Nitrogen-containing cyclic compound and pharmaceutical composition containing the compound

Abstract

The present invention provides a novel compound having a superior calcium antagonism, in particular, a neuron-selective calcium antagonism. Namely, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. In the formula, Ar indicates an optionally substituted 5- to 14-membered aromatic ring etc.; the ring A indicates any one ring selected from a piperazine, a homopiperazine, a piperidine and the like; the ring B indicates an optionally substituted C 3-14 hydrocarbon ring etc.; E indicates a single bond, a group represented by the formula —CO—, etc.; X indicates a single bond, an oxygen atom etc.; R 1 indicates a hydrogen atom, a halogen atom, a hydroxyl group etc.; and D 1 , D 2 , W 1 and W 2 are the same as or different from each other and each represents a single bond or an optionally substituted C 1-6 alkylene chain.

1 . A compound represented by the following formula (I), a salt thereof or a hydrate of them.  
       
         
           
           
               
               
           
         
         In the formula, Ar is (1) a C 6-14  aromatic hydrocarbon cyclic group which maybe substituted, (2) a 5- to 14-membered aromatic heterocyclic group which may be substituted, (3) a C 1-6  alkyl group substituted with a C 6-14  aromatic hydrocarbon cyclic group which may be substituted or (4) a C 1-6  alkyl group substituted with a 5- to 14-membered aromatic heterocyclic group which may be substituted; the ring A indicates a piperazine ring, homopiperazine ring, piperidine ring, homopiperidine ring, pyrrolidine ring or diazabicyclo[2,2,1]heptane ring which may be substituted, respectively; the ring B indicates (1) a C 3-14  hydrocarbon ring which may be substituted or (2) a 5- to 14-membered heterocyclic ring which may be substituted; E indicates (1) a single bond, a group represented by the formula (2) —CO— or (3) —CH(OH)—; X indicates (1) a single bond, (2) an oxygen atom, (3) a sulfur atom, (4) a C 1-6  alkylene chain which may be substituted, a group represented by (5) the formula —NR 2 — (wherein R 2  indicates a hydrogen atom, or a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a lower acyl group or a C 1-6  alkylsulfonyl group which maybe substituted), (6) —CO—, (7) —COO—, (8) —OOC—, (9) —CONR 3 — (wherein R 3  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (10) —NR 4 CO— (wherein R 4  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (11) —SO—, (12) —SO 2 —, (13) —SONR 5 — (wherein R 5  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (14) —NR 6 SO— (wherein R 6  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (15) —SO 2 NR 7 — (wherein R 7  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (16) —NR 8 SO 2 — (wherein R 8  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (17) >C═N—OR 9  (wherein R 9  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (18) —NR 10 —W 3 —O— (wherein R 10  indicates a hydrogen atom or a C 1-6  alkyl group, a C 3 - 8  cycloalkyl group, a lower acyl group or a C 1-6  alkylsulfonyl group which may be substituted; and W 3  indicates a C 1-6  alkylene group which may be substituted), (19) —NH—CO—NH—, (20) —NH—CS—NH—, (21) —C(═NR 15 )NR 16 — (wherein R 15  and R 16  are the same as or different from each other and each indicates a hydrogen atom, a nitrile group, a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-8  cycloalkyl group or a C 3-8  cycloalkenyl group), (22) —NHC(═NH)—, (23) —O—CO—S—, (24) —S—CO—O—, (25) —OCOO—, (26) —NHCOO—, (27) —OCONH—, (28) —CO(CH 2 ) m O— (wherein m indicates 0 or an integer of 1 to 6), (29) —CHOH— or (30) —CHOH(CH 2 ) n O— (wherein n indicates 0 or an integer of 1 to 6); R 1  indicates (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C 1-6  alkyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (5) a C 2-6  alkenyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (6) a C 2 - 6  alkynyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (7) a C 3-8  cycloalkyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (9) a C 1-6  alkoxy-C 1-6  alkyl group, (10) an amino-C 1-6  alkyl group in which the nitrogen may be substituted, (11) a group represented by the formula —N(R 11 )R 12 — (wherein R 11  and R 12  are the same as or different from each other and each indicates a hydrogen atom or a C 1-6  alkyl group), (12) an aralkyl group, (13) a morpholinyl group, (14) a thiomorpholinyl group, (15) a piperidyl group, (16) a pyrrolidinyl group or (17) a piperazinyl group; and D 1 , D 2 , W 1  and W 2  are the same as or different from each other and each indicates (1) a single bond or (2) a C 1-6  alkylene chain which may be substituted,  
         provided that, in the above definition,  
         1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine;  
         1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine; and  
         1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine are excluded.  
       
