Macrocyclic polyoxazole compounds and use thereof
The invention provides compounds of formula (I) wherein A, B, R 1 , F, G, n, n′ and the dotted line have any values defined herein, as well as salts thereof. The compounds have activity as anti-proliferative agents.
1. A compound of formula (I):
wherein:
one of A and B is —CH(R b )CH(R c )C(R d )(R e )—;
and the other of A and B is:
—CH(R a )NHC(═O)— or —CH(R b ′)CH(R c ′)C(R d ′)(R e ′)—;
one of F and G is X and the other is C(R 2 );
each X is independently NH, S, or O;
the dotted line in the ring containing F and G signifies that two double bonds are present in the ring, the positions of which depend upon the values selected for F and G;
n and n′ each independently represents 1, 2, 3, 4 and 5, provided that the sum of n and n′ is 6;
R a represents hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkanoyloxy is optionally substituted with OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryl, heteroaryl, NR f R g , or —C(═O)NR f R g ; and wherein each aryl and heteroaryl is optionally substituted with one or two substituents selected independently from halo, hydroxy, (C 1 -C 6 )alkyl, NR f R g , and NR f R g (C 1 -C 6 )alkyl-
R b and R c each represents hydrogen, or R b and R c together represent a bond or —O—;
R d and R e together represent (═O) or R d represents hydrogen and R e represents hydrogen, hydroxy, (C 1 -C 6 )alkanoyloxy, NR j R k , CH 2 C(═O)OR s or CH 2 C(═O)NR m R n , wherein each (C 1 -C 6 )alkanoyloxy is optionally substituted with one or more NR t R u ;
R b ′ and R c ′ each represents hydrogen, or R b ′ and R c ′together represent a bond or —O—;
R d ′ and R e ′ together represent (═O) or R d ′ represents hydrogen and R e ′ represents hydrogen, hydroxy, (C 1 -C 6 )alkanoyloxy, NR j R k , CH 2 C(═O)OR s or CH 2 C(═O)NR m R n , wherein each (C 1 -C 6 )alkanoyloxy is optionally substituted with one or more NR t R u ;
each of R f and R g is independently hydrogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R f and R g together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
each of R j and R k is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R j and R k together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
each of R m and R n is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R m and R n together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
each of R 1 , R 2 , and R 3 is independently hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl or heteroaryl wherein each (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy is optionally substituted with OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryl, NR o R p , or —C(═O)NR q R r ; and wherein each aryl or heteroaryl is optionally substituted with one or two substituents selected independently from a halogen atom and (C 1 -C 4 )alkyl wherein (C 1 -C 4 )alkyl is optionally substituted with NR o R p ;
each of R o and R p is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R o and R p together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring; and
each of R q and R r is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
R s is hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ;
each of R t and R u is independently hydrogen, (C 1 -C 6 )alky or (C 1 -C 6 )alkanoyl; or R t and R u together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
or a salt thereof.
