COMBINATION OF A CALCIUM CHANNEL BLOCKER AND AN ANTIOXYDANT FOR TREATING ISCHEMIC DISEASES

Abstract: The present invention provides a pharmaceutical composition that can be used in the treatment of ischemic diseases of various symptoms and degrees of severity comprising a calcium channel blocker and an antioxidant. The present invention also provides a method of treating or preventing ischemic diseases comprising the administration of a calcium channel blocker and an antioxidant.

Description: CO BINATION OF A CALCIUM CHANNEL BLOCKER AND AN ANTIOXIDANT FOR TREATING ISCHEMIC DISEASES Field of Industrial Utility The present invention relates to a pharmaceutical composition for the treatment and prevention of ischemic diseases comprising a calcium channel blocker and an antioxidant. The present invention also relates to a method of treating or preventing ischemic diseases using a pharmaceutical composition comprising a calcium channel blocker and an antioxidant. Said method of treatment includes the use of calcium channel Mockers in combination with antioxi- dants as appropriate for individual cases of disease. It is generally held that the peroxidation of membranes and the sudden influx of calcium ions into cells are both involved in the damage that is caused in cells and tissues by ischemia. It is also held, although not unanimously, that these factors work in either a complementary or synergistic way, and that blocking these two routes would be more effective in lessening the damage caused in cells and tissues by ischemia. Research efforts to find a drag that blocks both routes have centered on searching for a single compound capable of blocking the two routes at the same time. Examples of such a compound are flunarizine [Karasawa et al., J. Pharm. Dyn., 5, 295-300 (1982)] and naphthotiaz- epinones (Japanese Patent Application (Kokai) Hei- 1-272575). However, no compounds have yet been found that possess both the calcium channel blocking action and the antioxidizing action in a balanced way, nor is it easy to search for such compounds; furthermore, the degree of balance between the two actions would vary with the specific disease. Problems to be Solved by the Invention An object of the present invention is to provide a phaπnaceutical composition capable of treating or preventing various types of ischemic diseases according to their severity. Means for Solving the Problems The present inventors conducted intensive studies with a view to attaining the above- stated object and found that by administering a combination of a calcium channel blocker and a certain type of antioxidant in appropriate proportions, ischemia-caused damage to cells and tissues could be lessened synergistically, and that the resulting effect was much more significant compared to the effect attained by administering the calcium channel blocker and the antioxidant individually. The present invention has been accomplished on the basis of this finding. INFORMATION DISCLOSURE German Patent DE 382 0840 (1989) describes an aqueous composition for the treatment of tissue damage from acute peripheral emboism comprising a calcium antagonist and a radical trapping agent. The antioxidant effect of calcium antagonists is discussed in Oyanagui, Ensho 12(2):137-44 (1992); Vanella, et al., Int J. Dev. Neurosci. 10(l):75-80 (1992); Mak, et al., Circ Res. 70(6): 1099- 103 (1992); Mak, et al., Circ. Res. 66(5):1449-52 (1990); and Robak, et al., Pharmacol. Res. Commun., 18(12)1107-17, 1986. SUMMARY OF THE INVENTION Accordingly, the present invention provides a pharmaceutical composition for the treatment and prevention of ischemic diseases comprising a calcium channel blocker and an antioxidant. The present invention also provides a method for treating or preventing ischemic diseases using a phaπnaceutical composition comprising a calcium channel blocker and an antioxidant. Said method of treatment includes the use of calcium channel Mockers in combina¬ tion with antioxidants as appropriate for individual cases of disease. The present invention also provides a use of an antioxidant to prepare a medicament which is administered with a calcium channel blocker to a patient in need thereof to treat or prevent ischemic diseases. The term "calcium channel blocker" as applicable herein means calcium antagonists, and typical examples include verapamil, diltiazem, nifedipine, nicardipine, flunarizine, nilvadipine, nisoldipine, nitrendipine, manidipine, benidipine, bepridil, bamidipine and pharmaceutically acceptable salts thereof. The term "antioxidant" as applicable herein means compounds that are capable of potentiating the suppression of lipid peroxidation, radical trapping and the anti-oxidating action of vitamin E, and typical examples include the amines disclosed in WO88/8424 (Japanese Patent Application (Kohyo) Hei-2-503198) and the amino-steroid having 20-26 carbon atoms that is disclosed in WO87/1706 (Japanese Patent Application (Kohyo) Sho-63-500868). Fat-soluble antioxidant vitamin E and water-soluble antioxidant vitamin C, which are generally considered to be antioxidants, are also known to have the ability to suppress lipid peroxidation and trap radicals; however, it has been demonstrated that they exhibit only weak effects even if used in combination with the calcium channel blocker in the experimental model created for the purpose of the present invention. The antioxidants used in the present invention have high affinity for membranes (i.e., it is a membrane targeted antioxidant) and is anticipated to develop its action on membranes for a prolonged time; this would have a close relationship with the synergistic effect achieved by the present invention. Preferred antioxidants are a bicyclic amine represented by the following general formula I, pharmaceutically acceptable salts thereof, and hydrates and solvates thereof; where: W 2 is -0-, -S-, -NR 54 - where R 54 is -H or C r C 3 alkyl, n 6 is 0, 1 or 2, R 7 is -H or -C r C 4 alkyl, -CO-(C r C 4 alkyl), -CO-φ or -prodrug where prodrug is -PO 2 -O " , -CO-CH 2 -CO-NH-CH 2 -SO 2 -O " , -CO CH^-^ j -Rg j where I^J is 1-7 and R 51 is -COO " , -N g j .- j Rg-*^ where Rg j . j and R51.2 are the same or different and are -H or C j -C 3 alkyl, - ISrtRg j _ 2R 5 j are the same or different and are -H or C j - C 3 alkyl, and where halide is -Cl or -Br, -CO-CH=CH-CO-O _ , -CO-N*-CH=CH-N=CH* where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, -CO-C*=C[(CH 2 ) n22 -NH 2 ]-CH=CH-CH=CH* where n 22 is 1 or 2 and where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, -CO-C*=CH-CH=C(-NR 52 )-CH=CH* where R 52 is -H or C r C 3 alkyl and where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, sugars], -CO-0-CH(CH 2 -O-CO-R 53 ) 2 where the R5 3 's are the same or different and are C r C 18 , -CO-(CH 2 ) 6 -CO-N(CH 3 )-CH 2 -CH 2 -S0 3 ~ cation "1" where cation + is sodium, potassium or trialkylammonium where alkyl is C j -C 3 , -CH2-O-CO-(CH )n2 -NR5i-iR5i_2 wnere -^l * R 5l-l ------ ^51-2 are as denne d above, -CO-NH-C 6 H 4 -R 55 where R 55 is -H or C r C 3 alkyl, -NO 2 , -NR5i.