Benzamide derivatives as oxytocin agonists and vasopressin antagonists

Abstract

Novel compounds according to general formula 1, wherein G 1 is NR 5 R 6 or a fused polycyclic group that are specific OT receptor agonists and/or V 1a receptor antagonists. Pharmaceutical compositions comprising such compounds are useful in the treatment of, inter alia, primary dysmenorrhoea.

1 . A compound according to general formula 1, or a pharmaceutically acceptable salt thereof 
     
       
         
         
             
             
         
       
     
     wherein:
 G 1  is selected from a group according to general formula 2, a group according to general formula 3, a group according to general formula 4, a group according to general formula 5, a group according to general formula 6 and a group according to general formula 7; 
 
     
       
         
         
             
             
         
       
       A 1  is selected from CH 2 , CH(OH), NH, N-alkyl, O and S; 
       A 2  is selected from CH 2 , CH(OH), C(═O) and NH; 
       A 3  is selected from S, NH, N-alkyl, —CH═CH— and —CH═N—; 
       A 4  and A 5  are each selected from CH and N; 
       A 6  is selected from CH 2 , NH, N-alkyl and O; 
       A 7  and A 11  are selected from C and N; 
       A 8  and A 9  are selected from CH, N, NH, N(CH 2 ) d R 7  and S; 
       A 10  is selected from —CH═CH—, CH, N, NH, N(CH 2 ) d R 7  and S; 
       A 12  and A 13  are selected from N and C; 
       A 14 , A 15  and A 16  are selected from NH, N—CH 3 , S, N and CH; 
       X 1  is selected from O and NH; 
       R 1 , R 2  and R 3  are each selected from H, alkyl, O-alkyl, F, Cl and Br; 
       R 4  is selected from H, alkyl, alkenyl, alkynyl, optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, —(CH 2 ) e R 8 , —CH 2 —CH═CH—CH 2 —R 8 , —CH 2 —C≡C—CH 2 —R 8 , —(CH 2 ) g —CH(OH)—(CH 2 ) h —R 8 , —(CH 2 ) i —O—(CH 2 ) j —R 8  and 
     
     
       
         
         
             
             
         
       
     
     —R 5  and R 6  are independently selected from alkyl, Ar and —(CH 2 ) f —Ar;
 R 7  is selected from H, alkyl, optionally substituted phenyl, F, OH, O-alkyl, O-acyl, S-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN and CF 3 ; 
 R 8  is selected from H, alkyl, alkenyl, alkynyl, acyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, F, OH, hydroxyalkyl, O-alkyl, O-acyl, S-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, NH-acyl, N(alkyl)acyl, N 3 , CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN and CF 3 ; 
 Ar is selected from optionally substituted thienyl and optionally substituted phenyl; 
 a is 1 or 2, b is 1, 2 or 3; c is 1 or 2, d is 1, 2 or 3; e is 1, 2, 3 or 4; f is 1, 2 or 3 and g, h, i and j are all independently 1 or 2; 
 
     provided that:
 not more than one of A 8 , A 9  and A 10  is NH, N(CH 2 ) d R 7  or S; 
 A 7  and A 11  are not both simultaneously N; 
 neither A 7  nor A 11  is N if one of A 8 , A 9  and A 10  is NH, N(CH 2 ) d R 7  or S; 
 if A 10  is not —CH═CH— then one of A 8 , A 9  and A 10  is NH, N(CH 2 ) d R 7  or S or one of A 7  and 
 A 11  is N; 
 not more than one of A 14 , A 15  and A 16  is NH, N—CH 3  or S; 
 A 12  and A 13  are not both simultaneously N; 
 if one of A 14 , A 15  and A 16  is NH, N—CH 3  or S then A 12  and A 13  are both C; and 
 one of A 14 , A 15  and A 16  is NH, N—CH 3  or S or one of A 12  and A 13  is N, 
 
     wherein said compound is selected from the group consisting of: 
     4-(3,3-Dimethyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-(2-Cyclopropyl-ethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-(2-Hydroxymethyl-cyclopropylmethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-(3-Methyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclopentylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclohexylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-(2-Cyclopropyl-ethyl)-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Pentyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Hexyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     (R)-4-(2-Methyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-(2-Ethyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-(2-Methyl-but-2-enyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-ethyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; and 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-methoxy-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide. 
   
   
       2 . A pharmaceutical composition comprising a compound according to  claim 1  as an active agent. 
   
   
       3 . A pharmaceutical composition according to  claim 2  formulated as a tablet or capsule for oral administration. 
   