     
     
         2 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein Ar is a C 6-14  aromatic hydrocarbon ring or 5- to 14-membered aromatic heterocyclic ring, which may be substituted.  
     
     
         3 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein Ar is a thiophene ring or benzene ring, which may be substituted.  
     
     
         4 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein Ar is a C 6-14  aromatic hydrocarbon ring or 5- to 14-membered aromatic heterocyclic ring, which may be substituted with anyone or more groups selected from a nitrile group and a halogen atom.  
     
     
         5 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein Ar is a thiophene ring or a benzene ring which may be substituted with anyone or more groups selected from a nitrile group and a halogen atom, respectively.  
     
     
         6 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the ring A is a piperazine ring, a homopiperazine ring or a piperidine ring.  
     
     
         7 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the ring A is a piperazine ring.  
     
     
         8 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the ring A is a piperazine ring, a homopiperazine ring or a piperidine ring which may be substituted with any one or more groups selected from a hydroxyl group, a halogen atom, a cyano group, a C 1-6  alkyl group which may be substituted, a C 2-6  alkenyl group which may be substituted, a C 2-6  alkynyl group which may be substituted, a C 1-6  alkoxy group which may be substituted, a C 2-6  alkenyloxy group which may be substituted, a C 1-6  alkylcarbonyl group which may be substituted, a C 2-6  alkenylcarbonyl group which may be substituted, a C 1-6  alkoxycarbonyl group which may be substituted and a C 2-6  alkenyloxycarbonyl group which may be substituted.  
     
     
         9 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the ring B is a C 6-14  aromatic hydrocarbon ring or a 5- to 14-membered aromatic heterocyclic ring which may be substituted, respectively.  
     
     
         10 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the ring B is a benzene, a thiophene, a pyridine, a 1,4-benzodioxane, an indole, a benzothiazole, a benzoxazole, a benzimidazole, a 2-keto-1-benzimidazole, a thiazole, an oxazole, an isoxazole, a 1,2,4-oxadiazole, an indanone, a benzofuran, a quinoline, a 1,2,3,4-tetrahydroquinoline, a naphthalene or a 1,2,3,4-tetrahydronaphthalene which may be substituted, respectively.  
     
     
         11 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the ring B is a C 6-14  aromatic hydrocarbon ring or a 5- to 14-membered aromatic heterocyclic ring which may be substituted with any one or more groups selected from a halogen atom, a nitrile group, a C 1-6  alkyl group, a lower acyl group, a C 1-6  alkylsulfonyl group and an aralkyl group, respectively.  
     
     
         12 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein D 1  and D 2 are the same as or different from each other and each represents (1) a single bond or (2) a C 1-6  alkylene chain which may be substituted with any one or more groups selected from a hydroxyl group, a halogen atom, a nitrile group, a C 1-6  alkyl group, a C 2 - 6  alkenyl group and a C 1-6  alkoxy group.  
     
     
         13 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein E is a single bond.  
     
     
         14 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein D 1  and D 2  are a C 1-6  alkylene chain; and E is a single bond.  
     
     
         15 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the partial structure -D 1 -E-D 2 - is a C 1-4  alkylene group.  
     