2. The compound of claim 1 wherein:
one of A and B is —CH(R b )CH(R c )C(R d )(R e )—;
and the other of A and B is:
—CH(R a )NHC(═O)— or —CH(R b ′)CH(R c ′)C(R d ′)(R e ′)—;
one of F and G is X and the other is C(R 2 );
each X is independently NH, S, or O;
the dotted line in the ring containing F and G signifies that two double bonds are present in the ring, the positions of which depend upon the values selected for F and G;
n and n′ each independently represents 1, 2, 3, 4 and 5, provided that the sum of n and n′ is 6;
R a represents hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkanoyloxy, wherein each (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkanoyloxy, is optionally substituted with OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryl, heteroaryl, NR f R g or —C(═O)NR f R g ; and wherein each aryl and heteroaryl is optionally substituted with one or two substituents selected independently from halo, (C 1 -C 6 )alkyl, NR f R g and NR f R g (C 1 -C 6 )alkyl-
R b and R c each represents hydrogen, or R b and R c together represent a bond or —O—;
R d and R e together represent (═O) or R d represents hydrogen and R e represents hydrogen, hydroxy, (C 1 -C 6 )alkanoyloxy, NR j R k , CH 2 C(═O)OR s or CH 2 C(═O)NR m R n , wherein each (C 1 -C 6 )alkanoyloxy is optionally substituted with one or more NR t R u ;
R b ′ and R c ′ each represents hydrogen, or R b ′ and R c ′ together represent a bond or —O—;
R d ′ and R e ′ together represent (═O) or R d ′ represents hydrogen and R e ′ represents hydrogen, hydroxy, (C 1 -C 6 )alkanoyloxy, NR j R k , CH 2 C(═O)OR s or CH 2 C(═O)NR m R n , wherein each (C 1 -C 6 )alkanoyloxy is optionally substituted with one or more NR t R u ;
each of R f and R g is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R f and R g together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
each of R j and R k is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R j and R k together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
each of R m and R n i s independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R m and R n together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
each of R 1 , R 2 , and R 3 is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryl or heteroaryl wherein each (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy is optionally substituted with OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryl, NR o R p , or —C(═O)NR q R r ; and wherein each aryl or heteroaryl is optionally substituted with one or two substituents selected independently from a halogen atom and (C 1 -C 4 )alkyl wherein (C 1 -C 4 )alkyl is optionally substituted with NR o R p ;
each of R o and R p is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R o and R p together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring; and
each of R q and R r is independently hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;
R s is hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted with one or more NR t R u ;
each of R t and R u is independently hydrogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl, or R t and R u together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring.
3. A compound as claimed in claim 1 , in which n and n′ each represents 3.
4. A compound as claimed in claim 1 , which is selected from formulae:
5. A compound as claimed in claim 1 , which has formula (Ia′):
6. A compound as claimed in claim 1 , which has formula (Ig′):
7. A compound as claimed in claim 1 , which has formula (Ih′):
8. A compound as claimed in claim 1 , in which each X is O.
9. A compound as claimed in claim 1 , in which each R 1 is hydrogen.
10. A compound as claimed in claim 1 , in which each R 2 is hydrogen.
11. A compound as claimed in claim 1 , in which
R a is selected from hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, benzyl, 4-hydroxybenzyl, 4-iodobenzyl, 4-aminobenzyl, and 4-(2-N,N-dimethylaminoethylamino)benzyl;
R b and R c are, together are a bond;
R d is hydrogen and
R e is hydrogen, hydroxy, CH 2 C(═O)OCH 3 , CH 2 C(═O)N(CH 3 ) 2 , or CH 2 C(═O)NHCH 2 CH 2 N(CH 3 ) 2 .
12. A compound as claimed in claim 1 , in which
R b ′ and R c ′ together are a bond;
R d ′ is hydrogen; and
R e ′ is hydrogen, hydroxy, CH 2 C(═O)OCH 3 or CH 2 C(═O)N(CH 3 ) 2 , or CH 2 C(═O)NHCH 2 CH 2 N(CH 3 ) 2 .
13. A compound as claimed in claim 1 , in which R a is alkyl.
14. A compound as claimed in claim 1 , in which R a is isopropyl.
15. A compound as claimed claim 1 in which R a is (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl wherein each (C 1 -C 6 )alkyl, and (C 2 -C 6 )alkenyl, is optionally substituted with NR f R g .
16. A compound as claimed in claim 1 in which R a is aminomethyl, 2-aminoethyl, 3-aminopropyl or 4-aminobutyl.
17. A compound as claimed in claim 1 , in which R d and R e are hydrogen.
18. The compound of claim 1 which is
or a salt thereof.
19. The compound of claim 1 which is,
or a salt thereof.
20. The compound of claim 1 which is,
or a salt thereof.
21. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 ; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
22. A method to stabilize G-quadruplex DNA comprising contacting the G-quadruplex DNA with a compound of formula I as defined in claim 1 , or a salt thereof.