   
       4 . A pharmaceutical composition according to  claim 2 , comprising an amount of said compound according to  claim 1  effective for treatment of primary dysmenorrhoea. 
   
   
       5 . A pharmaceutical composition according to  claim 2 , comprising an amount of said compound according to  claim 1  effective for treatment of male erectile dysfunction. 
   
   
       6 . A pharmaceutical composition according to  claim 2 , comprising an amount of said compound according to  claim 1  effective for treatment of a condition selected from the group consisting pre-term labour, hypertension, Raynauld's disease, brain oedema, motion sickness, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure. 
   
   
       7 .- 35 . (canceled) 
   
   
       36 . A method for treatment of a disorder selected from the group consisting of primary dysmenorrhoea, pre-term labour, hypertension, Raynauld's disease, brain oedema, motion sickness, small cell lung cancer, depression, anxiety, hyponatremia, liver cirrhosis and congestive heart failure which comprises the administration to a person in need of such treatment of therapeutically effective amount of a compound according to general formula 1, or a pharmaceutically acceptable salt thereof 
     
       
         
         
             
             
         
       
     
     wherein:
 G 1  is selected from a group according to general formula 2, a group according to general formula 3, a group according to general formula 4, a group according to general formula 5, a group according to general formula 6 and a group according to general formula 7; 
 
     
       
         
         
             
             
         
       
       A 1  is selected from CH 2 , CH(OH), NH, N-alkyl, O and S; 
       A 2  is selected from CH 2 , CH(OH), C(═O) and NH; 
       A 3  is selected from S, NH, N-alkyl, —CH═CH— and —CH═N—; 
       A 4  and A 5  are each selected from CH and N; 
       A 6  is selected from CH 2 , NH, N-alkyl and O; 
       A 7  and A 11  are selected from C and N; 
       A 8  and A 9  are selected from CH, N, NH, N(CH 2 ) d R 7  and S; 
       A 10  is selected from —CH═CH—, CH, N, NH, N(CH 2 ) d R 7  and S; 
       A 12  and A 13  are selected from N and C; 
       A 14 , A 15  and A 16  are selected from NH, N—CH 3 , S, N and CH; 
       X 1  is selected from O and NH; 
       R 1 , R 2  and R 3  are each selected from H, alkyl, O-alkyl, F, Cl and Br; 
       R 4  is selected from H, alkyl, alkenyl, alkynyl, optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, —(CH 2 ) e R 8 , —CH 2 —CH═CH—CH 2 —R 8 , —CH 2 —C≡C—CH 2 —R 8 , —(CH 2 ) g —CH(OH)—(CH 2 ) h —R 8 , —(CH 2 ) i —O—(CH 2 ) j —R 8  and 
     
     
       
         
         
             
             
         
       
       R 5  and R 6  are independently selected from alkyl, Ar and —(CH 2 ) f Ar; 
       R 7  is selected from H, alkyl, optionally substituted phenyl, F, OH, O-alkyl, O-acyl, S-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN and CF 3 ; 
       R 8  is selected from H, alkyl, alkenyl, alkynyl, acyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, F, OH, hydroxyalkyl, O-alkyl, O-acyl, S-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, NH-acyl, N(alkyl)acyl, N 3 , CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN and CF 3 ; 
       Ar is selected from optionally substituted thienyl and optionally substituted phenyl; 
       a is 1 or 2, b is 1, 2 or 3; c is 1 or 2, d is 1, 2 or 3; e is 1, 2, 3 or 4; f is 1, 2 or 3 and g, h, i and j are all independently 1 or 2; 
     
     provided that:
 not more than one of A 8 , A 9  and A 10  is NH, N(CH 2 ) d R 7  or S; 
 A 7  and A 11  are not both simultaneously N; 
 neither A 7  nor A 11  is N if one of A 8 , A 9  and A 10  is NH, N(CH 2 ) d R 7  or S; 
 if A 10  is not —CH═CH— then one of A 8 , A 9  and A 10  is NH, N(CH 2 ) d R 7  or S or one of A 7  and 
 A 11  is N; 
 not more than one of A 14 , A 15  and A 16  is NH, N—CH 3  or S; 
 A 12  and A 13  are not both simultaneously N; 
 if one of A 14 , A 15  and A 16  is NH, N—CH 3  or S then A 12  and A 13  are both C; and 
 one of A 14 , A 15  and A 16  is NH, N—CH 3  or S or one of A 12  and A 13  is N. 
 
   
   
       37 . The method of  claim 36 , wherein at least one of R 1 , R 2  and R 3  is H and at least one is not H. 
   
