Pharmaceutical compositions and methods for use

Abstract

The present invention relates to diazabicyclic compounds, preferably to N-aryl diazabicyclic compounds. Of particular interest are 2-pyridinyl diazabicyclic compounds, such as (1S,4S)-2-(5-(3-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. Other exemplary compounds of the present invention include (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane, (1S,4S)-2-(5-(3-thienyl)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane, (1S,4S)-2-(5-(4-fluorophenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane, and (1S,4S)-2-(5-benzoyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. The present invention also relates to prodrug derivatives of the compounds of the present invention.

1. A compound of the formula: 
                 
 wherein: 
 Q is (CH 2 ) u , Q i  is (CH 2 ) v , Q ii  is (CH 2 ) w , Q iii  is (CH 2 ) x , and Q iv  is (CH 2 ) y , ; 
 where u, v, w, and x are individually 0, 1, 2, 3, or 4; and  
 y is 1;  
 wherein u, v, w, and x are selected such that the ring is a diazabicyclo [3.3.1]nonane;  
 Z is a substituent species G;  
 j is from 0 to 10; and  
 Cy is 
                 
 
 where each of X, X′, and X″ are individually nitrogen, nitrogen bonded to oxygen, or carbon bonded to H or a substituent species G;  
 A is O or C═O;  
 D is a substituent species G;  
 k is 0, 1, or 2; and  
 Cx is selected from a group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, non-aromatic heterocyclylalkyl, and substituted non-aromatic heterocyclylalkyl, ;  
 wherein G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2  ≡CR′, —SR′, —SOR′, —SO 2 CH 3 , —SO 2 NR′R″, —C(═O)NR′R″, —NR′C(═O)R″, NR′SO 2 R″, —C(═O)R′, —C(═O)OR′, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C (═O)R′, —O(CR′R″) q C(═O)R′, —C≡C(CR′R″) q OR′, —(CR′R″) q NR′N″, —OC(═O)NR′R″, and —NR′C (═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein the substituent is G and the aromatic group containing species is phenyl, biphenyl, naphthyl, pyridinyl, pyrimidinyl, quinolinyl, or indolyl, ; and  
 q is an integer from 1 to 6, ;  
 wherein heterocyclyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, and piperidinyl, ; and  
 wherein substituted alkyl, substituted alkenyl, substituted non-aromatic heterocyclyl, substituted aryl, substituted heteroaryl, substituted alkylaryl, and substituted arylalkyl groups are alkyl, alkenyl, non-aromatic heterocyclyl, aryl, heteroaryl, alkylaryl, and arylalkyl groups groups  further bearing one or more substituent species G.  
 
     
     
       2. The compound of  claim 1 , wherein X″ is nitrogen. 
     
     
       3. The compound of  claim 1 , wherein X′ and X″ are nitrogen. 
     
     
       4. The compound of  claim 1 , wherein j is 0, 1, or 2. 
     
     
       5. The compound of  claim 1 , wherein Cx is selected from the group consisting of 
                 
 wherein: 
 Y, Y′, Y″, and Y′″ are individually nitrogen, nitrogen bonded to oxygen, or carbon bonded to hydrogen or a substituent species,  G;  
 E is oxygen, sulfur, or nitrogen bonded to hydrogen or a substituent species,  G;  
 E′, E″, and E′″ are individually nitrogen, or carbon bonded to hydrogen or a substituent species,  G;  
 m is 0, 1, 2, 3, or 4;  
 p is 0, 1, 2, or 3;  
 n is 0, 1, 2, 3, or 4; and  
 G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2  ≡CR′, —SR′, —SOR′, —SO 2  CH 3 , —SO 2 NR′R″, —C(═O)NR′R″, —NR′C (═O)R″, NR′SO 2 R″, —C(═O)R′, —C(═O)OR″, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C(═O)R′, —O(CR′R″) q C(═O)R′, —C 2  ≡C(CR′R″) q OR′, —(CR′R″) q NR′N″, —OC(═O)NR′R″, and —NR′C(═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein the aromatic group-containing species and substituted aromatic group-containing species are as defined in  claim 1 .  
 
     
     
       6. The compound of  claim 5 , wherein Y, Y′, Y″, and Y′″ all are carbon bonded to H or a substituent species G. 
     
     
       7. The compound of  claim 5 , wherein one or two of Y, Y′, Y″, and Y′″ are nitrogen and the remaining are carbon bonded to H or a substituent species G. 
     
