Compositions and methods for treating osteoporosis and lowering cholesterol

Abstract

This invention relates to methods, pharmaceutical compositions and kits useful in promoting bone formation and/or preventing bone loss and lowering blood cholesterol. The compositions are comprised of an estrogen agonist/antagonist as a first active component and a statin as a second active component and a pharmaceutically acceptable vehicle, carrier or diluent. The compositions and methods of treatment are effective while substantially reducing the concomitant liability of adverse effects associated with estrogen administration.

1 . A pharmaceutical composition comprising: 
 (a) an estrogen agonist/antagonist; and    (b) a statin.    
     
     
         2 . A pharmaceutical composition as in  claim 1  wherein said estrogen agonist/antagonist of the following formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is selected from CH 2  and NR;  
 B, D and E are independently selected from CH and N;  
 Y is 
 (a) phenyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (c) C 3 -C 8  cycloalkyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (d) C 3 -C 8  cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R 4 ;  
 (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n — optionally substituted with 1-3 substituents independently selected from R 4 ; or  
 (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR 2 — and —S(O) n —, optionally substituted with 1-3 substituents independently selected from R 4 ;  
 
 Z 1  is 
 (a) —(CH 2 ) p  W(CH 2 ) q —;  
 (b) —O(CH 2 ) p  CR 5 R 6 —;  
 (c) —O(CH 2 ) p W(CH 2 ) q —;  
 (d) —OCHR 2 CHR 3 —; or  
 (e) —SCHR 2 CHR 3 —;  
 
 G is 
 (a) NR 7 R 8 ;  
                     
  wherein n is 0, 1 or 2; m is 1, 2 or 3; Z 2  is —NH—, —O—, —S—, or —CH 2 —; optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R 4 ; or  
 (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R 4 ; or  
 
 Z 1  and G in combination may be  
                     
 W is 
 (a) —CH 2 —;  
 (b) —CH═CH—;  
 (c) —O—;  
 (d) —NR 2 —;  
 (e) —S(O) n —;  
                     
 (g) —CR 2 (OH)—;  
 (h) —CONR 2 —;  
 (i) —NR 2 CO—;  
                     
 (k) —C≡C—;  
 
 R is hydrogen or C 1 -C 6  alkyl;  
 R 2  and R 3  are independently 
 (a) hydrogen; or  
 (b) C 1 -C 4  alkyl;  
 
 R 4  is 
 (a) hydrogen;  
 (b) halogen;  
 (c) C 1 -C 6  alkyl;  
 (d) C 1 -C 4  alkoxy;  
 (e) C 1 -C 4  acyloxy;  
 (f) C 1 -C 4  alkylthio;  
 (g) C 1 -C 4  alkylsulfinyl;  
 (h) C 1 -C 4  alkylsulfonyl;  
 (i) hydroxy (C 1 -C 4 )alkyl;  
 (j) aryl (C 1 -C 4 )alkyl;  
 (k) —CO 2 H;  
 (l) —CN;  
 (m) —CONHOR;  
 (n) —SO 2 NHR;  
 (o) —NH 2 ;  
 (p) C 1 -C 4  alkylamino;  
 (q) C 1 -C 4  dialkylamino;  
 (r) —NHSO 2 R;  
 (s) —NO 2 ;  
 (t) -aryl; or  
 (u) —OH;  
 
 R 5  and R 6  are independently C 1 -C 8  alkyl or together form a C 3 -C 10  carbocyclic ring;  
 R 7  and R 8  are independently 
 (a) phenyl;  
 (b) a C 3 -C 10  carbocyclic ring, saturated or unsaturated;  
 (c) a C 3 -C 10  heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;  
 (d) H;  
 (e) C 1 -C 6  alkyl; or  
 (f) form a 3 to 8 membered nitrogen containing ring with R 5  or R 6 ;  
 
 R 7  and R 8  in either linear or ring form may optionally be substituted with up to three substituents independently selected from C 1 -C 6  alkyl, halogen, alkoxy, hydroxy and carboxy;  
 a ring formed by R 7  and R 8  may be optionally fused to a phenyl ring;  
 e is 0, 1 or 2;  
 m is 1, 2 or 3;  
 n is 0, 1 or 2;  
 p is 0, 1, 2 or 3;  
 q is 0, 1, 2 or 3;  
 or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
 
     
     
         3 . A pharmaceutical composition as in  claim 2  wherein said estrogen agonist/antagonist is a compound of formula (IA):  
       
         
           
           
               
               
           
         
         wherein G is  
         
           
             
             
                 
                 
             
           
         
         R 4  is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.  
       
     
     
         4 . A pharmaceutical composition as in  claim 3  wherein said estrogen agonist/antagonist is (−)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.  
     
     
         5 . A pharmaceutical composition as in  claim 4  wherein said estrogen agonist/antagonist is in the form of a D-tartrate salt.  
     
