable angina and antihypertensive therapy as described above, for example a non-Q wave infarction), myocardial infarction, heart failure, Subject having resistant hypertension. Optionally, adminis systolic heart failure, diastolic heart failure (also known as tration of the compound of formula (I) and the inhibitor of diastolic dysfunction), stroke, occlusive stroke, hemorrhagic renin activity or release is adjunctive to the baseline therapy, stroke and combinations thereof. “Preventing in the present which can, if desired, be modified as described above, for context includes reducing risk, incidence and/or severity of example by dose reduction or elimination of at least one of a Subsequent cardiovascular adverse effect. A monotherapy the drugs in the baseline therapy. or combination or adjunctive therapy of a compound of formula (I) with one or more additional drugs as described 0557 Variants and illustrative modalities of the method herein can be administered. of this embodiment, for example selection of a compound of formula (I), routes of administration, dosages, durations of 0563. In another aspect of the present embodiment, a treatment, frequency of administration, formulations of the method for providing a beneficial effect on renal function in compound of formula (I) and particular blood pressure a Subject having resistant hypertension comprises adminis tering a compound of formula (I) to the Subject. A mono benefits provided, are as described hereinabove. therapy or combination or adjunctive therapy of a compound 0558. In a further embodiment, a method for lowering of formula (I) with one or more additional drugs as described blood pressure in a Subject having diabetes and/or chronic herein can be administered. kidney disease comprises administering a compound of formula (I) to the subject. The particular effectiveness of 0564) A beneficial effect on renal function can be compounds of formula (I) in lowering blood pressure is observed, for example, by monitoring one or more blood believed to be especially useful in such a subject, given the and/or urinary biomarkers. Examples of Such biomarkers criticality of blood pressure control and the more aggressive include without limitation serum creatinine, serum insulin, SBP and DBP goals (per JNC 7, <130 mmHg and <80 serum glutamic acid decarboxylase (GAD), serum protein mmHg respectively) in such a subject. The subject can be, tyrosine phosphatase-like molecule IA2, blood urea nitro but is not necessarily, one exhibiting resistance to a baseline gen, urinary protein, urinary albumin, microalbuminuria, antihypertensive therapy, for example a Subject having resis urinary B2-microglobulin, urinary N-acetyl-3-glucosamini tant hypertension. A monotherapy or combination or adjunc dase, urinary retinol binding protein, urinary Sodium, glom tive therapy of a compound of formula (I) with one or more erular filtration rate, urinary albumin to creatinine ratio, additional drug(s) as described herein can be administered. urine Volume, and combinations thereof. 0559 For example, such additional drug(s) can comprise 0565 Illustratively, the compound of formula (I) can be a diuretic and/or one or more antihypertensive drugs administered in a dose effective to lower urinary albuminto selected from the group consisting of (a) ACE inhibitors and creatinine ratio. This can be especially beneficial where the angiotensin II receptor blockers, (b) beta-adrenergic recep baseline urinary albumin to creatinine ratio is greater than tor blockers, (c) calcium channel blockers, (d) direct vasodi about 30 mg/g or where baseline 24-hour urinary albumin is lators, (e) alpha-1-adrenergic receptor blockers, (f) central greater than about 30 mg/day. alpha-2-adrenergic receptor agonists and other centrally acting antihypertensive drugs, (g) aldosterone receptor 0566 Variants and illustrative modalities of the method antagonists, (h) vasopeptidase inhibitors, (i) NEP inhibitors, of the present embodiment, for example selection of a (j) prostanoids, (k) PDE5 inhibitors, (1) nitrosylated com compound of formula (I), routes of administration, dosages, durations of treatment, frequency of administration, formu pounds, (m) oral nitrates and (n) inhibitors of renin activity lations of the compound of formula (I), patient population or release. and particular blood pressure benefits provided, are as 0560 Variants and illustrative modalities of the present described hereinabove. embodiment, for example selection of a compound of for mula (I), routes of administration, dosages, durations of 0567 Atherapeutic combination comprising a compound treatment, frequency of administration, formulations of the of formula (I), at least one diuretic, and at least two compound of formula (I) and particular