     
       8. The compound of  claim 5 , wherein E′, E″, and E′″ all are carbon bonded to H or a substituent species G. 
     
     
       9. The compound of  claim 5 , wherein one or two of E′, E″, and E′″ are nitrogen and the remaining are carbon bonded to H or a substituent species G. 
     
     
       10. A compound or the formula: 
                 
 wherein:  
 Q is (CH 2 ) u , Q i  is (CH 2 ) v , Q ii  is (CH 2 ) w , Q iii  is (CH 2 ) x , and Q iv  is (CH 2 ) y , ;  
 where u, v, w, and x are individually 0, 1, 2, 3, or 4; and  
 y is 1;  
 wherein u, v, w, and x are selected such that the ring is a diazabicyclo [3.3.1]nonane;  
 Z is a substituent species G;  
 j is from 0 to 10;  
 and Cy is 
                 
 
 where each of X, X′, and X″ are individually nitrogen, nitrogen bonded to oxygen, or carbon bonded to H or a substituent species G;  
 A is a covalent bond;  
 D is a substituent species G;  
 k is 0, 1, or 2;  
 Cx is selected from a group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, non-aromatic heterocyclylalkyl, and substituted non-aromatic heterocyclylalkyl;  
 G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2  ≡CR′, —SR′, —SOR′, —SO 2 CH 3 , —SO 2 NR′R″, —C(═O)NR′R″, —NR′C(═O)R″, NR′SO 2 R″, —C(═O)R′, —C(═O)OR″, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C(═O)R′, —O(CR′R″) q C(═O)R′, —C 2  ≡C(CR′R″) q OR′, —(CR′R″) q NR′N″, —OC(═O) NR′R″, and —NR′C(═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein the substituent is G and the aromatic group containing species is phenyl, biphenyl, naphthyl, pyridinyl, pyrimidinyl, quinolinyl, or indolyl, ;  
 and q is an integer from 1 to 6, ;  
 wherein heterocyclyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, and piperidinyl, ; and  
 wherein substituted alkyl, substituted alkenyl, substituted non-aromatic heterocyclyl, substituted aryl, substituted heteroaryl, substituted alkylaryl, and substituted arylalkyl groups are alkyl, alkenyl, non-aromatic heterocyclyl, aryl, heteroaryl, alkylaryl, and arylalkyl groups groups  further bearing one or more substituent species G.  
 
     
     
       11. The compound of  claim 10  wherein X″ is nitrogen. 
     
     
       12. The compound of  claim 10 , wherein X′ and X″ are nitrogen. 
     
     
       13. The compound of  claim 10 , wherein j is 0, 1, or 2. 
     
     
       14. The compound of  claim 10 , wherein Cx is selected from the group consisting of 
                 
 wherein:  
 Y, Y′, Y″, and Y′″ are individually nitrogen, nitrogen bonded to oxygen, or carbon bonded to hydrogen or a substituent species,  G;  
 E is oxygen, sulfur or nitrogen bonded to hydrogen or a substituent species,  G;  
 E′, E″, and E′″ are individually nitrogen or carbon bonded to hydrogen or a substituent species,  G;  
 m is 0, 1, 2, 3, or 4;  
 p is 0, 1, 2, or 3;  
 n is 0, 1, 2, 3, or 4; and  
 G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2 — ≡CR′, —SR′, —SOR′, —SO 2  CH 3 , —SO 2 NR′R″, —C(═O)NR′R″, —NR′C(═O)R″, NR′SO 2 R″, —C(═O)R′, —C(═O)OR″, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C(═O)R′, —O(CR′R″) q C(═O)R′, —C 2  ≡C(CR′R″) q OR′, —(CR′R″) q NR′R″, —OC(═O)NR′R″, and —NR′C (═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein aromatic group-containing species and substituted aromatic group-containing species are as defined in  claim 10 .  
 
     
     
       15. The compound of  claim 14 , wherein Y, Y′, Y′″  Y″, and Y′″ all are carbon bonded to H or a substituent species G. 
     
     
       16. The compound of  claim 14 , wherein one or two of Y, Y′, Y″, and Y′″ are nitrogen and the remaining are carbon bonded to H or a substituent species G. 
     
     
       17. The compound of  claim 14 , wherein E′, E″, and E′″ all are carbon bonded to H or a substituent species G. 
     
     
       18. The compound of  claim 14 , wherein one or two of E′, E′  E″, and E′″ are nitrogen and the remaining are carbon bonded to H or a substituent species G. 
     
