Selective opioid compounds
View Patent ↗The present invention relates to compounds of Formula I or II, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which relates to morphinan compounds useful as μ, δ, and/or κ receptor opioid compounds and pharmaceuticals containing same that may be useful for mediating analgesia, combating drug addiction, alcohol addiction, drug overdose, mental illness, bladder dysfunctions, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, lung edema, diarrhea, cardiac disorders, cardioprotection, depression, and cognitive, respiratory, diarrhea, irritable bowel syndrome and gastro-intestinal disorders, immunomodulation, and anti-tumor agents.
1. A compound of formula II:
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
R a , R b , R c are each independently selected from:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocyclic or substituted heterocyclic; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
alternatively, R b and R c are taken together to form a heterocyclic or substituted heterocyclic;
Q is absent or selected from (C═O), (SO 2 ), (C═NH), (C═S), or (CONR a );
W is O, S, NOR a or NR a ;
R 3 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocyclic or substituted heterocyclic; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
R 4 is hydrogen, OR a , or NR b -Q 1 -R c , where Q 1 is absent or selected from (C═O) or (SO 2 );
R 5 is (C═W)NR b R c ;
Y is hydrogen, lower alkyl, or lower alkoxy;
V 1 is C═O, C 1 -C 6 alkylene, or substituted alkylene; V 2 is absent, alkylene, substituted alkylene, or C═O; V 3 is absent; V 4 is absent;
n is 1, 2, 3 or 4; wherein each repeating unit can be the same or different;
Z is (C═W)OH or C(O)NHOH;
alternatively,
can be selected from natural amino acids; and
denotes a carbon-carbon single or double bond.
2. A compound of Formula V:
or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, where A 1 is absent, C 1 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; A 2 hydrogen, NR b R c , (C═W)NR b R c , NR a (C═W)NR b R c , (C═W)OH, heteroaryl or substituted heteroaryl;
R a , R b , R c are each independently selected from:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocyclic or substituted heterocyclic; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
alternatively, R b and R c are taken together to form a heterocyclic or substituted heterocyclic;
R 3 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocyclic or substituted heterocyclic; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 or more heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
Y is hydrogen, lower alkyl, or lower alkoxy;
V 1 is C═O, SO 2 , C 1 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; V 3 is absent, alkylene, substituted alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; heterocyclic, heteroaryl, aryl or C═O; V 4 is absent, alkylene, substituted alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; heterocyclic, heteroaryl, aryl or C═O;
n is 1, 2, 3 or 4; wherein each repeating unit can be the same or different;
Z is hydrogen, NR b R c , (C═W)NR b R c , NR a (C═W)NR b R c , (C═W)OH, C(O)NHOH, heteroaryl, or substituted heteroaryl.
3. The compound of claim 2 , wherein the compound is of Formula VI:
or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein R 30 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, heterocyclic or substituted heterocyclic; where A 1 is absent, C 1 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; A 2 hydrogen, NR b R c , (C═W)NR b R c , NR a (C═W)NR b R c , (C═W)OH, heteroaryl or substituted heteroaryl; and n, R 3 , V 1 , V 3 , V 4 , W, R a , R b , R c and Z are as defined in claim 2 .
4. A compound of Formula VII:
or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein X − is counterion selected from the group consisting of halide, sulfate, phosphate, nitrate, and anionic-charged organic species; R 30 and R 31 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, heterocyclic or substituted heterocyclic; where A 1 is absent, C 1 -C 6 alkylene, substituted alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; A 2 hydrogen, NR b R c , (C═W)NR b R c , NR a (C═W)NR b R c , (C═W)OH, heteroaryl or substituted heteroaryl; and n, R 3 , V 1 , V 3 , V 4 , W, R a , R b , R c and Z are as defined in claim 2 .
5. A compound selected from compounds in Table A, or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient:
TABLE A
Compound
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13