blood pressure antihypertensive drugs selected from at least two of (a) ACE benefits provided, are as described hereinabove. inhibitors and angiotensin II receptor blockers, (b) beta 0561. In a still further embodiment, a method for provid adrenergic receptor blockers and (c) calcium channel block ing a beneficial effect on renal and/or cardiovascular func ers, wherein the at least one diuretic and/or the at least one tion in a Subject having resistant hypertension comprises antihypertensive drug are present at Substantially less than a administering a compound of formula (I) to the Subject. full dose, is itself a further embodiment of the invention. “Providing a beneficial effect” in the present context “Substantially less than a full dose' is as defined and includes enhancing, maintaining or moderating a decline in illustrated hereinabove. renal or cardiovascular function and also includes prevent 0568 Such a combination can have utility in a number of ing one or more cardiovascular adverse events. A mono situations, not limited to methods described herein. How therapy or combination or adjunctive therapy of a compound ever, a combination of this embodiment can be especially of formula (I) with one or more additional drugs as described useful for lowering blood pressure in a subject exhibiting herein can be administered. resistance to a baseline antihypertensive therapy with one or US 2007/0293552 A1 Dec. 20, 2007
more drugs; for lowering blood pressure in a Subject having can be in a formulation adapted for once a day oral admin diabetes and/or chronic kidney disease; and/or for producing istration. Each of the drugs other than the compound of a beneficial effect on renal and/or cardiovascular function in formula (I) can be present in the combination in an amount a Subject having resistant hypertension. providing a full, adequate or reduced dose of the drug as 0569. The at least one diuretic in the combination can indicated hereinabove. One of skill in the art can readily illustratively be selected from those listed hereinabove. In identify a full dose for any particular drug from publicly particular embodiments the diuretic comprises a thiazide available information in printed or electronic form, for diuretic or a loop diuretic. Suitable ACE inhibitors, angio example on the internet, and can, if desired, reduce the dose tensin II receptor blockers, beta-adrenergic receptor block in accordance with certain embodiments of the present ers and calcium channel blockers can illustratively be invention based on the disclosure herein. selected from those listed hereinabove. Optionally, the com 0578 Any two or more drugs in the combination can bination can further comprise one or more additional drugs optionally be coformulated to provide a fixed dose combi selected from direct vasodilators, alpha-1-receptor blockers, nation. For example, the compound of formula (I) can be central alpha-2-adrenergic receptor agonists and other cen coformulated with any one or more of the other drugs in the trally acting antihypertensive drugs, and aldosterone recep combination. tor antagonists. Suitable drugs of these classes are illustra 0579 All patents and publications cited herein are incor tively listed hereinabove. porated by reference into this application in their entirety. 0570. In one embodiment, the combination comprises a compound of formula (I), for example sitaxsentan or 0580. The words “comprise”, “comprises, and “com TBC3711, plus (a) and at least two of (b), (c) and (d) as prising are to be interpreted inclusively rather than exclu described below: sively. 0571 (a) a diuretic selected from the group consisting What is claimed is: of chlorothiazide, chlorthalidone, hydrochlorothiazide, 1. A method for lowering blood pressure in a subject indapamide, metolaZone, polythiazide, bumetanide, exhibiting resistance to a baseline antihypertensive therapy furosemide, torsemide and combinations thereof. with one or more drugs, the method comprising administer 0572 (b) an angiotensin converting enzyme inhibitor ing to the Subject, adjunctively with the baseline therapy, a Selected from the group consisting of benazepril, cap compound of formula (I) topril, enalapril, fosinopril, lisinopril, moexipril, perin dopril, quinapril, ramipril, trandolapril and combina tions thereof, and/or an angiotensin II receptor blocker (I) Selected from the group consisting of candesartan, HC RI eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, Valsartan and combinations thereof; ( \ 0573 (c) a beta-adrenergic receptor blocker selected Yo NH from the group consisting of acebutolol, atenolol, SO betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, 7 R2 nadolol, penbutolol, pindolol, propranolol, timolol and Z R3 combinations thereof S