     
       19. A pharmaceutical composition useful for treatment of central nervous system disorders comprising a therapeutically effective amount of a compound of the formula: 
                 
 wherein Q is (CH 2 ) u , Q i  is (CH 2 ) v , Q ii  is (CH 2 ) w , Q iii  is (CH 2 ) x , and Q iv  is (CH 2 ) y , ;  
 where u, v, w, and x are individually 0, 1, 2, 3, or 4; and  
 y is 1 or 2;  
 wherein u, v, w, and x are selected such that the ring is a diazabicyclo[3.3.1]nonane;  
 Z is a substituent species G;  
 j is from 0 to 10; and  
 Cy is 
                 
 
 where each of X, X′, and X″ are individually nitrogen, nitrogen bonded to oxygen, or carbon bonded to H or a substituent species G;  
 A is O or C═O;  
 D is a substituent species G;  
 k is 0, 1, or 2; and  
 Cx is selected from a group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, non-aromatic heterocyclylalkyl and substituted non-aromatic heterocyclylalkyl, ; 
 wherein G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2 — ≡CR′, —SR′, —SOR′, —SO 2 CH 3 , —SO 2 NR′R″, —C(═O)NR′R″, —NR′C(═O)R″, NR′SO 2 R″, —C(═O)R′, —C(═O)OR″, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C(═O)R′, —O(CR′R″) q C(═O)R′, —C 2  ≡C(CR′R″) q OR′, —(CR′R″) q NR′N″, —OC(═O)NR′R″, and —NR′C(═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein the substituent is G and the aromatic group containing species is phenyl, biphenyl, naphthyl, pyridinyl, pyrimidinyl, quinolinyl, or indolyl, ; and  
 q is an integer from 1 to 6, ;  
 wherein heterocyclyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, and piperidinyl, ; and  
 wherein substituted alkyl, substituted alkenyl, substituted non-aromatic heterocyclyl, substituted aryl, substituted heteroaryl, substituted alkylaryl, and substituted arylalkyl groups are alkyl, alkenyl, non-aromatic heterocyclyl, aryl, heteroaryl, alkylaryl, and arylalkyl groups groups  further bearing one or more substituent species G.  
 
     
     
       20. The pharmaceutical composition of  claim 19 , wherein X″ is nitrogen. 
     
     
       21. The pharmaceutical composition of  claim 19 , wherein X′ and X″ are nitrogen. 
     
     
       22. The pharmaceutical composition of  claim 19 , wherein j,  is 0, 1, or 2. 
     
     
       23. The pharmaceutical composition of  claim 19 , wherein Cx is selected from the group consisting of 
                 
 wherein:  
 Y, Y′, Y″, and Y′″ are individually nitrogen, nitrogen bonded to oxygen, or carbon bonded to hydrogen or a substituent species,  G;  
 E is oxygen, sulfur, or nitrogen bonded to hydrogen or a substituent species,  G;  
 E′, E″, and E′″ are individually nitrogen or carbon bonded to hydrogen or a substituent species,  G;  
 m is 0, 1, 2, 3, or 4;  
 p is 0, 1, 2, or 3;  
 n is 0, 1, 2, 3, or 4; and  
 G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′″ R′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2  ≡CR′, —SR′, —SOR′, —SO 2  CH 3 , —SO 2  NR′R″, —C(═O)NR′R″, —NR′C(═O)R″ R″, —NR′SO 2 R″ R′, —C(═O)R′, —C(═O)OR″, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C(═O)R′, —O(CR′R″) q C(═O)R′, —C 2  ≡C(CR′R″) q OR′, —(CR′R″) q NR′N″, —OC(═O)NR′R″, and —NR′C(═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein aromatic group-containing species and substituted aromatic group-containing species are as defined in  claim 19 .  
 
     
     
       24. The pharmaceutical composition of  claim 23 , wherein Y, Y′, Y″, and Y′″ all are carbon bonded to H or a substituent species G. 
     
     
       25. The pharmaceutical composition of  claim 23 , wherein one or two of Y, Y′, Y″, and Y′″ are nitrogen and the remaining are carbon bonded to H or a substituent species G. 
     
     
       26. The pharmaceutical composition of  claim 23 , wherein E′, E″, and E′″ all are carbon bonded to H or a substituent species G. 
     
