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(12) Patent Application Publication (10) Pub. No.: US 2003/0220312 A1 Schuh (43) Pub US 2003O220312A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0220312 A1 Schuh (43) Pub. Date: Nov. 27, 2003 (54) EPOXY-STEROIDAL ALDOSTERONE tinuation-in-part of application No. 09/854.264, filed ANTAGONST AND CALCIUM CHANNEL on May 11, 2001. BLOCKER COMBINATION THERAPY FOR TREATMENT OF CARDIOWASCULAR (60) Provisional application No. 60/221,359, filed on Jul. DSORDERS 27, 2000. Provisional application No. 60/203,637, filed on May 11, 2000. (75) Inventor: Joseph R. Schuh, St. Louis, MO (US) Publication Classification Correspondence Address: Pharmacia Corporation (51) Int. Cl." ........................ A61K 31/58; A61K 31/585 Corporate Patent Department (52) U.S. Cl. ............................................ 514/173; 514/175 Mail Zone O4E 800 N. Lindbergh Blvd. (57) ABSTRACT St. Louis, MO 63167 (US) A combination therapy comprising a therapeutically-effec tive amount of an epoxy-Steroidal aldosterone receptor (73) Assignee: G.D. Searle & Co., Chicago, IL antagonist and a therapeutically-effective amount of a cal Appl. No.: 10/324,330 cium channel blocker is described for treatment of circula (21) tory disorders, including cardiovascular disorderS Such as (22) Filed: Dec. 19, 2002 hypertension, angina and congestive heart failure. Preferred calcium channel blockers are those compounds having high Related U.S. Application Data potency and bioavailability. Preferred epoxy-steroidal aldos terone receptor antagonists are 20-Spiroxane Steroidal com (63) Continuation-in-part of application No. 10/126,134, pounds characterized by the presence of a 9C,11C.-Substi filed on Apr. 19, 2002, now abandoned, which is a tuted epoxy moiety. A preferred combination therapy continuation of application No. 09/917,425, filed on includes the calcium channel blocker amlodipine and the Jul. 27, 2001, now abandoned, and which is a con aldosterone receptor antagonist eplerenone. Patent Application Publication Nov. 27, 2003 Sheet 1 of 38 US 2003/0220312 A1 Z `N?LOOO! –||–||–0 -000!! -0009! --00091 -000y| -000Cl --000z? -000!!! -0000!. 0006 0000 -0001 -0009 --0009 -000V -000€ 000Z (SunOO) ul Patent Application Publication Nov. 27, 2003 Sheet 2 of 38 US 2003/0220312 A1 S. s 9 s (SunOO) Uup Patent Application Publication Nov. 27, 2003 Sheet 3 of 38 US 2003/0220312 A1 04 Patent Application Publication Nov. 27, 2003 Sheet 4 of 38 US 2003/0220312 A1 O'.9 cosN 2 D O O N s S. 9 e55 esis ve a S9 O O ve O t O. m -OP t- O t c a (6IM) moleeH Patent Application Publication Nov. 27, 2003. Sheet 5 of 38 US 2003/0220312 A1 00909200! (o))elnyeleduje1nox=} NVAOBTVBS:?uauuuJOO drºnOx o o vis d O (6IM) molee Patent Application Publication Nov. 27, 2003 Sheet 6 of 38 O (6M) MoleeH Patent Application Publication Nov. 27, 2003. Sheet 7 of 38 00909ZOOZ09?, NwaOBTVES:?uauuuuoO (6M) Moleah Patent Application Publication Nov. 27, 2003 Sheet 8 of 38 US 2003/0220312 A1 Patent Application Publication Nov. 27, 2003. Sheet 9 of 38 US 2003/0220312 A1 O o O o o O s o O qr A tes s e? a E ge 2 9 CO sS. O O t N O O r N O O O 3 aoueuSue Patent Application Publication Nov. 27, 2003 Sheet 10 of 38 US 2003/0220312 A1 . C O o O O O s 8 S S al s A. 5? ebr e 9 9 3 S.& O O N o O ve N 3 o s 3 eoueuSue Patent Application Publication Nov. 27, 2003 Sheet 11 of 38 US 2003/0220312 A1 O o (e. O O 9 O O a st 5 E 9 S5 O O u? SN -o O V 3 3 3 . S aoueuSue Patent Application Publication Nov. 27, 2003 Sheet 12 of 38 US 2003/0220312 A1 s 9. 3. OYa e s ve o O N Se 3 s eoueuSue Patent Application Publication Nov. 27, 2003 Sheet 13 of 38 US 2003/0220312 A1 8 gss3 Patent Application Publication Nov. 27, 2003 Sheet 14 of 38 US 2003/0220312 A1 o Go O O ve. ta ss e Patent Application Publication Nov. 27, 2003 Sheet 15 of 38 US 2003/0220312 A1 |06 02 09 Patent Application Publication Nov. 27, 2003 Sheet 16 of 38 US 2003/0220312 A1 S e 9 ASueu Patent Application Publication Nov. 27, 2003 Sheet 17 of 38 US 2003/0220312 A1 s s CO S. | 2 9 KSueu Patent Application Publication Nov. 27, 2003. Sheet 18 of 38 US 2003/0220312 A1 o GN on g SP O s p se - to ASueu Patent Application Publication Nov. 27, 2003. Sheet 19 of 38 US 2003/0220312 A1 o g g { e 3 SN & se 2 ep- . s 9. O 2 9 KisuayupazieuON Patent Application Publication Nov. 27, 2003 Sheet 20 of 38 US 2003/0220312 A1 9. e g S. p 9 KisueupazLeu10N Patent Application Publication Nov. 27, 2003 Sheet 21 of 38 US 2003/0220312 A1 C r e g N s & E & O epd () th O 2 9 KSueu pezieu.JON Patent Application Publication Nov. 27, 2003 Sheet 22 of 38 US 2003/0220312 A1 O 9 6 GN g -s 2 St.or O C)s NN -as s t 2 C S. AISueu pezieu.JON Patent Application Publication Nov. 27, 2003. Sheet 23 of 38 US 2003/0220312 A1 o r e g : e. S un N s st O SP in ()g s p i-- Se s le Ausuaui pezleuoN Patent Application Publication Nov. 27, 2003 Sheet 25 of 38 US 2003/0220312 A1 cy e w ve 5 w MO Es g 5 sh 9 9 OO c O O C O 92O. O.S O. 99O.) OOOO. SO9N. co 9w S2CN o Aliqeqol % euoNeH. Patent Application Publication Nov. 27, 2003 Sheet 26 of 38 US 2003/0220312 A1 Á?nd:apueele,fiullooov?ouo?oelayu! 