     
         16 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein W 1  and W 2  are the same as or different from each other and each represents (1) a single bond or (2) a C 1-6  alkylene chain which may be substituted with any one or more groups selected from hydroxyl group, a halogen atom, a nitrile group, a C 1-6  alkyoxy group and a C 2-6  alkenyloxy group.  
     
     
         17 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein W 1  is (1) a single bond or (2) a C 1-6  alkylene chain which may be substituted with any one or more groups selected from (i) a nitrile group, (ii) a C 1-6  alkyl group which may be substituted with any one or more groups selected from a C 1-6  alkoxy group and a C 2-6  alkenyloxy group and (iii) a C 2-6  alkenyl group; and W 2  is a single bond.  
     
     
         18 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein W 1  and W 2  are the same as or different from each other and each is a C 1-6  alkylene chain substituted with any one or more groups selected from a C 1-6  alkyl group and a C 2-6  alkenyl group, and further the above-mentioned C 1-6  alkyl group and/or C 2-6  alkenyl group may be bound together to form a ring or the above-mentioned C 1-6  alkyl group or C 2-6  alkenyl group is bound to the ring B or X to form a ring.  
     
     
         19 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein X is (1) a single bond, (2) an oxygen atom, a group represented by (3) the formula —NR 2 — (wherein R 2  indicates a hydrogen atom, or a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a lower acyl group or a C 1-6  alkylsulfonyl group which may be substituted), (4) —NR 10 —W 3 —O— (wherein R 10  indicates a hydrogen atom, or a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a lower acyl group or a C 1-6  alkylsulfonyl group which may be substituted; and W 3  indicates a C 1-6  alkylene group which may be substituted) or (5) —NH—SO 2 —.  
     
     
         20 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein X is (1) an oxygen atom, a group represented by (2) the formula —NR 2 — (wherein R 2  indicates a hydrogen atom, or a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a lower acyl group or a C 1-6  alkylsulfonyl group which may be substituted) or (3) —NH—SO 2 —.  
     
     
         21 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the partial structure —W 1 —X—W 2 — is a C 1-6  alkylene group which may be substituted.  
     
     
         22 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein W 1  is a C 1-6  alkylene chain which may be substituted; W 2  is a single bond; and X is an oxygen or a group represented by the formula —NR 2 — (wherein R 2  has the same meaning as the above-mentioned definition).  
     
     
         23 . The compound according to  claim 22 , a salt thereof or a hydrate of them, wherein the substituent of W 1  is any one or more groups selected from (1) a nitrile group, (2) a C 1-6  alkyl group which may be substituted with a C 1-6  alkyoxy group or a C 2-6  alkenyloxy group and (3) a C 2-6  alkenyl group; and R 2  is a C 1-6  alkyl group which may be substituted.  
     
     
         24 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein R 1  is a C 1-6  alkyl group.  
     
     
         25 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein R 1  is a methyl group, an ethyl group, a n-propyl group or an isopropyl group.  
     
     
         26 . The compound represented by the following formula (II), a salt thereof or a hydrate of them.  
       
         
           
           
               
               
           
         
         In the formula, R 1  has the same meaning as in the above definition; R 13  and R 14  are the same as or different from each other and each indicates (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a mercapto group, (5) a C 1-6  alkyl group which may be substituted with any one or more groups selected from a hydroxyl group and a halogen atom, (6) a C 1-6  alkoxy group which may be substituted with any one or more groups selected from a hydroxyl group, a halogen atom and a C 1-6  alkoxycarbonyl group, (7) a nitro group, (8) an amino group which may be substituted, (9) a cyano group, (10) a carboxyl group, (11) a C 1-6  alkoxycarbonyl group, (12) a C 1-6  thioalkoxy group, (13) a C 1-6  alkylsulfonyl group, (14) a lower acyl group, (15) a C 6-14  aromatic hydrocarbon cyclic group which may be substituted, (16) a 5- to 14-membered aromatic heterocyclic group which may be optionally substituted, (17) an aryloxy group or (18) an aralkyloxy group, or (19) R 13 s themselves or R 14 s themselves may be bound together to form (i) an aliphatic ring which may be substituted, (ii) a heterocyclic ring which may be substituted or (iii) an alkylenedioxy group; n indicates 0 or an integer of 1 to 3; p indicates an integer of 1 to 6; q indicates an integer of 1 to 6; and r indicates 0 or an integer of 1 to 5,  
         provided that, in the above definition,  
         1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine;  
         1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine; and  
         1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine are excluded.  
       