0574 (d) a calcium channel blocker selected from the O group consisting of amlodipine, diltiazem, felodipine, H3C R4 isradipine, nicardipine, nifedipine, nisoldipine, Vera pamil and combinations thereof. or a pharmaceutically acceptable salt thereof, wherein: 0575. In another embodiment, a therapeutic combination is provided, comprising a compound of formula (I), for R" is halo or C alkyl: example sitaxsentan or TBC3711, and an inhibitor of renin R is hydrogen, Cls alkyl (Cs alkyl)carbonyl (Cs. activity or release, for example a renin inhibitor Such as cycloalkyl)carbonyl, cyano, halo, aminocarbonyl, aliskiren, ciprokiren, diteidren, enalkiren, remikiren, terla di(C. alkyl)aminocarbonyl (Cs alkyl)sulfonyl, kiren or Zankiren. oxazol-2-yl or benzoyl: 0576 Typically in a therapeutic combination of the R and Rare independently hydrogen or Cos alkyl, or invention, at least the compound of formula (I) is provided together form a methylenedioxy bridge; and in an orally deliverable formulation, for example a formu lation adapted for oral delivery of a compound of formula (I) Z is CH or NH; dose of about 1 to about 600 mg/day, e.g., about 10 to about and wherein 200 mg/day. The formulation can be adapted for any suitable frequency of administration, but in one embodiment is (a) the adjunctively administered baseline therapy is adapted for once a day oral administration. modified by dose reduction or elimination of at least one of said drugs; 0577. In one embodiment at least one of the drugs other than the compound of formula (I) in the combination is (b) the adjunctively administered baseline therapy is provided in an orally deliverable formulation; for example, modified in a manner that results in a reduced risk or each of the drugs can be so provided, and each of the drugs incidence of adverse events; and/or US 2007/0293552 A1 Dec. 20, 2007
(c) a beneficial change in the Subject's 24-hour pattern of 13. The method of claim 7, wherein the adjunctively systolic and/or diastolic blood pressure is obtained. administered baseline therapy is modified by dose reduction 2. The method of claim 1, wherein the subject has or elimination, by split-dose administration, by non-simul diabetes, chronic kidney disease or both. taneous administration of different drugs, by controlled 3. The method of claim 1, wherein the compound of release formulation and/or by selection of a non-peroral formula (I) is sitaxsentan or TBC37.11. route of administration of at least one of said drugs. 4. The method of claim 3, wherein the compound of 14. The method of claim 1, wherein a beneficial change in formula (I) is TBC3711 and is administered in a daily dose the subjects 24-hour pattern of systolic and/or diastolic of about 1 to about 600 mg. blood pressure is obtained and the adjunctively administered 5. The method of claim 1, wherein the baseline therapy to baseline therapy is optionally modified (a) by dose reduction which the Subject exhibits resistance comprises administra or elimination of at least one of said drugs and/or (b) in a tion of one or more diuretics and/or one or more antihyper manner that results in a reduced risk or incidence of adverse tensive drugs selected from the group consisting of (a) ACE eVentS. inhibitors and angiotensin II receptor blockers, (b) beta 15. The method of claim 14, wherein the subject at adrenergic receptor blockers, (c) calcium channel blockers, baseline exhibits a bimodal waveform 24-hour pattern of (d) direct vasodilators, (e) alpha-1-adrenergic receptor systolic and/or diastolic blood pressure. blockers, (f) central alpha-2-adrenergic receptor agonists 16. The method of claim 14, wherein the beneficial and other centrally acting antihypertensive drugs, (g) aldos change comprises at least one of terone receptor antagonists, (h) vasopeptidase inhibitors, (i) (a) lowering of 24-hour mean ambulatory blood pressure; NEP inhibitors, () prostanoids, (k) PDE5 inhibitors, (1) nitrosylated compounds, (m) oral nitrates and (n) inhibitors (b) lowering of trough sitting systolic blood pressure; of renin activity or release. (c) lowering of trough sitting diastolic blood pressure; 6. The method of claim 1, wherein the subject has resistant hypertension, and the baseline therapy to which the (d) lowering of diurnal maximum ambulatory blood pres Subject exhibits resistance comprises administration of at Sure; least one diuretic and at least two antihypertensive drugs (e) a trend away from a bimodal waveform pattern selected from at least two of (a) ACE inhibitors and angio towards a unimodal or less pronouncedly bimodal tensin II receptor blockers, (b) beta-adrenergic receptor pattern consistent with normotensive Subjects; blockers and (c) calcium channel blockers. 