09’00), ººººº?una?enov Patent Application Publication Nov. 27, 2003 Sheet 27 of 38 US 2003/0220312 A1 O Aund Patent Application Publication Nov. 27, 2003 Sheet 28 of 38 US 2003/0220312 A1 E. Auqeqold %euON leH Patent Application Publication Nov. 27, 2003 Sheet 29 of 38 US 2003/0220312 A1 Patent Application Publication Nov. 27, 2003 Sheet 30 of 38 US 2003/0220312 A1 g g g S. 2 9 i Ssg i 2 Patent Application Publication Nov. 27, 2003 Sheet 31 of 38 --?••••---- sm - Wu) dropus moto Patent Application Publication Nov. 27, 2003. Sheet 32 of 38 US 2003/0220312 A1 5uuOo]euoueueId='+lex10019OO. Oq30eId+10X10OIGOO 6uuOGeuoueueId='+uexioolº90 oqeoeld+10X10O1800 Patent Application Publication Nov. 27, 2003 Sheet 34 of 38 US 2003/0220312 A1 s L O O sen?eAueÐINFØRERFESTATTFÆRT__)---- Patent Application Publication Nov. 27, 2003 Sheet 35 of 38 US 2003/0220312 A1 s N T n 2 a 3 ? or r in c s s is e g is (6Hulu) eBueto UeeN n n . CD . d 8 n it e g s g 9 Lls a 9, 9 s s O (5 OO (BHulu) eBuelo Leew CN C. Y. g 5 CD s isodds st92 Patent Application Publication Nov. 27, 2003 Sheet 36 of 38 US 2003/0220312 A1 ·r·…….....+…......No. (Bulu) afueuo Ueew 100'0>d :(IsAuoea)dau96ueuoueºW ZZ(61-) euoueue|d=|pueGOO Patent Application Publication Nov. 27, 2003. Sheet 37 of 38 US 2003/0220312 A1 :?uOu??SOp|V/pueu?uÐH?A??OV/ euoueue|d=|pueGOO US 2003/0220312 A1 Nov. 27, 2003 EPOXY-STEROIDALALDOSTERONE hypertension. Activation of the renin-angiotensin-aldoster ANTAGONST AND CALCIUM CHANNEL one System begins with renin Secretion from the juxtaglom BLOCKER COMBINATION THERAPY FOR erular cells in the kidney and culminates in the formation of TREATMENT OF CARDIOWASCULAR angiotensin II, the primary active species of this System. DISORDERS This octapeptide, angiotensin II, is a potent vasoconstrictor and also produces other physiological effects Such as Stimu FIELD OF THE INVENTION lating aldosterone Secretion, promoting Sodium and fluid 0001 Combinations of an epoxy-steroidal aldosterone retention, inhibiting renin Secretion, increasing Sympathetic receptor antagonist and a calcium channel blocker are nervous System activity, Stimulating vasopressin Secretion, described for use in treatment of circulatory disorders, causing positive cardiac inotropic effect and modulating including cardiovascular diseaseS Such as hypertension, con other hormonal Systems. gestive heart failure, cardiac hypertrophy, angina, cirrhosis 0008. In addition to aldosterone, calcium channels play and ascites. Of particular interest are therapies using an an important role in heart failure. In both vascular and epoxy-containing Steroidal aldosterone receptor antagonist cardiac tissue, muscle cell contraction occurs when cells are compound Such as eplerenone in combination with a cal depolarized from the infulx of calcium through calcium cium channel blocker compound. channels in the cell. The increased cytosolic calcium binds to calmodulin, activating myosin light-chain kinase which BACKGROUND OF THE INVENTION phosphorylate myosin. The phosphorylated myosin can then 0002 Myocardial (or cardiac) failure, whether a conse interact with actin, resulting in muscle contraction. Calcium quence of a previous myocardial infarction, heart disease channel blockers inhibit muscle contraction and promote asSociated with hypertension, or primary cardiomyopathy, is relaxation. In vascular Smooth muscle this results in Vessel a major health problem of worldwide proportions. The dilation, reduced blood pressure (anti-hypertensive effect) incidence of Symptomatic heart failure has risen Steadily and a reduction in the force required to pump blood by the over the past Several decades. heart. Calcium channel blockers also act on the heart to improve filling by promoting relaxation of cardiac muscle in 0003. In clinical terms, decompensated cardiac failure diastole. However, calcium channel blockerS also reduce the consists of a constellation of Signs and Symptoms that arises force of contraction during Systole (negative inotropy) and from congested organs and hypoperfused tissues to form the therefore are often not the drug of choice for treating heart congestive heart failure (CHF) Syndrome.
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