ιR 51 .2 he re R51. and R51.2 ar e as defined above and R 10 is -H or -CH 3 , R π is -H or -CH 3 , R 12 is -H or -CH 3 , [I] R 16 is ** s "H» "CH3, -CH 2 CH 3 or -φ and the other is -X 3 -M where X 3 is -CO-, -(CH 2 ) nl6 -CO- where n 16 is 1 or 2, -(CH 2 ) n3 - where n 3 is 1-6, or -CO-O-(CH 2 ) nl5 - where n 15 is 2-6, R 25 and R 26 are -H and where M is (I) -NR A R B where: (A) R A is (1) -(CH 2 ) m -NR M _ 1 -heteroaryl, where m is 2, 3 or 4, where RJ^.J is -H or C j -C- j alkyl, where heteroaryl is: (a) pyridin-2- (F-l), 3- (F-2) or 4-yl (F-3) or the N-oxide thereof optionally substituted by 1 or 2 R M _ 2 , being the same or different, where R M . 2 is (i) -F, (ϋ) -Cl, (iii) -Br, (iv) C r C 5 alkyl, (vi) -aryl, where aryl is phenyl optionally substituted with 1 through 2 -F, -Cl, -Br, C j -C***. alkoxy, -COOH, -NH 2 . C 1" 3 alkylamino, di(C 1 -C 3 )alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1- hexamethylenimino-, 1-heptamethylenimino-, C 2 -C acylamino, -NH-CHO, with 1 -F or -CF 3 or with 3,4-methylenedioxy and 3,4-ethylenedioxy; (vii) _N M-3 R M-3 wnere me are me same or different and are -H, C r C 3 alkyl or -CH 2 -CH=CH 2 , (viiiα) *CH 2 -(CH 2 ) -CH 2 -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring where q is 1 through 5, (viiiβ) *CH 2 -(CH 2 ) c -G-(CH 2 ) d -CH 2 -N*-where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring (F-4), where G is -O-, -S-, -SO-, -SO 2 - or is -H, C j -C*-** alkyl, or aryl as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, (ix) 3-pyrrolin-l-yl, (F-5) (x) pyπol-1-yl optionally substituted with C j -C 3 alkyl, (F-6) (xi) piperidin-1-yl optionally substituted with 1 or 2 C- [ -C 3 alkyl, (F-7) (xii) 1,2,3,6-tetrahydropyridin-l-yl, (F-8) (xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, (F-9) (xiv) 1,4-dihydro-l-pyridinyl substituted in the 4 position by two C j -C 3 alkyl being the same or different, (F-10) (xv) -OH, (xvi) C- C- j alkoxy, (xvii) -NR M . 7 -(CH 2 ) e -Q where Q is 2-pyridinyl where R j ^.γ is -H or C- [ -C 3 alkyl and e is 0 through 3, (xviii) pyridin-2-, 3- or 4-yl, (xix) -CF 3 , (xx) -CC1 3 , (xxi) -SCH 3 , (b) l,3,5-triazin-2-yl or the N-oxide thereof optionally substituted at the 4- and/or 6- position with R M _ 2 is as defined above, (F-l 1) (c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6-, and 5- and/or 6- position with R M _ 2 is as defined above, (F-12) (d) pyrimidin-2-yl optionally substituted at 4- and/or 6- position with 1 or 2 as is defined above, (F-l 3) (e) pyrazin-2-yl optionally substituted with 1 or 2 R jγ f_ as is defined above, (F-14) (f) imidazol-2-yl optionally substituted in the 1 position with CyC- alkyl or -aryl, where aryl is as defined above, and further optionally substituted with 1 or 2 R M _ 2 as defined above, (F-15) (g) l,3,4-triazol-2-yl optionally substituted in the 1 position with C j -C 3 alkyl or -aryl, where aryl is as defined above, and further optionally substituted with R M _ 2 as defined above, (F-l 6) (h) imidazol-4- or 5-yl optionally substituted in the 1 position with C* [ -C 3 alkyl or -aryl, where aryl is as defined above, and further optionally substituted with 1 or 2 R M _ 2 as defined above, (F-l 7) (i) benzo[b]thien-2-yl, (F-l 8) (j) indol-2-yl, (F-19) (k) benzo[b]thiazol-2-yl, (F-20) (1) benzimidazol-2-yl, (F-21) (m) 4-[2-[4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]- 1- piperazinyl]ethyl], (F-22) (n) l,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position with j ^ .2 as is defined above, (F-23) (2) -(CH 2 ) 2 _ -(l-piperazinyl) optionally substituted in the 4- position with - aryl or -heteroaryl as defined above, (F-24) (3) -heteroaryl, as defined above, (4) -(CH 2 ) m -X 4 where m is as defined above and where X 4 is (a) -O-CH 2 CH 2 -Y, where Y is C r C 3 alkylamino, di(C r C 3 )alkylamino where the alkyl groups are the same or different, C 3 -C 6 alkyleneimino, optionally substituted with 1 or 2 C j -C--. alkyl, (b) -NR M . 5 CH 2 CH 2 -Y, where R M _ 5 is -H or C r C 3 alkyl and Y is as defined above, (c) -(CH 2 ) -N(R M . 5 )-heteroaryl, where g is 2, 3 or 4, and where R M _ 5 and heteroaryl are as defined above, (5) -( CH 2)m "NR M-6 R M-8' wnere R M-6 is "H or C 1 "C 3 alk y ! and R M-8 is " aryl or -heteroaryl as defined above, or R M _g and R j ^. are taken together with the attached nitrogen atom to form a saturated mono-nitrogen yC 6 heterocyclic ring and where m is as defined above, (6) -(CHCHg^CH^aryl where b is 0 and f is 1 through 4 or b is 1 and f is 0 through 3, where aryl is as defined above, (7) -(CH 2 ) j -heteroaryl, where i is 1 through 4 and heteroaryl is as defined above, (8) (l-piperazinyl)acetyl substituted in the 4- position by heteroaryl where heteroaryl is as defined above, (F-25) (9) (l-piperazinyl)carbonylmethyl substituted in the 4- position by - heteroaryl where heteroaryl is as defined above, and (F-26) (B) R B is (1) -H, (2) C r C 3 alkyl, (3) Cg-Cγ cycloalkyl, (4) -(CH 2 ) m -NR M . 1 -heteroaryl, where m, R M _- [ and heteroaryl are as defined above, (5) (l-piperazinyl)-(C2-C 4 )alkyl optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24) (6) -(CH 2 ) m -X 4 , where m and X are as defined above, (7) "(CH 2 ) m -NR M _ 6 R M . 8 , where m, R M _ 6 and R M _ 8 are as defined above, (8) -(CHCH 3 ) b -(CH 2 ) f -R M _ 9 , where b, f and are as defined above, (9) 2-pyridinylmethyl, (10) 2-phenylethyl, (C) R A and R B are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-l-pyrrolidinyl optionally as the C j -C 3 alkyl ester or as a pharmaceutically acceptable salt, (F-27) (2) 2-(carboxy)τl-piperidϊnyl optionally as the C j ^ alkyl ester or as a pharmaceutically acceptable salt, (F-28) (3) 2-(carboxy)-l-hexamethyleneimino optionally as the C j -C^ alkyl ester or as a pharmaceutically acceptable salt, (F-29) (4) 2-(carboxy)-l-heptamet__yleneimino optionally as the C j -C 3 alkyl ester or as a pharmaceutically acceptable salt, (F-30) (5) 1-piperazinyl optionally substituted in the 4- position with R M-i2~CO- (CH 2 ) j - where R j j _ι 2 is -aryl, -heteroaryl, -NR M _ 13 -heteroaryl and 2-fiιranyl, where R M _ 3 is - H or C j -G- j alkyl, where j is 0 through 3, and aryl and heteroaryl are as defined above, (F-31) (6) 1-piperazinyl substituted in the 4-position with heteroaryl(CH 2 ) - where heteroaryl and j are as defined above with the proviso that j is not 1 when heteroaryl is pyridin- 4-yl or pyridin-4-yl substituted with C j -G*-* alkoxy, optionally substituted at the 2-position with - NR.44 R 45 where R ^ and R 45 are the same or different and are -H, C j -C 3 alkyl and where R^ and R 45 can be taken together with the attached nitrogen atom to form 1-pyπolidinyl, 1- morpholinyl and 1-piperidinyl, (F-32) (7) 1-piperazinyl substituted in the 4-position with aryl-(CH 2 )*-, where aryl and j are as defined above with the proviso that j is not 1, (F-33) (8) 4-hydroxy-l-piperidinyl substituted in the 4- position with aryl as defined above, " (F-34) (9) 1-piperazinyl substituted in the 4- position with heteroaryl-NR M _ 13 -CO- (CH 2 ) j -, where heteroaryl, j ^.