     
       27. The pharmaceutical composition of  claim 23 , wherein one or two of E′, E″, and E′″ are nitrogen and the remaining are carbon bonded to H or a substituent species G. 
     
     
       28. A pharmaceutical composition useful for treatment of central nervous system disorders comprising a therapeutically effective amount of a compound of the formula: 
                 
 wherein:  
 Q is (CH 2 ) u , Q i  is (CH 2 ) v , Q ii  is (CH 2 ) w , Q iii  is (CH 2 ) x , and Q iv  is (CH 2 ) y , ;  
 where u, v, w, and x are individually 0, 1, 2, 3, or 4; and  
 y is 1;  
 wherein u, v, w, and x are selected such that the ring is a diazabicyclo [3.3.1]nonane;  
 Z is a substituent species G;  
 j is from 0 to 10; and  
 Cy is 
                 
 
 where each of X, X′, and X″ are individually nitrogen, nitrogen bonded to oxygen, or carbon banded  bonded to H or a substituent species G;  
 A is a covalent bond;  
 D is a substituent species G;  
 k is 0, 1, or 2;  
 Cx is selected from a group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, non-aromatic heterocyclylalkyl and substituted non-aromatic heterocyclylalkyl;  
 G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2  ≡CR′, —SR′, —SOR′, —SO 2 CH 3 , —SO 2 NR′R″, —C(═O)NR′R″, —NR′C(═O)R″, NR′SO 2 R″, —C(═O)R′, —C(═O)OR″, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C(═O)R′, —O(CR′R″) q C(═O)R′, —C 2  ≡C(CR′R″) q OR′, —(CR′R″) q NR′N″, —OC(═O)NR′R″, and —NR′C(═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein the substituent is G and the aromatic group containing species is phenyl, biphenyl, naphthyl, pyridinyl, pyrimidinyl, quinolinyl, or indolyl, ; and  
 q is an integer from 1 to 6, ;  
 wherein heterocyclyl groups are selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, and piperidinyl, ; and  
 wherein substituted alkyl, substituted alkenyl, substituted non-aromatic heterocyclyl, substituted aryl, substituted heteroaryl, substituted alkylaryl, and substituted arylalkyl groups are alkyl, alkenyl, non-aromatic heterocyclyl, aryl, heteroaryl, alkylaryl, and arylalkyl groups groups  further bearing one or more substituent species G.  
 
     
     
       29. The pharmaceutical composition of  claim 28 , wherein Cx is selected from the group consisting of 
                 
 wherein: 
 Y, Y′, Y″, and Y′″ are individually nitrogen, nitrogen bonded to oxygen, or carbon bonded to hydrogen or a substituent species,  G;  
 E is oxygen, sulfur or nitrogen bonded to hydrogen or a substituent species,  G;  
 E′, E″, and E′″ are individually nitrogen or carbon bonded to hydrogen or a substituent species,  G;  
 m is 0, 1, 2, 3, or 4;  
 p is 0, 1, 2, or 3;  
 n is 0, 1, 2, 3, or 4; and  
 G is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, non-aromatic heterocyclyl, substituted non-aromatic heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —F, —Cl, —Br, —I, —OR′, —NR′R″, —CF 3 , —CN, —N 3 , —NO 2 , —C 2  ≡CR′, —SR′, —SOR′, —SO 2  CH 3 , —SO 2 NR′R″, —C(═O)NR′R″, —NR′C(═O)R″, NR′SO 2 R″, —C(═O)R′, —C(═O)OR″, —(CH 2 ) q OR′, —OC(═O)R′, —(CR′R″) q OCH 2 C 2  ≡CR′, —(CR′R″) q C(═O)R′, —O(CR′R″) q C(═O)R′, —C 2  ≡C(CR′R″) q OR′, —(CR′R″) q NR′N″, —OC(═O)NR′R″, and —NR′C(═O)OR′;  
 where R′ and R″ are individually hydrogen, C 1-8  alkyl, an aromatic group-containing species, or a substituted aromatic group-containing species, wherein aromatic group-containing species and substituted aromatic group-containing species are as defined in  claim 28 .  
 
     
     
       30. The pharmaceutical composition of  claim 29 , wherein Y, Y′, Y″, and Y′″ all are carbon bonded to H or a substituent species G. 
     
     
       31. The pharmaceutical composition of  claim 29 , wherein one or two of Y, Y′, Y″, and Y′″ are nitrogen and the remaining are carbon bonded to H or a substituent species G.