7. The method of claim 1, wherein the adjunctively (f) an increase in day/night ambulatory blood pressure administered baseline therapy is modified by dose reduction ratio; and or elimination of at least one of said drugs and/or in a (g) at least about 10% nocturnal dipping of ambulatory manner that results in a reduced risk or incidence of adverse blood pressure. eVentS. 17. The method of claim 14, wherein the beneficial 8. The method of claim 7, wherein the compound of change is evident from ambulatory blood pressure monitor formula (I) is administered at a dose and frequency effective, 1ng. in combination with the modified baseline therapy, to pro 18. The method of claim 14, wherein the subject has vide a reduction of at least about 3 mmHg in one or more resistant systolic hypertension, and the compound of for blood pressure parameters selected from trough sitting sys mula (I) is administered at a dose and frequency effective, in tolic, trough sitting diastolic, 24-hour ambulatory systolic, combination with the optionally modified baseline therapy, 24-hour ambulatory diastolic, maximum diurnal systolic and to provide a reduction of at least about 3 mmHg in one or maximum diurnal diastolic blood pressures. more systolic blood pressure parameters selected from 9. The method of claim 8, wherein the subject has trough sitting, 24-hour ambulatory and maximum diurnal resistant systolic hypertension, and the compound of for systolic blood pressures. mula (I) is administered at a dose and frequency effective, in 19. The method of claim 18, wherein a JNC 7, BHD-IV, combination with the modified baseline therapy, to provide ESH/ESC or WHO/ISH goal for systolic blood pressure is a reduction of at least about 3 mmHg in one or more systolic achieved. blood pressure parameters selected from trough sitting, 20. The method of claim 14, wherein the subject has 24-hour ambulatory and maximum diurnal systolic blood resistant diastolic hypertension, and the compound of for pressures. mula (I) is administered at a dose and frequency effective, in 10. The method of claim 9, wherein a JNC 7, BHD-IV, combination with the optionally modified baseline therapy, ESH/ESC or WHO/ISH goal for systolic blood pressure is to provide a reduction of at least about 3 mmHg in one or achieved. more diastolic blood pressure parameters selected from 11. The method of claim 8, wherein the subject has trough sitting, 24-hour ambulatory and maximum diurnal resistant diastolic hypertension, and the compound of for diastolic blood pressures. mula (I) is administered at a dose and frequency effective, in 21. The method of claim 20, wherein a JNC 7, BHD-IV, combination with the modified baseline therapy, to provide ESH/ESC or WHO/ISH goal for diastolic blood pressure is a reduction of at least about 3 mmHg in one or more diastolic achieved. blood pressure parameters selected from trough sitting, 22. A method for treating a hypertensive disorder, com 24-hour ambulatory and maximum diurnal diastolic blood prising administering in combination therapy TBC3711 and pressures. at least one inhibitor of renin activity or release. 12. The method of claim 11, wherein a JNC 7, BHD-IV, 23. The method of claim 22, wherein the hypertensive ESH/ESC or WHO/ISH goal for diastolic blood pressure is disorder is selected from the group consisting of systolic achieved. hypertension; diastolic hypertension; isolated systolic US 2007/0293552 A1 Dec. 20, 2007 18 hypertension; hypertension in the elderly; essential hyper 31. The method of claim 29, wherein the baseline therapy tension; hypertension secondary to obesity, diabetes, renal comprises administration of one or more diuretics and/or disorders, adrenal disorders, Cushing's syndrome, insulin one or more antihypertensive drugs selected from the group resistance, salt sensitivity, polycystic ovary syndrome, sleep consisting of (a) ACE inhibitors and angiotensin II receptor apnea, preeclampsia, thyroid and parathyroid diseases and/ blockers, (b) beta-adrenergic receptor blockers, (c) calcium or transplantation; and pulmonary arterial hypertension. channel blockers, (d) direct vasodilators, (e) alpha-1-adren 24. The method of claim 22, wherein the inhibitor of renin ergic receptor blockers, (f) central alpha-2-adrenergic recep activity or release is a renin inhibitor selected from the group tor agonists and other centrally acting antihypertensive consisting of alliskiren, ciprokiren, ditekiren, enalkiren, drugs, (g) aldosterone receptor antagonists, (h) vasopepti remikiren, terlakiren and Zankiren. dase inhibitors, (i) NEP inhibitors, (ii) prostanoids, (k) PDE5 25. The method of claim 22, wherein the TBC37.11 is inhibitors, (1) nitrosylated compounds, (m) oral nitrates and administered in a daily dose of about 1 to about 600 mg. (n) inhibitors of renin activity or release. 