ι 3 and i are as defined above; (F-35) (10) 1-piperazinyl substituted in the 4- position with -(CH 2 ) j -C*=C(2- pyridinyl)-N=N-C(2-pyridinyl)=C*H, where * and j are as defined above, (F-36) (11) 1-piperazinyl substituted in the 4- position with -(CH 2 ) j -[4-[2,6-bis(l- pyrrolidinyl)-4-pyrimidinyl]-l-piperazine] (F-37) (12) 1-piperazinyl substituted in the 4-position with C C- alkyl optionally substituted with 1 or 2 aryl, or (II) -C*=C(2-pyridinyl)-N=N-C(2-pyridinyl)=C*H where * is as defined above [II] n 6 is 0, R 16 is R i6-3 :R i6-4 where one of R 16 . 3 and R*^ is taken together with R 25 to form a second bond between the carbon atoms to which R 16 and R 25 are attached and the other of j6 _ 3 and j g^ is -X 3 -M where X 3 and M are as defined above, [III] n 6 is 1, R 25 and R 26 are taken together to form a second bond between the carbon atoms to which R 25 and R 26 are attached. Among the compounds of the general formula I shown above, particularly preferred antioxidants are 2-[[4-[2,6-bisφyrrolidino)-4-pyrimidinyl]-l-piperazinyl]-methyl]-3,4-dihydro- 2,5,7,8-tetramethyl-2H-l-benzopyran-6-ol or phaimaceutically acceptable salts thereof, hydrates or solvates thereof. More prefeπed antioxidants are an amino-substituted steroid represented by the following general formula Ila or lib and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof. (Ila) (lib) where: „^ is a single or double bond and ΛΛ ^ indicates that there are 2 possible orientations for the attached group, (1) α or β when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond; and R- Q is «- R ιιι-β- R ιi2- where one of R 11;l and R 112 is taken together with R-. to form a second bond between C 9 and C^ and the other of R ι π and R 112 is -H; R 9 is -Cl and R π is =0 or α-H:β-R 114 where R 11 is -Cl or -OH; R 9 is -H or -F and R is =0 or α-R 115 :β-R 116 , where one of R 115 and R 116 is -H, and the other of R 115 and R 116 is -H, -OH or C j -C 12 alkoxy; R 9 is -H or -F and R π is α-0-CO-R 117 :β-H, where R 117 is (A) C r C 3 alkyl, (B) C r C 12 alkoxy, (C) furanyl, (D) "*^ R i22 R 123* where one of R 122 and R 123 is -H, methyl or ethyl and the other is -H, C j -C alkyl or phenyl, (E) -XyX where X 3 is -0- or a valence bond, where X j is phenyl optionally substituted with 1 through 2 -Cl, -Br, C r C 3 alkoxy, -COOH, -NH 2 , C r C 3 alkylamino, di(C 1 -C 3 )alkylamino, where the alkyl groups are the same or different, 1- pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C2-C 4 acylamino and -NH-CHO or with 1 -F or -CF 3 ; where: (A) R 21 is (1) "(CH 2 ) m -NR 211 -X 2 , where m is 2, 3 or 4, where R 211 is -H or C C- alkyl, where X 2 is: (a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R 2 2 , being the same or different, where R 212 is (i) -F, (ϋ) -Cl, (ϋi) -Br, (iv) C r C 5 alkyl, (v) -CH 2 -CH=CH 2 , (vi) -X j , where X j is as defined above, (vii) "NR2i3 R 2i3 where the 2i3' s are the same or different and are -H, C r C 3 alkyl or -CH 2 -CH=CH 2 , (viiiα) *CH 2 -(CH 2 ) -CH 2 -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5, (viiiβ) *CH 2 -CH 2 -(CH 2 ) c -G-(CH 2 ) d -CH 2 -CH 2 -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where G is -0-, -S-, -SO-, -S0 2 - or -NHR 214 , where R^ is -H, C j -C 3 alkyl, or X j as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, (F-38) (ix) 3-ρyrrolin-l-yl, (F-39) (x) pyrrol- 1-yl optionally substituted with C j -G*. alkyl,(F-40) (xi) piperidin-1-yl optionally substituted with 1 or 2 C j -G j alkyl, (F-41) (xii) 1,2,3,6-tetrahydropyridin- 1-yl, (F- 2) (xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, (F-43) (xiv) 1,4-dihydro-l-pyridinyl substituted in the 4 position by two C j -G j alkyl being the same or different, (F-44) (xv) -OH, (xvi) C r C 3 alkoxy, (xvii) -NR 217 -(CH 2 ) e -Q where Q is 2-pyridinyl where R 217 is -H or C j -C 3 alkyl and e is 0 through 3, (xviii) pyridin-2-, 3- or 4-yl, (F-45, 46, 47) (b) l,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R 212 is as defined above, (F-48) (c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R 212 is as defined above, (F-49) (d) pyrimidin-2-yl optionally substituted at 4- and/or 6- position with 1 or 2 R^ as is defined above, (F-50) (e) pyrazin-2-yl optionally substituted with 1 or 2 R 212 as is defined above, (F-51) (f) imidazol-2-yl optionally substituted in the 1 position with C j -C- j alkyl or -X j , where X j is as defined above, and further optionally substituted with 1 or 2 R 212 as defined above, (F-52) (g) l,3,4-t_iazol-2-yl optionally substituted in the 1 position with C j -C 3 alkyl or -X j , where X j is as defined above, and further optionally substituted with R 212 as defined above, (F-53) (h) imidazol-4- or 5-yl optionally substituted in the 1 position with C j -C*- ) alkyl or -X j , where X j is as defined above, and further optionally substituted with 1 or 2 R 212 as defined above, (F-54) (i) benzo[b]tiιien-2-yl, (F-55) (j) indol-2-yl, (F-56) (k) benzo[b]thiazol-2-yl, (F-57) (1) benzimidazol-2-yl, (F-58) (m) 4-[2-[4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]-l- piperazinyl]ethyl]piperazinyl, (F-59) (n) l,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position with R 212 as is defined above, (F-60) (2) (l-piperazinyl)-(C 2 -C )alkyl optionally substituted in the 4-position with -X j or -X 2 as defined above, (3) -X 2 , as defined above, (4) -(CH 2 ) m -X 4 where m is as defined above and where X 4 is (a) -0-CH 2 CH 2 -Y, where Y is C r C 3 alkylamino, di(C r C 3 )alkylamino where the alkyl groups are the same or different, C 3 -C 6 alkyleneimino, optionally substituted with 1 or 2 C j -C 3 alkyl, (b) -NR 220 CH 2 CH 2 -Y, where R^ Q is -H or C j -C j alkyl and Y is as defined above, (c) -(CH 2 ) -N(R 220 )-X 2 , where g is 2, 3 or 4, and where R 220 and X 2 are as defined above, (5) "(CH 2 ) m -NR 222 R 223 , where R 22 2 is -H or CJ-GJ alkyl and R 223 is -X- j or -X 2 as defined above, or R 22 2 and R223 are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C 3 -C 6 heterocyclic ring and where m is as defined above, (6) -(CHCH 3 ) t) -(CH2)f*R224> where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R 2 24 is phenyl substituted with 1 through 3 -OH, CJ-GJ alkoxy, -NR225 226 where R225 and R 22 6 are the same or different and are -H, CJ-G-J alkyl or are taken together with the attached nitrogen