     
         6 . A pharmaceutical composition as in  claim 1  wherein said estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, raloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         7 . A pharmaceutical composition as in  claim 1  wherein said estrogen agonist/antagonist is a compound selected from the formulas V or VI:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1B  is selected from H, OH, —O—C(O)-C 1 -C 12  alkyl (straight chain or branched), —O-C 1 -C 12  alkyl (straight chain or branched or cyclic), or halogens or C 1 -C 4  halogenated ethers,  
 R 2B , R 3B , R 4B , R 5B , and R 6B  are independently selected from H, OH, —O—C(O)-C 1 -C 12  (straight chain or branched), —O-C 1 -C 12  (straight chain or branched or cyclic), halogens, or C 1 -C 4  halogenated ethers, cyano, C 1 -C 6  alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R 1B  is H, R 2B  is not OH;  
 X A  is selected from H, C 1 -C 6  alkyl, cyano, nitro, triflouromethyl, and halogen;  
 s is 2 or 3;  
 Y A  is the moiety:  
                     
 wherein:  
 a) R 7B  and R 8B  are independently selected from the group of H, C 1 -C 6  alkyl, or phenyl optionally substituted by CN, C 1 -C 6  alkyl (straight chain or branched), C 1 -C 6  alkoxy (straight chain or branched), halogen, —OH, —CF 3 , or —OCF 3 ; or  
 b) R 7B  and R 8B  are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 c) R 7B  and R 8B  are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 d) R 7B  and R 8B  are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 e) R 7B  and R 8B  are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 f) R 7B  and R 8B  are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2  H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 ) alkyl;  
 or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
 
     
     
         8 . A pharmaceutical composition as in  claim 7  wherein said estrogen agonist/antagonist is the compound, TSE-424, of formula Va below:  
       
         
           
           
               
               
           
         
       
       or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
     
     
         9 . A pharmaceutical composition as in  claim 1  wherein said estrogen agonist/antagonist is EM-652 of formula III below or is EM-800 of formula IV below:  
       
         
           
           
               
               
           
         
       
       or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
     
     
         10 . A pharmaceutical composition as claimed in  claim 1  wherein said statin is a member selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velbstatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104, ZD-4522 and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         11 . A pharmaceutical composition as claimed in  claim 2  wherein said statin is a member selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104, ZD-4522 and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         12 . A pharmaceutical composition as claimed in  claim 5  wherein said statin is a member selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104, ZD-4522 and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         13 . A pharmaceutical composition as claimed in  claim 8  wherein said statin is a member selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104, ZD-4522 and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         14 . A pharmaceutical composition as in  claim 5  wherein said statin is atorvastatin or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
     
     
         15 . A method of promoting bone formation and/or preventing bone loss and/or lowering blood cholesterol comprising: 
 co-administering to a subject in need thereof, an effective amount of a estrogen agonist/antagonist and a statin.    
     
     
         16 .- 19 . (canceled).  
     
     
         20 . A method as in  claim 15  wherein said estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, raloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, EM-652, EM-800, GW 5638, GW 7604 and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         21 . A method as in  claim 15  wherein said estrogen agonist/antagonist is a compound selected from the formulas V or VI:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1B  is selected from H, OH, —O—C(O)-C 1 -C 12  alkyl (straight chain or branched), —O-C 1 -C 12  alkyl (straight chain or branched or cyclic), or halogens or C 1 -C 4  halogenated ethers,  
 R 2B , R 3B , R 4B , R 5B , and R 6B  are independently selected from H, OH, —O—C(O)-C 1 -C 12  (straight chain or branched), —O-C 1 -C 12  (straight chain or branched or cyclic), halogens, or C 1 -C 4  halogenated ethers, cyano, C 1 -C 6  alkyl (straight chain or branched), or trifluoromethyl, with the proviso that, when R 1B  is H, R 2B  is not OH;  
 X A  is selected from H, C 1 -C 6  alkyl, cyano, nitro, triflouromethyl, and halogen;  
 s is 2 or 3;  
 Y A  is the moiety:  
                     
 wherein:  
 a) R 7B  and R 8B  are independently selected from the group of H, C 1 -C 6  alkyl, or phenyl optionally substituted by CN, C 1 -C 6  alkyl (straight chain or branched), C 1 -C 6  alkoxy (straight chain or branched), halogen, —OH, —CF 3 , or —OCF 3 ; or  
 b) R 7B  and R 8B  are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 c) R 7B  and R 8B  are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —N H 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 d) R 7B  and R 8B  are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 e) R 7B  and R 8B  are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 )alkyl; or  
 f) R 7B  and R 8B  are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4  alkyl, trihalomethyl, C 1 -C 4  alkoxy, trihalomethoxy, C 1 -C 4  acyloxy, C 1 -C 4  alkylthio, C 1 -C 4  alkylsulfinyl, C 1 -C 4  alkylsulfonyl, hydroxy (C 1 -C 4 )alkyl, —CO 2 H, —CN, —CONHR 1B , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NHSO 2 R 1B , —NHCOR 1B , —NO 2 , or phenyl optionally substituted with 1-3 (C 1 -C 4 ) alkyl;  
 or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
 
     
     
         22 . A method as in  claim 15  wherein said estrogen agonist/antagonist is the compound, TSE-424, of formula Va below:  
       
         
           
           
               
               
           
         
       
       or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
     
     
         23 . A method as in  claim 15  wherein said estrogen agonist/antagonist is EM-652 of formula III below or is EM-800 of formula IV below:  
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.  
     
     
         24 . A method as in  claim 15  wherein said statin is a member selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104, ZD-4522 and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         25 .- 26 . (canceled).  
     
     
         27 . A method as claimed in  claim 22  wherein said statin is a member selected from the group consisting of simvastatin, pravastatin, cerivastatin, mevastatin, fluindostatin, velostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, lovastatin, atorvastatin, bervastatin, NK-104, ZD-4522 and optical or geometric isomers thereof; and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.  
     
     
         28 .- 29 . (canceled).