     
     
         27 . A compound represented by the following formula (III), a salt thereof or a hydrate of them.  
       
         
           
           
               
               
           
         
         In the formula, R 1  and R 2 have the same meanings as defined above; R 13  and R 14  are the same as or different from each other and each indicates (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a mercapto group, (5) a C 1-6  alkyl group which may be substituted with any one or more groups selected from a hydroxyl group and a halogen atom, (6) a C 1-6  alkoxy group which may be substituted with any one or more groups selected from a hydroxyl group, a halogen atom and a C 1-6  alkoxycarbonyl group, (7) a nitro group, (8) an amino group which may be substituted, (9) a cyano group, (10) a carboxyl group, (11) a C 1-6  alkoxycarbonyl group, (12) a C 1-6  thioalkoxy group, (13) a C 1-6  alkylsulfonyl group, (14) a lower acyl group, (15) a C 6-14  aromatic hydrocarbon cyclic group which may be substituted, (16) a 5- to 14-membered aromatic heterocyclic group which may be substituted, (17) an aryl oxy group or (18) an aralkyl oxy group, or (19) R 13 s themselves or R 14 s themselves may be bound together to form (i) an aliphatic ring which may be substituted, (ii) a heterocyclic ring which may be substituted or (iii) an alkylenedioxy group; n indicates 0 or an integer of 1 to 3; p indicates an integer of 1 to 6; q indicates an integer of 1 to 6; r indicates 0 or an integer of 1 to 5.  
       
     
     
         28 . The compound according to  claim 1 , a salt thereof or a hydrate of them, wherein the compound is any one selected from 
 4-[(4-cyano-5-methyl-4-phenyl)hexyl]-N-(4-fluorophenyl)-N′-(2-methylpropyl)-1(2H)-pyrazinecarboxyimidamide;    1-isopropyl-4-[4-(1-isobutyl-1H-benzo[d]imidazol-2-yl)piperazino]-1-phenylbutyl cyanide;    1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[3-(5-cyano-2-thienyl)propyl]piperazine;    1-[4-cyano-5-methyl-4-(3-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-{4-cyano-5-methyl-4-[4-(2-cyano)-thienyl]hexyl}-4-[2 -(3-cyanophenoxy)ethyl]piperazine;    1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[(2-benzoxazolyl)amino]piperidine;    1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine;    1-[4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl]-(3R)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine;    1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(benzothiazolyl]piperazine;    1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-methoxy)benzothiazolyl]piperazine;    1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-benzoxazolyl]piperazine;    1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(2-quinolinyl]piperazine;    4-[4-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutyl cyanide;    4-[4-(1-ethyl-1H-benzo[d]imidazol-2-yl)-1,4-diazepan-1-yl]-1-isopropyl-1-phenylbutyl cyanide;    ethyl 4-(4-cyano-5-methyl-4-phenylhexyl)-1-[2-(4-fluorophenoxy)ethyl]-2-piperazinecarboxylate;    1-[(2-oxo-1,2-dihydro-3-quinolyl)methyl]-4-[(4-cyano-5-methyl-4-phenyl)hexyl]piperidine;    4-[(4-cyano-5-methyl-4-phenyl)hexyl]-i-{[2-(methanesulfonylamino)phenyl]methyl}piperazine;    4-[(4-cyano-5-methyl-4-phenyl)hexyl]-1-{[2-(methanesulfonylamino)phenyl]methyl}piperidine;    (S)-3-phenyl-2-amino-propanoic acid {1-[4-cyano-5-methyl-5-(2-thionyl)hexyl]piperazinyl}amide;    4-[4-(4-phenylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylbutyl cyanide;    4-[4-(4-cyano-4-phenylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylbutyl cyanide; and    4-[4-(4-benzylpiperidinyl)piperidinyl]-1-isopropyl-1-phenylbutyl cyanide.    
     