atom to form a C 4 -C-*, cyclicamino ring, (7) -(CH 2 ) j -X2- where i is 1 through 4 and X 2 is as defined above, (8) (l-piperazinyl)acetyl substituted in the 4-position by X where X 2 is as defined above, (9) (l-piperazinyl)carbonylmethyl substituted in the 4- position by -X 2 where X 2 is as defined above, and (B) R 210 is (1) -H, (2) C r C 3 alkyl, (3) C 5 -C 7 cycloalkyl, (4) -(CH 2 ) m -NR 211 -X2, where m, R 211 and X 2 are as defined above, (5) (l-piperazinyl)-(C 2 -C 4 )alkyl optionally substituted in the 4- position with -X j or -X 2 as defined above, (6) -(CH 2 ) m -X 4 , where m and X 4 are as defined above, (7) "( CH 2- ) m" NR 222 R 223' where m, R^ and R 223 are as defined above, (8) -(CHCH 3 ) b -(CH 2 )^ R 224 , where b, f and R 22 are as defined above, (C) R 2 * [ and R 210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-l-pyrrolidinyl optionally as the C j -C j alkyl ester or as a pharmaceutically acceptable salt, (2) 2-(carboxy)-l-piperidinyl optionally as the C j ^ alkyl ester or as a pharmaceutically acceptable salt, (3) 2-(carboxy)-l-hexamethyleneimino optionally as the C j -C j alkyl ester or as a pharmaceutically acceptable salt, (4) 2-(carboxy)-l-heptamethyleneimino optionally as the C j -C 3 alkyl ester or as a pharmaceutically acceptable salt, (5) 1-piperazinyl substituted in the 4- position with R 2 2g-CO-(CH 2 ) j - where 228 ' s ~^1' "-^229^1 - m ~' ^-furanyl, where R 22 9 is -H or Cj-C-j alkyl, where j is 0 through 3 and X j is as defined above, (6) 1-piperazinyl substituted in the 4- position with X2-(CH 2 ) j -, where X 2 and j are as defined above, (7) 1-piperazinyl substituted in the 4- position with X j -(CH 2 )*-, where X j and j are as defined above, (8) 4-hydroxy-l-piperidinyl substituted in the 4-position with X j as defined above, (9) 1-piperazinyl substituted in the 4- position with X 2 -NR229-CO-(CH 2 ) i -, where X 2 , R 2 29 and i are as defined above; R 6 is α-R 61 :β-R 62 and R 10 is α-R 101 :β-R 102 , where one of R 61 and R 62 is -H, and the other is -H, -F or C j -G** alkyl; R 33 is -O or α-H:β-OR 34 or α-OR 3 :β-H, where R 34 is -H, -P(=O)(OH) 2 , -CO-CH 3 , -CO-C2H 5 , -CO-C 6 H 5 , -CO-O-CH 3 or -CO-O-C 2 H 5 ; R 165 is -H, -OH, -F or -CH 3 and R 166 is -H, -OH, -F, or -CH 3 , with the proviso that at least one of R 165 and R- 166 must be -H, where R 175 is -H, -OH, -CH 3 , -CH j CHg, 2 -Qη alkanoyloxy or -O-CO-X j ; Z is =0, =CH 2 or R 179 :-H where R 179 is -H or -CH 3 , where n is 0 through 6. Among the compounds of the general formula π shown above, particularly preferred antioxidants are 16α-methyl-21-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-l-piperazinyl]pregna- 1,4,9(1 l)-triene-3,20-dione or pharmaceutically acceptable salts thereof, hydrates or solvates thereof. Ischemic diseases are those diseases which are caused by occlusion of the blood stream and they include strokes (inclusive of subarachnoid hemoπhage) and cerebrovascular disorders that are either post-traumatic or sequela of brain surgery, as well as cardiovascular disorders such as angina pectoris, myocardiac infarction and arrhythmia caused upon reflowing of the coronary blood stream by PTCA/PTCR/OABG, and also damage due to bums, organ transplantation and radiation exposure. The term "treatment" as used herein means partial or total lessening of indications of the disease a patient suffers from; the teim "prevention" as used herein means partial or total avoidance of indications of a disease in a patient who, according to a doctor's diagnosis, may suffer from the disease or a related state unless the preventive measure is taken. The pharmaceutical compositions of the present invention are useful in various dosage forms that comply with the specific object of administration in light of its pharmacological actions. The compositions are manufactured by mixing a pharmaceutically effective amount of the specified compound, as an active ingredient, which is in a free state or in the form of an acid addition salt, a hydrate or a solvate, uniformly with a phaimaceutically acceptable carrier. The carrier can be selected from a broad spectrum in accordance with a dosage form that is suitable for administration, and peroral or parenteral preparations can be produced using conventional carrier substances for pharmaceutical formulation procedures, such as lactose, sucrose, glucose, mannitol, starch, crystalline cellulose, low substitution hydroxypropyl cellulose, magnesium stearate, talc, precipitated silicic anhydride, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, gelatin, aliphatic acid esters, glycerin, water, polyethylene glycol, propylene glycol, paraffin, carboxymethyl cellulose sodium and com oil. The thus formulated phaπnaceutical preparations may be used either in a solid state as powders, granules, tablets or capsules, or in a liquid state as solutions, suspensions, emulsions or as those which are dissolved or suspended in solvents just prior to use. Various pharmaceutical adjuvants may be added to the preparations, some examples being salts as preservatives, stabilizers, surfactants and buffers. The compositional ratio of the calcium channel blocker to the antioxidant should be determined according to various factors such as the type of disease to be treated or prevented, its severity and the route of administration; the weight ratio of the calcium channel blocker to the antioxidant is generally in the range of from about 0.1 to about 99.9 wt%, preferably from about 1 to 99 wt%. The calcium channel blocker and the antioxidant may be used as two components of a single preparation but, depending on the drug to be formulated, they may be mixed just prior to use. The effective dose of the pharmaceutical composition of the present invention should be determined by the doctor in charge in accordance with various factors such as the disease to be treated or prevented, the patient's age and body weight, the severity of the disease, the route of administration, and the types of calcium channel blocker and antioxidant to be combined. To give guide figures, the effective daily dose is 0.01-10 mg/kg for the calcium channel blocker and 0.05-300 mg/kg for the antioxidant The composition is preferably administered 1-4 times a day. A chart of the preferred antioxidants that can be used in the present invention is given below. Name Chemical Structure or 4-yl optionally substituted optionally as the N-oxide (F-3) 3-pyrrolin-l-yl •— N (F-5) pyπol-1-yl optionally substituted (F-6) piperidin-1-yl optionally substituted (F-7) 1 ,2,3,6-tetrahydropyridin- 1 -yl (F-8) - 1-hexamethyleneimino containing a 3- or 4-double bond or 3- and 5- double bonds (F-9) l,3,5-triazin-2-yl or the N j -oxide thereof optionally substituted at the 4- and/or 6- position (F-ll) pyrimidin-4-yl or the N j -oxide thereof optionally