26. A method for lowering blood pressure in a subject 32. The method of claim 29, wherein the subject has having diabetes and/or chronic kidney disease, the method resistant hypertension, and the baseline therapy to which the comprising administering to the Subject a compound of Subject exhibits resistance comprises administration of at formula (I) least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angio tensin II receptor blockers, (b) beta-adrenergic receptor (I) blockers and (c) calcium channel blockers. H3C RI 33. The method of claim 32, wherein the subject has resistant systolic hypertension, and the compound of for mula (I) is administered at a dose and frequency effective, in combination with the optionally modified baseline therapy, ( ) NH o to provide a reduction of at least about 3 mmHg in one or SO more systolic blood pressure parameters selected from 7 R2 trough sitting, 24-hour ambulatory and maximum diurnal systolic blood pressures. S Z R3 34. The method of claim 32, wherein the subject has resistant diastolic hypertension, and the compound of for O mula (I) is administered at a dose and frequency effective, in HC R4 combination with the optionally modified baseline therapy, to provide a reduction of at least about 3 mmHg in one or or a pharmaceutically acceptable salt thereof, wherein: more diastolic blood pressure parameters selected from trough sitting, 24-hour ambulatory and maximum diurnal R" is halo or Cs alkyl; diastolic blood pressures. R is hydrogen, Cls alkyl (Cs alkyl)carbonyl, (Cs. 35. The method of claim 26, wherein the compound of cycloalkyl)carbonyl, cyano, halo, aminocarbonyl, formula (I) is TBC3711 and is administered in a daily dose di(C. alkyl)aminocarbonyl, (Cs alkyl)sulfonyl, of about 1 to about 600 mg. oxazol-2-yl or benzoyl; 36. A method for providing a beneficial effect on renal and/or cardiovascular function in a Subject having resistant R and R are independently hydrogen or C alkyl, or hypertension, the method comprising administering to the together form a methylenedioxy bridge; and Subject a compound of formula (I) Z is CH or NH. 27. The method of claim 26, wherein the compound of (I) formula (I) is sitaxsentan or TBC37.11. HC RI 28. The method of claim 26, wherein a blood pressure goal according to JNC 7, BHD-IV, ESH/ESC or WHO/ISH guidelines, more stringent than set for Subjects not having ( \ diabetes or chronic kidney disease, is achieved. Yo NH V 29. The method of claim 26, wherein the subject exhibits SO resistance to a baseline antihypertensive therapy with one or 7 R2 more drugs, and the compound of formula (I) is adminis Z R3 tered adjunctively with said baseline therapy, which is S optionally modified (a) by dose reduction or elimination of at least one of said drugs and/or (b) in a manner that results O in a reduced risk or incidence of adverse events. H3C R4 30. The method of claim 29, wherein the compound of formula (I) is administered at a dose and frequency effective, or a pharmaceutically acceptable salt thereof, wherein: in combination with the optionally modified baseline therapy, to provide a reduction of at least about 3 mmHg in R" is halo or Cs alkyl: one or more blood pressure parameters selected from trough R is hydrogen, Cls alkyl (Cs alkyl)carbonyl (Cs. sitting systolic, trough sitting diastolic, 24-hour ambulatory cycloalkyl)carbonyl, cyano, halo, aminocarbonyl, systolic, 24-hour ambulatory diastolic, maximum diurnal di(C. alkyl)aminocarbonyl (Cs alkyl)sulfonyl, systolic and maximum diurnal diastolic blood pressures. oxazol-2-yl or benzoyl: US 2007/0293552 A1 Dec. 20, 2007
R and R are independently hydrogen or Cs alkyl, or together form a methylenedioxy bridge; and (I) Z is CH or NH. HC RI 37. The method of claim 36, wherein the compound of formula (I) is sitaxsentan or TBC37.11. 38. The method of claim 36, wherein the beneficial effect ( \ comprises preventing one or more cardiovascular adverse Yo NH events in the subject. SO 39. The method of claim 38, wherein the one or more 7 R2 cardiovascular adverse events are selected from the group Z R3 consisting of acute coronary syndrome, myocardial infarc S tion, heart failure, systolic heart failure, diastolic heart failure, stroke, occlusive stroke, hemorrhagic stroke and O combinations thereof. H3C R4 40. The method of claim 36, wherein the beneficial effect is on renal function and is observable by monitoring one or or a pharmaceutically acceptable salt thereof, wherein: more blood and/or urinary biomarkers. 