Therapeutic compounds and methods
The invention provides kappa receptor agonists of formula (I) and delta receptor antagonists of formula (II), wherein R 1 –R 6 X and n have any of the meanings given in the specification, as well as compositions comprising them, methods for their use, and synthetic procedures and intermediates useful for their preparation.
1. A compound of formula (I):
wherein
R 1 is (C 1 –C 6 )alkyl, (C 2 –C 6 )alkenyl, (C 2 –C 6 )alkynyl, (C 3 –C 7 )cycloalkyl, (C 5 –C 7 )cycloalkenyl, (C 3 –C 6 )cycloalkyl(C 1 –C 6 )alkyl, (C 5 –C 7 )cycloalkenyl(C 1 –C 6 )alkyl, aryl, heteroaryl, aryl(C 1 –C 6 )alkyl, or heteroaryl(C 1 –C 6 )alkyl;
R 2 is H, OH, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkanoyloxy, NR a R b or SR c ;
R 3 is H, aryl(C 1 –C 6 )alkyl, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkanoyl, or (C 1 –C 6 )alkylC(═S);
R 4 is ═O, ═S, or ═NR d ;
R d is H, CN, CONH 2 , COCF 3 , (C 1 –C 6 )alkanoyl, (C 1 –C 6 )alkyl, or (CH 2 ) p NR e R f ; or R d together with R 6 is —(CH 2 ) q — and forms a ring;
p is 1, 2, 3, or 4;
R 5 is NR m ;
R 6 is H, (C 1 –C 6 )alkyl, (C 3 –C 7 )cycloalkyl, aryl, heteroaryl, aryl(C 1 –C 6 )alkyl, heteroaryl(C 1 –C 6 )alkyl, NR g R h (C 1 –C 6 )alkyl, or C(═NR j )NHR k ; or when R 4 is ═NR d , R 6 together with R d is —(CH 2 ) q — and forms a ring;
q is 2 or 3;
X is O, S, or NY;
Y is H, (C 1 –C 6 )alkyl, or aryl(C 1 –C 6 )alkyl;
n is 0, 1, 2, 3, or 4;
R a –R c and R e –R f are each independently H, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkanoyl, or —C(═S)(C 1 –C 6 )alkyl;
R g and R h are each independently H, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkanoyl, —C(═NH)NR a R b , or —C(═S)(C 1 –C 6 )alkyl, or R g and R h together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R j and R k are each independently H, (C 1 –C 6 )alkyl, (C 2 –C 6 )alkenyl, (C 2 –C 6 )alkynyl, (C 3 –C 7 )cycloalkyl, (C 3 –C 7 )cycloalkyl(C 1 –C 6 )alkyl, (C 5 –C 7 )cycloalkenylalkyl, aryl, heteroaryl, aryl(C 1 –C 6 )alkyl, or heteroaryl(C 1 –C 6 )alkyl; and
R m is hydrogen or (C 1 –C 6 )alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R 1 is (C 2 –C 6 )alkenyl or (C 3 –C 6 )cycloalkyl(C 1 –C 6 )alkyl.
3. The compound of claim 1 wherein R 1 is cyclopropylmethyl or allyl.
4. The compound of claim 1 wherein R 2 is OH.
5. The compound of claim 1 wherein R 3 is H.
6. The compound of claim 1 therein R 4 is ═NR d .
7. The compound of claim 1 therein R 4 is ═NH or ═NCN.
8. The compound of claim 1 therein R 5 is NH.
9. The compound of claim 1 therein R 6 is H.
10. The compound of claim 1 therein R 6 is hydrogen, ethyl, n-butyl, 3-(dimethylamino)propyl, or 2-pyrrolidinoethyl.
11. The compound of claim 1 wherein R 6 is C(═NR j )NHR k .
12. The compound of claim 1 wherein R d , together with R 6 , is —(CH 2 ) q — and forms a ring.
13. The compound of claim 1 wherein R m is hydrogen.
14. The compound of claim 1 wherein n is 0.
15. The compound of claim 1 wherein n is 1.
16. The compound of claim 1 wherein X is NH.
17. The compound of claim 1 wherein R 1 is cyclopropylmethyl; R 2 is hydroxy; R 3 is H; R 4 is ═NH; R 5 is NH; and R 6 is H.
18. A composition comprising a compound of claim 1 , and a pharmaceutically acceptable diluent or carrier.
19. A therapeutic method for treating a pathological condition or symptom in a mammal wherein kappa receptor activity is implicated and agonism of kappa receptors is desired comprising administering to the mammal an effective amount of a compound of claim 1 wherein the condition or symptom is pain.