substituted at the 2- and/or 6- and 5- and/or 6- position (F-12) pyrimidin-2-yl optionally N— Λ /C R -2 ) 0-2 substituted N********-- 7 (F-13) pyrazin-2-yl optionally substituted (F-14) benzimidazol-2-yl (F-21) position (F-23) (l-piperazinyl)-(C 2 -C ) -(C2-C 4 alkyl) -N N-(aryl or heteroaryl) optionally substituted in the 4-position (F-24) ( 1 -piperazinyl)acetyl -f_0-CH2— N N-heteroaryl substituted in the 4-position (F-25) (l-piperazinyl)carbonyl-methyl -CHn-OO— N N— heteroaryl substituted in the 4-position (F-26) 2-(carboxy)-l-piperidinyl (F-28) 1-piperazinyl substituted in the 4-position (F-31) 1-piperaziniyl substituted in — N N- (C__2 j -heteroaryl the 4-position (F-32) -N N-CGH^-aryl 1-piperazinyl substituted in the 4-position (F-33) 4-hydroxy- 1 -piperidinyl substituted in the 4-position (F-34) 1-piperazinyl substituted in the 4-position 1-piperazinyl 3-pyrrolin-l-yl — N (F-39) ,G r C 3 alkyl pyπol-1-yl optionally substituted (F-40) piperidin-1-yl optionally substituted (F-41) 1,2,3,6-tetrahydropyridin-l-y (F-42) -o 1-hexamethyleneimino containing a 3- or 4-double bond or 3- and 5- double bonds (F-43) 1 ,4-dihydro- 1 -pyridinyl substituted in the 4-position (F-44) pyridine-2-yl optionally C R 212)0-2 substituted optionally as I the N-oxide ( P ) o-ι (F-45) pyridin-3-yl optionally , /( R 212)0-2 substituted optionally as the N-oxide (F-46) pyridin-4-yl optionally ^ ^ /( R 212)θ-2 substituted optionally as -<QN-CO)O-I the N-oxide (F-47) l,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position (F-48) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position (F-49) pyrimidin-2-yl optionally substituted (F-50) pyrazin-2-yl optionally N— ~ s Λ /( R 212)θ-2 substituted (F-51) imidazol-2-yl optionally R 212)θ-2 substituted (F-52) CJ-CJ alkyl or -Xi p peraz ny (F-59) l,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position (F-60) The following examples are provided for the purpose of illustrating the synergistic effect of the pharmaceutical composition of the present invention, as well as specific dosage forms into which it can be formulated. It should, however, be noted that the scope of the present invention is by no means limited by these examples. EXAMPLE 1 Synergistic Effect of the Combination of Calcium Channel Blocker and Antioxidant (test for Efficacy Against Potassium Cyanide (KCN)-Induced Lethality in Mice) Investigation was made on a KCN model to check whether the administration of a calcium channel blocker in combination with an antioxidant would have a significant effect against ischemic disease compared to the administration of individual agents. Male ICR mice weighing 30-40 g (6-8 weeks old) were used as experimental animals. The mice were injected intravenously with the test compounds. Five minutes later, the mice were injected intravenously with a lethal dose of KCN (3.0 mg/kg) as dissolved in physiological saline. The test compounds were 2-[[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-l-piperazinyl]- methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-l-penzopyran-6-ol dicitrate (hereinafter designated as "compound A") which was used as an antioxidant, and diltiazem as a calcium channel blocker. Compound A was administered in an amount of 30 mg/kg or 100 mg kg, and diltiazem was admimstered in an amount of 3 mg/kg or 10 mg/kg. The results are shown in Fig. 1. When compound A was administered alone, doses of 30 mg/kg and 100 mg/kg achieved 0% protection (i.e., all animals died) and 37.5 % protection, respectively, against KCN-induced lethality. When diltiazem was administered alone in doses of 3 mg/kg and 10 mg/kg, it achieved 0% protection and 40% protection, respectively, against KCN-induced lethality. In contrast, when compound A (30 mg/kg) and diltiazem (3 mg/kg) were administered in combination, the protection was 40%; when compound A (100 mg/kg) was administered in combination with 3 mg/kg or 10 mg/kg of diltiazem, 100% protection was achieved (i.e., all animals survived). These results show that administering the calcium channel blocker in combination with the antioxidant achieved a significant protective effect on the KCN model compared to administering either agent alone. The results also suggest that the influx of calcium ions and oxygen radicals may play an important role in ischemic diseases. EXAMPLE 2 Synergistic Effect of the Combination of Calcium Channel Blocker and Antioxidant (Test for KCN-induced Failure of Cerebral Energy Metabolism) The inhibitory action on cerebral energy metabolism that followed the arrest of oxygen supply as induced by KCN, as well as the efficacy of a calcium channel blocker and an antioxidant against that phenomenon were tested. Male ICR mice were injected intravenously with a sublethal dose of KCN (1.8 mg/kg). One minute later, the head of each animal was exposed to a microwave radiation to arrest the cerebral metabolism momentarily. The whole cerebrum was extracted, acidified with 1 ml of 3 M percMoric acid for 10 min, mixed with 3 ml of water and homogenized. Thereafter , the homogenate was centrifuged at 30,000 x g at 4°C for 10 min. The supernatant was neutralized with 1.5 ml of 2 M KHC0 3 and various energy metabolites (glucose, ATP, G-6-P, creatine phosphate, pyruvate and lactate) in the supernatant were measured by the enzymatic-fluorometric technique of Lowry and Passonneau. Calcium channel Mockers were admimstered perorally one hour before KCN injection, and an antioxidant was injected intravenously 5 min before KCN injection. The test compounds were nifedipine and diltiazem as calcium channel Mockers, and 16α-methyl-21-[4-[2,6- bis(pyrτolidino)-4-pyrimidinyl] - 1 -piperazinyl]pregna- 1,4,9(11 )-triene-3 ,20-dione mono methaensulfonate (hereinafter called "compound B") as antioxidant The results are shown in Table 1 (in which G-6-P stands for glucose-6-phosphate, Glu glucose, CRP creatine phosphate, Pyr pyruvate, and Lac lactate). The failure of metabolic energy induced by KCN is indicated as a shift from aerobic to anaerobic metabolism in the cerebrum; hence, the amounts of high-energy phosphorylated metabolites (G-6-P,ATP and creatine phosphate) and glucose decrease, but that of lactate increases (compare normal control and KCN control in Table 1). To begin with, the efficacy of administering the test compounds individually was checked. Administering compound B in high dose (20 mg/kg i.v.) or nifedipine (10 or 30 mg/kg, p.o.) was effective in lessening the KCN-induced failure of metabolic energy excepting the increase in lactate. On the other hand, no improvement was achieved at all in the parameters of interest by administering diltiazem in high dose (10, 30 or 100 mg/kg, p.o.) or compound B in low dose (2 or 6 mg/kg, i.v.) or nifedipine in low dose (3 mg/kg, p.o.). Next, the efficacy of administering compound B in combination with