41. The method of claim 40, wherein the one or more R" is halo or C alkyl: biomarkers are selected from the group consisting of serum creatinine, serum insulin, serum GAD, serum IA2, blood R is hydrogen, Cls alkyl (Cs alkyl)carbonyl (Cs. urea nitrogen, urinary protein, urinary albumin, microalbu cycloalkyl)carbonyl, cyano, halo, aminocarbonyl, minuria, urinary B2-microglobulin, urinary N-acetyl-3-glu di(C. alkyl)aminocarbonyl (Cs alkyl)sulfonyl, cosaminidase, urinary retinol binding protein, urinary oxazol-2-yl or benzoyl: Sodium, glomerular filtration rate, urinary albumin to crea R and R are independently hydrogen or C alkyl, or tinine ratio, urine Volume and combinations thereof. together form a methylenedioxy bridge; and 42. The method of claim 40, wherein the compound of formula (I) is administered in a dose effective to lower Z is CH or NH; urinary albumin to creatinine ratio. (b) at least one diuretic; and (c) at least one antihyper 43. The method of claim 42, wherein the subject exhibits, tensive drug selected from the group consisting of ACE prior to administration of the compound of formula (I), a inhibitors, angiotensin II receptor blockers, beta-adr baseline urinary albumin to creatinine ratio greater than energic receptor blockers and calcium channel block about 30 mg/g. ers; wherein the at least one diuretic and/or the at least 44. The method of claim 42, wherein the subject exhibits, one antihypertensive drug are present at Substantially prior to administration of the compound of formula (I), a less than a full dose. baseline 24-hour urinary albumin greater than about 30 mg/day. 50. The combination of claim 49, wherein the compound 45. The method of claim 36, wherein the compound of of formula (I) is sitaxsentan or TBC37.11. formula (I) is administered adjunctively with one or more 51. The combination of claim 49, comprising a compound diuretics and/or one or more antihypertensive drugs selected of formula (I), at least one diuretic, and at least two from the group consisting of (a) ACE inhibitors and angio antihypertensive drugs selected from at least two of (a) tensin II receptor blockers, (b) beta-adrenergic receptor angiotensin converting enzyme inhibitors and angiotensin II blockers, (c) calcium channel blockers, (d) direct vasodila receptor blockers, (b) beta-adrenergic receptor blockers and tors, (e) alpha-1-adrenergic receptor blockers, (f) central (c) calcium channel blockers, wherein the at least one alpha-2-adrenergic receptor agonists and other centrally diuretic and/or at least one of the antihypertensive drugs are acting antihypertensive drugs, (g) aldosterone receptor present at Substantially less than a full dose. antagonists, (h) vasopeptidase inhibitors, (i) NEP inhibitors, 52. The combination of claim 49, further comprising one (j) prostanoids, (k) PDE5 inhibitors, (1) nitrosylated com or more additional antihypertensive drugs. pounds, (m) oral nitrates and (n) inhibitors of renin activity 53. The combination of claim 49, comprising a compound or release. of formula (I); a diuretic selected from the group consisting 46. The method of claim 36, wherein the subject has of chlorothiazide, chlorthalidone, hydrochlorothiazide, inda resistant hypertension, and the compound of formula (I) is pamide, metolaZone, polythiazide, bumetanide, furosemide, administered adjunctively with at least one diuretic and at torsemide and combinations thereof, and at least two of least two antihypertensive drugs selected from at least two (a) an angiotensin converting enzyme inhibitor selected of (a) ACE inhibitors and angiotensin II receptor blockers, from the group consisting of benazepril, captopril, (b) beta-adrenergic receptor blockers and (c) calcium chan enalapril, fosinopril, lisinopril, moexipril, perindopril, nel blockers. quinapril, ramipril, trandolapril and combinations 47. The method of claim 36, wherein the subject has thereof, and/or an angiotensin II receptor blocker diabetes, chronic kidney disease or both. Selected from the group consisting of candesartan, 48. The method of claim 36, wherein the compound of eprosartan, irbesartan, losartan, olmesartan, tasosartan, formula (I) is TBC3711 and is administered in a daily dose telmisartan, Valsartan and combinations thereof. of about 1 to about 600 mg. 49. Atherapeutic combination comprising (a) a compound (b) a beta-adrenergic receptor blocker selected from the of formula (I) group consisting of acebutolol, atenolol, betaxolol, US 2007/0293552 A1 Dec. 20, 2007 20
bisoprolol, carvedilol, labetalol, metoprolol, nadolol, 54. The combination of claim 49, wherein the compound penbutolol, pindolol, propranolol, timolol and combi- of formula (I) is TBC3711 and is formulated in a form nations thereof, and adapted for delivery of a TBC3711 dose of about 1 to about (c) a calcium channel blocker selected from the group 600 mg/day. consisting of amlodipine, diltiazem, felodipine, israd ipine, nicardipine, nifedipine, nisoldipine, Verapamil and combinations thereof. k . . . .