     
         29 . A pharmaceutical composition comprising a compound represented by the following formula (I), a salt thereof or a hydrate of them.  
       
         
           
           
               
               
           
         
         In the formula, Ar is (1) a C 6-14  aromatic hydrocarbon cyclic group which may be substituted, (2) a 5- to 14-membered aromatic heterocyclic group which may be substituted, (3) a C 1-6  alkyl group substituted with a C 6-14  aromatic hydrocarbon cyclic group which may be substituted or (4) a C 1-6  alkyl group substituted with a 5- to 14-membered aromatic heterocyclic group which may be substituted; the ring A indicates a piperazine ring, a homopiperazine ring, a piperidine ring, a homopiperidine ring, a pyrrolidine ring, a diazabicyclo[2,2,1]heptane ring which may be substituted, respectively; the ring B indicates (1) a C 3 - 14  hydrocarbon ring which may be substituted or (2) a 5- to 14-membered heterocyclic ring which may be substituted; E indicates (1) a single bond, a group represented by (2) the formula —CO— or (3) —CH(OH)—; X indicates (1) a single bond, (2) an oxygen atom, (3) a sulfur atom, (4) a C 1-6  alkylene chain which may be substituted, a group represented by (5) the formula —NR 2 — (wherein R 2  indicates a hydrogen atom, or a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a lower acyl group or a C 1-6  alkylsulfonyl group which maybe substituted.), (6) —CO—, (7) —COO—, (8) —OOC—, (9) —CONR 3 — (wherein R 3  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (10) —NR 4 CO— (wherein R 4  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (11) —SO—, (12) —SO 2 —, (13) —SONR 5 — (wherein R 5  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (14) —NR 6 SO— (wherein R 6  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (15) —SO 2 NR 7 — (wherein R 7  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (16) —NR 8 SO 2 — (wherein R 8  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (17) >C═N—OR 9  (wherein R 9  indicates a hydrogen atom or a C 1-6  alkyl group which may be substituted), (18) —NR 10 —W 3 —O— (wherein R 10  indicates a hydrogen atom, or a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a lower acyl group or a C 1-6 alkylsulfonyl group which may be substituted; and W 3  indicates a C 1-6  alkylene group which may be substituted), (19) —NH—CO—NH—, (20) —NH—CS—NH—, (21) —C (═NR 15 )NR 16 — (wherein R 15  and R 16  are the same as or different from each other and each indicates a hydrogen atom, a nitrile group, a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 3-8  cycloalkyl group or a C 3-8  cycloalkenyl group), (22) —NHC(═NH)—, (23) —O—CO—S—, (24) —S—CO—O—, (25) —OCOO—, (26) —NHCOO—, (27) —OCONH—, (28) —CO(CH 2 ) m O— (wherein m indicates 0 or an integer of 1 to 6), (29) —CHOH— or (30) —CHOH(CH 2 ) n O— (wherein n indicates 0 or an integer of 1 to 6.); R 1  indicates (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C 1-6  alkyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (5) a C 2-6  alkenyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (6) a C 2-6  alkynyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (7) a C 3-8  cycloalkyl group which may be substituted with one or more groups selected from a hydroxyl group, a halogen atom and a nitrile group, (9) a C 1-6  alkoxy-C 1-6  alkyl group, (10) an amino-C 1-6  alkyl group in which the nitrogen atom may be substituted, (11) a group represented by the formula —N(R 11 )R 12 —(wherein R 11  and R 12  are the same as or different from each other and each indicates a hydrogen atom or a C 16  alkyl group), (12) an aralkyl group, (13) a morpholinyl group, (14) a thiomorpholinyl group, (15) a piperidyl group, (16) a pyrrolidinyl group or (17) a piperazinyl group; and D 1 , D 2 , W 1  and W 2  are the same as or different from each other and each indicates (1) a single bond or (2) a C 1-6  alkylene chain which may be substituted,  
         provided that, in the above definition,  
         1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine;  
         1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine; and  
         1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine are excluded.  
       