diltiazem or nifedipine was tested. As is clear from Table 1, administering compound B in low dose (2 or 6 mg/kg, i.v.) as combined with diltiazem (10 or 30 mg/kg, p.o.) or nifedipine (3 mg/kg, p.o.) achieved marked lessening of the KCN-induced failure of energy metabolism. Hence, it was demonstrated experimentally that the combined use of a calcium channel blocker and an antioxidant had synergistic effect on the failure of cerebral energy metabolism in histotoxic hypoxia under KCN induction. EXAMPLE 3 Pharmaceutical Formulation 1 (for oral administration) A tablet and a powder were prepared in the usual manner according to the formulas indicated below. Tablet Powder EXAMPLE 4 Pharmaceutical Formulation 2 (for injection) An injection was prepared in the usual manner according to the formula indicated below. EXAMPLE 5 Pharmaceutical Formulation 3 (for ointment) An ointment was prepared in the usual manner according to the formula indicated below. Chart 1 is a graph showing the synergistic effect of administering a calcium channel blocker and an antioxidant in combination to a KCN model. Normal Control 10 0.38 0.89*** 12.41*** 13.63*** j 7 73*** Q 74*** 34 *** ±0.01 ±0.04 ±0.39 ±0.35 ±0.51 ±0.06 ±0.19 KCN Control 0.44 0.40 6.17 7.71 9.58 0.29 . 9.04 ±0.01 ±0.03 ±0.33 ±0.35 ±0.60 ±0.04 ±0.37 Compound B 0.40 0.44 4.34 5.61 10.86 0.62*** 8.06 ±0.01 ±0.06 ±0.13 ±0.65 ±1.13 ±0.09 ±0.38 0.40 0.37 3.93 5.65 12.09 0.58** 8.08 ±0.01 ±0.03 ±0.13 ±0.30 ±0.50 ±0.04 ±0.33 Chart 1 Synergistic Effect of the Combination of Calcium Channel Blocker and Antioxidant % of survival Compound A (mg/kg) 30 100 0 30 100 Diltiazem (mg/kg) Q 0 3 3 3

Claims: CLAIMS 1. A pharmaceutical composition for the treatment and prevention of ischemic diseases comprising a calcium channel blocker and an antioxidant 2. A pharmaceutical composition of Claim 1 wherein the calcium channel blocker is selected from the group which comprises verapamil, diltiazem, nifedipine, nicardipine, flunarizine, nilvadipine, nisoldipine, nitrendipine, manidipine, benidipine, bepridil, barnidipine and pharmaceutically acceptable salts thereof; and the antioxidant is selected from the group which comprises a bicyclic amine of the following formula (I), pharmaceutically acceptable salts thereof, and hydrates and solvates thereof: (I) wherein: W 2 is -0-, -S-, -NR54- where R 54 is -H or C r C 3 alkyl, n 6 is 0, 1 or 2, R 7 is -H or -C r C 4 alkyl, -CO-(C r C 4 alkyl), -CO-φ or -prodrug where prodrug is -P0 2 -O " , -CO-CH 2 -CO-NH-CH 2 -SO 2 -0 " , -CO-CCH^- βj -R jj where n^ is 1-7 and R 51 is -COO " , -NR 51 _2R 51 _ 2 where R51.1 and R5i_ 2 are the same or different and are -H or C j -C 3 alkyl, - are me same or different and are -H or C- * - C~ alkyl, and where halide is -Cl or -Br, -CO-CH=CH-CO-0 " , -CO-N*-CH=CH-N=CH* where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, -CO-C*=C[(CH 2 ) n22 -NH 2 ]-CH=CH-CH=CH* where n 22 is 1 or 2 and where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, -CO-C*=CH-CH=C(-NR 52 )-CH=CH* where R 52 is -H or C r C 3 alkyl and where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, -CO-(CH 2 ) n21 -CO-O-[C 6 H 12 O 6 sugars], -CO-O-CH(CH 2 -0-CO-R 5 3) 2 where the R^'s are the same or different and are 1 "C 18' -CO-(CH 2 ) 6 -CO-N(CH 3 )-CH 2 -CH 2 -S0 3 " cation "1" where cation "1" is sodium, potassium or trialkylammonium where alkyl is C j ^, -CH 2 -0-CO-(CH 2 ) n2j -NR 51 _- ( R 51 _ 2 where n 21 , R 5i .ι and R5i_ 2 are as defined above, -CO-NH-C 6 H 4 -R 55 where R 55 is -H or C r C 3 alkyl, -N0 2 , -NR 5 R 51 _ 2 where R 51 _2 and R5 j . 2 are as defined above and R 10 is -H or -CH 3 , R π is -H or -CH 3 , R 12 is -H or -CH 3 , [I] R 16 is -CH 2 CH 3 or -φ and the other is -X3-M where X 3 is -CO-, -(CH 2 ) nl6 -CO- where n 16 is 1 or 2, -(CH 2 ) n3 - where n 3 is 1-6, or -CO-0-(CH 2 ) nl5 - where n 15 is 2-6, R 25 and R 26 are -H and where M is (I) -NR A R B where: (A) R A is (1) -(CH 2 ) m -NR M . 1 -heteroaryl, where m is 2, 3 or 4, where R j ^. j is -H or C j -C alkyl, where heteroaryl is: (a) pyridin-2- (F-l), 3- (F-2) or 4-yl (F-3) or the N-oxide thereof optionally substituted by 1 or 2 R M . , being the same or different, where -^ .2 is (0 " -F, (ii) -Cl, (iii) -Br, (iv) C r C 5 alkyl, (v) -CH 2 -CH=CH 2 , (vi) -aryl, where aryl is phenyl optionally substituted with 1 through 2 -F, -Cl, -Br, C r C 3 alkoxy, -COOH, -NH 2 , C r C 3 alkylamino, dKC- C^alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1- hexamethylenimino-, 1-heptamethylenimino-, C 2 -C acylamino, -NH-CHO, with 1 -F or -CF3 or with 3,4-methylenedioxy and 3,4-ethylenedioxy; (vii) nere me R M-3 S are me same or different and are -H, C r C 3 alkyl or -CH 2 -CH=CH 2 , (viiiα) *CH 2 -(CH 2 ) -CH 2 -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring where q is 1 through 5, (viiiβ) *CH 2 -(CH 2 ) c -G-(CH 2 ) d -CH 2 -N*-where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring (F-4), where G is -O-, -S-, -SO-, -SO 2 - or -NR M ^-, where R M-4 is -H, C-*^ alkyl, or aryl as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, (ix) 3-pyrrolin-l-yl, (F-5) (x) pyrrol- 1-yl optionally substituted with C j ^ alkyl, (F-6) (xi) piperidin-1-yl optionally substituted with 1 or 2 C j -C 3 alkyl, (F-7) (xii) 1,2,3,6-tetrahydropyridin-l-yl, (F-8) (xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, (F-9) (xiv) 1,4-dihydro-l-pyridinyl substituted in the 4 position by two C j -C 3 alkyl being the same or different, (F-10) (xv) -OH, (xvi) C j -C 3 alkoxy, (xvii) -NR M . 7 -(CH 2 ) e -Q where Q is 2-pyridinyl where is -H or C j -C 3 alkyl and e is 0 through 3, (xviii) pyridin-2-, 3- or 4-yl, (xix) -CF 3 , (xx) -CC1 3 , (xxi) -SCH 3 , (b) l,3,5-triazin-2-yl or the N-oxide thereof optionally substituted at the 4- and/or 6- position with R M _ 2 is as defined above, (F-l 1) (c) pyιimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6-, and 5- and/or 6- position with R M _ 2 is as defined above, (F-l 2) (d) pyrimidin-2-yl optionally substituted at 4- and/or 6- position with 1 or 2 R M _ 2 as is defined above, (F-l 3) (e) pyrazin-2-yl optionally substituted with 1 or 2 R M _ 2 as is defined above, (F-14) (f) imidazol-2-yl optionally substituted in the 1 position with C j -C 3 alkyl or -aryl, where aryl is as defined above, and further optionally substituted with 1 or 2 R M _ 2 as defined above, (F-15) (g) l,3,4-triazol-2-yl optionally substituted in the 1 position with C- C 3 alkyl or -aryl, where aryl is as defined above, and further optionally substituted with R M . 