   
       38 . The method of  claim 36 , wherein one of R 1 , R 2  and R 3  is selected from an alkyl group, an O-alkyl group, F, Cl and Br and the others are H. 
   
   
       39 . The method of  claim 36 , wherein X 1  is NH. 
   
   
       40 . The method of  claim 36 , wherein a is 1 and b is 2. 
   
   
       41 . The method of  claim 36 , wherein G 1  is a group according to general formula 3. 
   
   
       42 . The method of to  claim 41 , wherein c is 2. 
   
   
       43 . The method of  claim 41 , wherein A 1  is CH 2  and A 2  is NH. 
   
   
       44 . The method of  claim 41 , wherein A 1  is NH or N-alkyl and A 2  is C(═O). 
   
   
       45 . The method of  claim 41 , wherein A 3  is S and A 4  and A 5  are both CH. 
   
   
       46 . The method of  claim 41 , wherein A 3  is —CH═CH— and A 4  and As are both CH. 
   
   
       47 . The method of  claim 41 , wherein A 3  is —CH═N— and A 4  and As are both CH. 
   
   
       48 . The method of  claim 41 , wherein A 3  is —CH═CH—, A 4  is CH and A 5  is N. 
   
   
       49 . The method of  claim 36 , wherein G 1  is a group according to general formula 6 or 7. 
   
   
       50 . The method of  claim 49 , wherein A 3  is S and A 4  and A 5  are both CH. 
   
   
       51 . The method of  claim 49 , wherein A 3  is —CH═CH— and A 4  and A 5  are both CH. 
   
   
       52 . The method of  claim 49 , wherein A 3  is —CH═N— and A 4  and A 5  are both CH. 
   
   
       53 . The method of  claim 49 , wherein A 3  is —CH═CH—, A 4  is CH and A 5  is N. 
   
   
       54 . The method of  claim 36 , wherein G 1  is a group according to general formula 4 or 6. 
   
   
       55 . The method of  claim 54 , wherein A 6  is NH. 
   
   
       56 . The method of  claim 54 , wherein A 8  is NH or N—(CH 2 ) d —R 7 . 
   
   
       57 . The method of  claim 56 , wherein A 9  is N and A 10  is CH. 
   
   
       58 . The method of  claim 36 , wherein one of R 1 , R 2  and R 3  is selected from an alkyl group, an O-alkyl group, F, Cl and Br and the others are H and X 1  is NH. 
   
   
       59 . The method of  claim 36 , wherein one of R 1 , R 2  and R 3  is selected from an alkyl group, an O-alkyl group, F, Cl and Br and the others are H and X 1  is NH, a is 1 and b is 2. 
   
   
       60 . The method of  claim 36 , wherein G 1  is a group according to general formula 6, A 4 , A 5  and A 10  are all CH, A 6  is NH, A 7  and A 11  are both C, A 8  is N—(CH 2 ) d —R 7  and A 9  is N. 
   
   
       61 . The method of  claim 36 , wherein R 1  is an alkyl group, an O-alkyl group, F, Cl or Br, R 2  and R 3  are both H, X 1  is NH, a is 1, b is 2, G 1  is a group according to general formula 6, A 4 , A 5  and A 10  are all CH, A 6  is NH, A 7  and A 11  are both C, A 8  is N—(CH 2 ) d —R 7  and A 9  is N. 
   
   
       62 . The method of  claim 36 , wherein said compound is selected from the group consisting of: 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(3,3-Dimethyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(3-Methylsulfanyl-propyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Cyclopropyl-ethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Hydroxymethyl-cyclopropylmethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(3-Methyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopentylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclohexylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Cyclopropyl-ethyl)-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Pentyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Hexyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     (R)-4-(2-Methyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Ethyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Methyl-but-2-enyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-ethyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, and 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-methoxy-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide. 
   
   
       63 . A method for treatment of male erectile dysfunction which comprises the administration to a person in need of such treatment of therapeutically effective amount of a compound selected from the group consisting of: 
     4-(3,3-Dimethyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Cyclopropyl-ethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Hydroxymethyl-cyclopropylmethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(3-Methyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopentylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclohexylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Cyclopropyl-ethyl)-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Pentyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Hexyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     (R)-4-(2-Methyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Ethyl-butyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-(2-Methyl-but-2-enyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-fluoro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-ethyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclopropylmethyl-piperazine-1-carboxylic acid 2-chloro-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide, 
     4-Cyclobutylmethyl-piperazine-1-carboxylic acid 3-methoxy-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; and 
     pharmaceutically acceptable salts of the above mentioned compounds.