     
     
         30 . The composition according to  claim 29 , which is a calcium antagonist.  
     
     
         31 . The composition according to  claim 29 , which is a neuron-selective calcium antagonist.  
     
     
         32 . The composition according to  claim 29 , which is at least one of P/Q-type calcium channel and an N-type calcium channel inhibitor.  
     
     
         33 . The composition according to  claim 29 , which is an agent for treating, preventing or improving a disease against which the inhibitory action of at least one of P/Q-type calcium channel and N-type calcium channel is efficacious.  
     
     
         34 . The composition according to  claim 29 , which is an agent for inhibiting the death of neural cells or for protecting cerebral neural cells.  
     
     
         35 . The composition according to  claim 29 , which is an agent for treating, preventing or improving neural disease.  
     
     
         36 . The composition according to  claim 35 , wherein the neural disease is any one disease selected from acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral neural cell death, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral circulation metabolic affection, cerebral dysfunction, pain, spasm, schizophrenia, migraine, epilepsy, manic-depression, neural degenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorder, diabetic neuropathy, cerebral vascular dementia and multiple sclerosis.  
     
     
         37 . The composition according to  claim 29 , which is an analgesic.  
     
     
         38 . Use of the compound according to  claim 1 , a salt thereof or a hydrate of them for producing a calcium antagonist, a neuron-selective calcium antagonist, a P/Q-type calcium channel and/or an N-type calcium channel inhibitor, an agent for treating, preventing or improving a disease against which a P/Q-type calcium channel and/or an N-type calcium channel inhibitory action is efficacious, an agent for inhibiting the death of neural cells or for protecting cerebral neural cells, an agent for treating, preventing or improving neural diseases or an analgesic.  
     
     
         39 . The use according to  claim 38 , wherein the neural disease is any one disease selected from acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral neural cell death, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral circulation metabolic affection, cerebral dysfunction, pain, spasm, schizophrenia, migraine, epilepsy, manic-depression, neural degenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorder, diabetic neuropathy, cerebral vascular dementia and multiple sclerosis.  
     
     
         40 . A method for preventing, treating or improving a disease against which a calcium antagonism is effective, a disease against which a neuron-selective calcium antagonism is effective or a disease against which a P/Q-type calcium channel inhibitory action and/or an N-type calcium channel inhibitory action is effective, by administering a pharmacologically effective amount of the compound according to  claim 1 , a salt thereof or a hydrate of them to a patient.  
     
     
         41 . A method for suppressing a neural cell death or protecting a cerebral neural cell by administering a pharmacologically effective amount of the compound according to  claim 1 , a salt thereof or a hydrate of them to a patient.  
     
     
         42 . A method for preventing, treating or improving neural disease or pain, by administering a pharmacologically effective amount of the compound according to  claim 1 , a salt thereof, or a hydrate of them to a patient.  
     
     
         43 . The method according to  claim 42 , wherein the neural disease is anyone selected from acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral neural cell death, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral circulation metabolic affection, cerebral dysfunction, pain, spasm, schizophrenia, migraine, epilepsy, manic-depression, neural degenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorder, diabetic neuropathy, cerebral vascular dementia and multiple sclerosis.