2 as defined above, (F-l 6) (h) imidazol-4- or 5-yl optionally substituted in the 1 position with C- ( -C 3 alkyl or -aryl, where aryl is as defined above, and further optionally substituted with 1 or piperazinyl]ethyl], (F-22) (n) l,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position with Rtø_ 2 as is defined above, (F-23) (2) -(CH 2 ) 2 ^-(l-piperazinyl) optionally substituted in the 4- position with - aryl or -heteroaryl as defined above, (F-24) (3) -heteroaryl, as defined above, (4) -(CH 2 ) m -X 4 where m is as defined above and where X 4 is (a) -O-CH 2 CH 2 -Y, where Y is C r C 3 alkylamino, di(C r C 3 )alkylamino where the alkyl groups are the same or different, C 3 -C 6 alkyleneimino, optionally substituted with 1 or 2 C j -C 3 alkyl, (b) -NR M . 5 CH 2 CH 2 -Y, where R M _ 5 is -H or C r C 3 alkyl and Y is as defined above, (c) -(CH 2 ) -N(R M . 5 )-heteroaryl, where g is 2, 3 or 4, and where R M _ 5 and heteroaryl are as defined above, (5) ~ ~ n ~ { R -8 is " aryl or -heteroaryl as defined above, or R-^g and R j ^.g are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C 3 -C 6 heterocyclic ring and where m is as defined above, (6) -(CHCH 3 ) b -(CH 2 ) r aryl where b is 0 and f is 1 through 4 or b is 1 and f is 0 through 3, where aryl is as defined above, (7) -(CH 2 ) j -heteroaryl, where i is 1 through 4 and heteroaryl is as defined above, (8) (l-piperazinyl)acetyl substituted in the 4- position by heteroaryl where heteroaryl is as defined above, (F-25) (9) (l-piperazinyl)carbonylmethyl substituted in the 4- position by - heteroaryl where heteroaryl is as defined above, and (F-26) (B) R B is (1) -H, (2) C r C 3 alkyl, (3) C 5 -C7 cycloalkyl, (4) - >-- heteroaryl are as defined above, (5) (l-piperazinyl)-(C 2 -C 4 )alkyl optionally substituted in the 4- position with -aryl or -heteroaryl as defined above, (F-24) (6) -(CH 2 ) m -X 4 , where m and X 4 are as defined above, (7) -(CH 2 ) m -NR M . 6 R M . g , where m, R M .g and R j ^. are <-- defined above, (8) -(CHCH 3 ) b -(CH 2 )f-R M _ 9 , where b, f and R M. are as defined above, (9) 2-pyridinylmethyl, (10) 2-phenylethyl, (C) R A and R B are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-l-pyrrolidinyl optionally as the C-*-C 3 alkyl ester or as a pharmaceutically acceptable salt, (F-27) (2) 2-(carboxy)-l-piperidinyl optionally as the C j ^ alkyl ester or as a pharmaceutically acceptable salt, (F-28) (3) 2-(carboxy)-l-hexamethyleneimino optionally as the C j -C^ alkyl ester or as a pharmaceutically acceptable salt, (F-29) (4) 2-(carboxy)-l -heptamethyleneimino optionally as the C-*-C 3 alkyl ester or as a pharmaceutically acceptable salt, (F-30) (5) 1-piperazinyl optionally substituted in the 4- position with (CH 2 ) j - where RM-12 1S -aryl. -heteroaryl, -NR M _ 13 -heteroaryl and 2-f ranyl, where j ^.^ is - H or C j -C 3 alkyl, where j is 0 through " 3, and aryl and heteroaryl are as defined above, (F-31) (6) 1-piperazinyl substituted in the 4-position with heteroaryl(CH 2 ) j - where heteroaryl and j are as defined above with the proviso that j is not 1 when heteroaryl is pyridin- 4-yl or pyridin-4-yl substituted with C j -C^ alkoxy, optionally substituted at the 2-position with - NR44R45 where R 4 and R 5 are the same or different and are -H, C j ^ alkyl and where R^ and R 45 can be taken together with the attached nitrogen atom to forai 1-pyrrolidinyl, 1- morpholinyl and 1-piperidinyl, (F-32) (7) 1-piperazinyl substituted in the 4-position with aryl-(CH 2 ) j -, where aryl and j are as defined above with the proviso that j is not 1, (F-33) (8) 4-hydroxy-l-piperidinyl substituted in the 4- position with aryl as defined above, (F-34) (9) 1-piperazinyl substituted in the 4- position with heteroaryl-NR j ^.^-CO- (CH 2 )p where heteroaryl, and i are as defined above; (F-35) (10) 1-piperazinyl substituted in the 4- position with -(CH 2 )--C*=C(2- pyridinyl)-N=N-C(2-pyridinyl)=C*H, where * and j are as defined above, (F-36) (11) 1-piperazinyl substituted in the 4- position with -(CH 2 ) j -[4-[2,6-bis(l- pyrrolidinyl)-4-pyrimidinyl] - 1 -piperazine] (F-37) (12) 1-piperazinyl substituted in the 4-position with C j -G- j alkyl optionally substituted with 1 or 2 aryl, or (II) -C*=C(2-pyridinyl)-N=N-C(2-pyridinyl)=C*H where * is as defined above [II] n 6 is 0, R 16 is i6_ 3 - i 6-4 where one of R^ . 3 and R-^g^ is taken together with R^ 5 to form a second bond between the carbon atoms to which R j g and R 2j are attached and the other of R j 6. 3 and R j g^ is -X 3 -M where X 3 and M are as defined above, [m] n 6 is 1, R 25 and R 26 are taken together to form a second bond between the carbon atoms to which R 25 and R 2 g are attached. 3. A pharmaceutical composition of Claim 2 wherein the calcium channel blocker is 2-[[4- [2,6-bisφyrrolidino)-4-pyrirru^inyl]-l-pipeι^inyl]-methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-l- benzopyran-6-ol or pharmaceutically acceptable salts thereof, or hydrates and solvates thereof. 4. A pharmaceutical composition of Claim 1 wherein the calcium channel blocker is selected from the group which comprises verapamil, diltiazem, nifedipine, nicardipine, flunarizine, nilvadipine, nisoldipine, nitrendipine, manidipine, benidipine, bepridil, bamidipine and pharmaceutically acceptable salts thereof; and the antioxidant is selected from the group which comprises an amino-substituted steroid of the following formula (II a) or (II b), pharmaceutically acceptable salts thereof, and hydrates and solvates thereof: (Ila) (lib) wherein: „^ is a single or double bond and * Λ/ ~ indicates that there are 2 possible orientations for the attached group, (1) α.or β when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond; and R j j is α-R 11;l :β-R 112 , where one of RJJ-J and R 112 is taken together with Rg to form a second bond between C 9 and C^ and the other of RJJJ and R 112 is -H; R is -Cl and R n is =0 or α-H:β-R 114 where R 11 is -Cl or -OH; R 9 is -H or -F and RJJ is =0 or α-R 115 :β-R 116 , where one of R 115 and R 116 is -H, and the other of R 115 and R 116 is -H, -OH or C j -C*-^ alkoxy; R 9 is -H or -F and R n is α-0-CO-R 117 :β-H, where R 117 is (A) C r C 3 alkyl, (B) C r C 12 alkoxy, (C) furanyl, (D) " NR 122 R 123' wnere one °f R 122 m ~- R 123 is ~H ' metn y 1 or ^Y 1 mι - the other is -H, C j -C alkyl or phenyl, (E) -X 3 -X j , where X 3 is -0- or a valence bond, where X j is phenyl optionally substituted with 1 through 2 -Cl, -Br, C r C 3 alkoxy, -COOH, -NH 2 , C r C 3 alkylamino, di(C j -C 3 )alkylamino, where the alkyl groups are the same or different, 1- pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C 2 -C 4 acylamino and -NH-CHO or with 1 -F or -CF 3 ; wherein: (A) R 21 is (1) "(CH 2 ) m -NR 211 -X 2 , where m is 2, 3 or 4, where R 211 is -H or C j -C 3 alkyl, where X 2 is: (a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R 212 , being the same or different, where R 212 is (i) -F, (ϋ) -Cl, (iii) -Br, (iv) C r C 5 alkyl, (v) -CH 2 -CH=CH 2 , (vi) -X j , where X j is as defined above, (vii) -NR213R213 where the R 2j3 's are the same or different and are -H, C j -C 3 alkyl or -CH 2 -CH=CH 2 , (viiiα) *CH 2 -(CH 2 ) -CH 2 -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5, (viiiβ) *CH 2 -CH 2 -(CH 2 ) c -G-(CH 2 ) d -CH 2 -CH 2 -N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where G is -0-, -S-, -SO-, -S0 2 - or -NHR 214 , where R 21 is -H, C j -C 3 alkyl, or X j as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, (F-38) (ix) 3-pyrrolin-l-yl, (F-39) (x) pyrrol- 1-yl optionally substituted with C j -C 3 alkyl,(F-40) (xi) piperidin-1-yl optionally substituted with 1 or 2 C j -C 3 alkyl, (F-41) (xii) 1,2,3,6-tetrahydropyridin-l-yl, (F-42) (xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, (F-43) (xiv) 1,4-dihydro-l-pyridinyl substituted in the 4 position by two C j -C 3 alkyl being the same or different, (F-44) (xv) -OH, (xvi) C j -C 3 alkoxy, (xvii) -NR 217 -(CH 2 ) e -Q where Q is 2-pyridinyl where R 217 is -H or C j -C-3 alkyl and e is 0 through 3, (xviii) pyridin-2-, 3- or 4-yl, (F-45, 46, 47) (b) l,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R 212 is as defined above, (F-48) (c) pyrimidin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R 212 is as defined above, (F-49) (d) pyrimidin-2-yl optionally substituted at 4- and/or 6- position with 1 or 2 R 212 as is defined above, (F-50) (e) pyrazin-2-yl optionally substituted with 1 or 2 R 212 as is defined above, (F-51) (f) imidazol-2-yl optionally substituted in the 1 position with CyC- alkyl or -X j , where X j is as defined above, and further optionally substituted with 1 or 2 R 212 as defined above, (F-52) (g) l,3,4-triazol-2-yl optionally substituted in the 1 position with CyC- alkyl or -X j , where X j is as defined above, and further optionally substituted with R 212 as defined above, (F-53) (h) imidazol-4- or 5-yl optionally substituted in the 1 position with CyC- alkyl or -X j , where X j is as defined above, and further optionally substituted with 1 or 2 R 212 as defined above, (F-54) (i) benzo[b]thien-2-yl, (F-55) (j) indol-2-yl, (F-56) . (k) benzo[b]thiazol-2-yl, (F-57) (1) benzimidazol-2-yl, (F-58) (m) 4-[2-[4-[2,6-bis(l-pyιτolidinyl)-4-pyrimidinyl]-l- piperazinyl]ethyl]piperazinyl, (F-59) (n) l,2,4-triazin-3-yl optionally substituted at the 5- and/or 6- position with R 212 as is defined above, (F-60) (2) (l-piperazinyl)-(C 2 -C )alkyl optionally substituted in the 4-position with -X j or -X 2 as defined above, (3) -X 2 , as defined above, (4) -(CH 2 ) m -X 4 where m is as defined above and where X is (a) -O-CH 2 CH 2 -Y, where Y is C r C 3 alkylamino, di(C r C 3 )alkylamino where the alkyl groups are the same or different, C 3 -C 6 alkyleneimino, optionally substituted with 1 or 2 CyC- alkyl, (b) -NR 220 CH 2 CH 2 -Y, where R^ is -H or C j -C^ alkyl and Y is as defined above, (c) -(CH 2 ) -N(R 220 )-X 2 , where g is 2, 3 or 4, and where R 220 and X 2 are as defined above, (5) "(CH2. m -N 222 R 223' where R 222 is -H or CyC- alkyl and R 223 is -X j or -X 2 as defined above, or R 222 and R 223 are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C 3 -C 6 heterocyclic ring and where m is as defined above, (6) -(CHCH 3 ) b -(CH 2 ) f -R 224 , where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R 22 is phenyl substituted with 1 through 3 -OH, C1-C3 alkoxy, -N R 225 R 226 wnere R 225 m ~- R 226 are me same or different and are -H, CyC- alkyl or are taken together with the attached nitrogen atom to foim a ^-Cy cyclicamino ring, (7) -(CH 2 ) j -X 2 , where i is 1 through 4 and X 2 is as defined above, (8) (l-piperazinyl)acetyl substituted in the 4-position by X 2 where X2 is as defined above, (9) (l-piperazinyl)carbonylmethyl substituted in the 4- position by -X 2 where X 2 is as defined above, and (B) R 210 is (1) -H, (2) C r C 3 alkyl, (3) Cg-Cy cycloalkyl, (4) "(CH 2 ) m -NR 211 -X 2 , where m, R 211 and X 2 are as defined above, (5) (l-piperazinyl)-(C 2 -C 4 )alkyl optionally substituted in the 4- position with -X j or -X 2 as defined above, (6) -(CH 2 ) m -X 4 , where m and X 4 are as defined above, (7) ~(CH 2 ) m -NR 222 R 223 , where m, R222 ------ R 223 ^^ -^ defined above, (8) -(CHCH 3 ) b -(CH 2 ) f -R224» where b, f and R^ are as defined above, (C) R 2j and R 2j0 are taken together with the attached nitrogen atom to foπn a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-l-pyrrolidinyl optionally as the CyC- alkyl ester or as a pharmaceutically acceptable salt (2) 2-(carboxy)-l-piperidinyl optionally as the CyC- alkyl ester or as a pharmaceutically acceptable salt (3) 2-(carboxy)-l-hexamethyleneimino optionally as the CyC- alkyl ester or as a pharmaceutically acceptable salt, (4) 2-(carboxy)-l -heptamethyleneimino optionally as the C j -C 3 alkyl ester or as a pharmaceutically acceptable salt, (5) 1-piperazinyl substituted in the 4- position with R 22 g-CO-(CH 2 ) j - where R 228 * s "^1* "* NR 229^1 an ~ 2-furanyl, where R 229 is -H or CyC- alkyl, where j is 0 through 3 and X j is as defined above, (6) 1-piperazinyl substituted in the 4- position with X 2 -(CH 2 ) j -, where X 2 and j are as defined above, (7) 1-piperazinyl substituted in the 4- position with X 1 -(CH 2 )-, where X j and j are as defined above, (8) 4-hydroxy-l-piperidinyl substituted in the 4-position with X j as defined above, (9) 1-piperazinyl substituted in the 4- position with X 2 -NR 229 -CO-(CH 2 ) j -, where X 2 , R 229 and i are as defined above; R 6 is α-R 61 :β-R 62 and R 10 is α -Rιoι : β _ i02- wnere one °f R 61 anc - 62 ~ s '** ' m ~- tne other is -H, -F or CyC- alkyl; R 33 is -O or α-H:β-OR 3 or α-OR 34 :β-H, where R 3 is -H, -P(=0)(OH) 2 , -CO-CH 3 , -CO-C 2 H 5 , -CO-C 6 H 5 , -CO-0-CH 3 or -CO-0-C 2 H 5 ; R 165 is -H, -OH, -F or -CH 3 and R 166 is -H, -OH, -F, or -CH 3 , with the proviso that at least one of R 165 and R- 166 must be -H, where R 175 is -H, -OH, -CH 3 , -CH 2 CH 3 , C j ,-^ alkanoyloxy or -O-CO-X j ; Z is =0, =CH 2 or R 179 :-H where R 179 is -H or -CH 3 , where n is 0 through 6. 5. A pharmaceutical composition of Claim 4 wherein the calcium channel blocker is 16α- methyl-21-[4-[2,6-bisφyrrolidine)-4-pyrimidinyl]-l-piperazinyl]pregna-l,4,9(ll)-triene-3,20- dione or pharmaceutically acceptable salts thereof, or hydrates and solvates thereof. 6. Use of an antioxidant to prepare a medicament which is administered with a calcium channel blocker to a patient in need thereof to treat or prevent ischemic diseases. 7. A method of treating or preventing ischemic diseases comprising the administration of an effective amount of a calcium channel blocker and an antioxidant to a patient in need thereof.

Inventors: HASHIMOTO MUNEHIRO, KUNIHARA MINEO, LIOU SHYH-YUH, HASHIMOTO, MUNEHIRO, KUNIHARA, MINEO, LIOU, SHYH-YUH
Applicants: HASHIMOTO MUNEHIRO, KUNIHARA MINEO, LIOU SHYH YUH, UPJOHN CO, HASHIMOTO, MUNEHIRO, KUNIHARA, MINEO, LIOU, SHYH-YUH, THE UPJOHN COMPANY
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61K45, A61K47, A61P9