IP Library › Granted Patent US 8,993,607

Granted Patent B2

US 8,993,607 · App. 12/671,888 · Granted Mar 31, 2015

Therapeutic compounds

Inventors: Edmond J. LaVoie (New Brunswick, NJ); Joseph E. Rice (New Brunswick, NJ)

Assignee: Rutgers, The State University of New Jersey

C07D498/22

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Quick Facts

Patent No.: US 8,993,607
App. No.: 12/671,888
Granted: Mar 31, 2015
Kind: B2

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Abstract

The invention provides compounds of formula I, II, and III as defined herein, as well as salts thereof. The compounds may have activity as anti-proliferative agents.

Claims (83)

1. A compound of formula (I):

wherein:

the bond represented by ---- is a single or double bond;

A is (—C(═O)NH—CH(R)—) x or (—CH(R)—NH—C(═O)—) x ;

B is a group of formula:

C is (—C(═O)NH—CH(R)—) y or (—CH(R)—NH—C(═O)—) y ;

n is 0, 1 or 2;

p is 0, 1, or 2;

x is 1 or 2;

y is 1 or 2;

provided that the sum of n, p, x and y is 4;

X is O or NH;

one of W and Z is O, S or NH and the other of W and Z is CR 6 ;

each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 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 7 R 8 , or —C(═O)NR 9 R 10 ; and wherein each aryl or heteroaryl is optionally substituted with one or two substituents selected independently from a halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, NR 7 R 8 , and NR 7 R 8 (C 1 -C 6 )alkyl-;

each R is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, aryl or heteroaryl, wherein each (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 1 -C 6 )alkoxy is optionally substituted with OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, aryl, NR 11 R 12 , or —C(═O)NR 13 R 14 ; and wherein each aryl or heteroaryl is optionally substituted with one or two substituents selected independently from halo, (C 1 -C 6 )alkyl, NR 11 R 12 , and NR 13 R 14 (C 1 -C 6 )alkyl-;

each of R 7 and R 8 is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, arylcarbonyl, heteroarylcarbonyl, (C 1 -C 6 )alkoxycarbonyl, carbamoyl, N—(C 1 -C 6 )alkylaminocarbonyl, aryl or heteroaryl, wherein each (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbony is optionally substituted with one or more NR 15 R 16 ; or R 7 and R 8 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring; and

each of R 9 and R 10 is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, carbamoyl, N—(C 1 -C 6 )alkylaminocarbonyl, aryl or heteroaryl, wherein each (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbony is optionally substituted with one or more NR 15 R 16 ; or R 9 and R 10 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;

each of R 11 and R 12 is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, carbamoyl, N—(C 1 -C 6 )alkylaminocarbonyl, aryl or heteroaryl, wherein each (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbony is optionally substituted with one or more NR 15 R 16 ; or R 11 and R 12 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring; and

each of R 13 and R 14 is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, carbamoyl, N—(C 1 -C 6 )alkylaminocarbonyl, aryl or heteroaryl, wherein each (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbony is optionally substituted with one or more NR 15 R 16 ; or R 13 and R 14 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;

each of R 15 and R 16 is independently hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkanoyl; or R 15 and R 16 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;

or a salt thereof; provided that the compound of formula (I) is not YM-216391.

2. The compound of formula (I) as claimed in claim 1 , wherein:

the bond represented by ---- is a single or double bond;

A is (—C(═O)NH—CH(R)—) x or (—CH(R)—NH—C(═O)—) x ;

B is a group of formula:

C is (—C(═O)NH—CH(R)—) y or (—CH(R)—NH—C(═O)—) y ;

n is 0, 1 or 2;

p is 0, 1, or 2;

x is 1 or 2;

y is 1 or 2;

provided that the sum of n, p, x and y is 4;

X is O or NH;

one of W and Z is O, S or NH and the other of W and Z is CR 6 ;

each R 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 11 R 12 , or —C(═O)NR 13 R 14 ; and wherein each aryl or heteroaryl is optionally substituted with one or two substituents selected independently from halo, (C 1 -C 6 )alkyl, NR 11 R 12 , and NR 13 R 14 (C 1 -C 6 )alkyl-;

each of R 7 and R 8 is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, carbamoyl, N—(C 1 -C 6 )alkylaminocarbonyl aryl or heteroaryl, wherein each (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbony is optionally substituted with one or more NR 15 R 16 ; or R 7 and R 8 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring; and

or a salt thereof; provided that the compound of formula (I) is not YM-216391.

3. The compound as claimed in claim 1 , in which the bond represented by ---- is a double bond.

4. The compound as claimed in claim 1 , which is of the formula (I′)

5. The compound as claimed in claim 1 , in which each X is O.

6. The compound as claimed in claim 1 , in which each R is selected independently from hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl and benzyl.

7. A compound as claimed in claim 1 in which each R is selected independently from (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 11 R 12 .

8. A compound as claimed in claim 1 in which each R is selected independently from aminomethyl, 2-aminoethyl, 3-aminopropyl or 4-aminobutyl.

9. The compound as claimed in claim 1 , in which A is —C(═O)NH—CH(R)—.

10. The compound as claimed in claim 1 , in which A is —C(═O)NH—CH(R)—C(═O)NH—CH(R)—.

11. The compound as claimed in claim 1 , in which A is —C(═O)NH—CH 2 —.

12. The compound as claimed in claim 1 , in which A is —C(═O)NH—CH 2 —C(═O)NH—CH 2 —.

13. The compound as claimed in claim 1 , in which A is —CH(R)—NH—C(═O)—.

14. The compound as claimed in claim 1 , in which A is —CH(R)—NH—C(═O)—CH(R)—NH—C(═O)—.

15. The compound as claimed in claim 1 , in which A is —CH 2 —NH—C(═O)—.

16. The compound as claimed in claim 1 , in which A is —CH 2 NH—C(═O)—CH 2 —NH—C(═O)—.

17. The compound as claimed in claim 1 , which is of the formula:

18. The compound as claimed in claim 1 , which is of the formula:

19. The compound as claimed in claim 1 , which is of the formula:

20. The compound as claimed in claim 1 , which is of the formula:

21. The compound as claimed in claim 1 , which is of the formula:

22. The compound as claimed in claim 1 , which is of the formula:

23. The compound as claimed in claim 1 , which is of the formula:

24. The compound of claim 18 wherein W is O or S and Z is CR 6 .

25. The compound of claim 18 wherein Z is O or S and W is CR 6 .

26. The compound of claim 1 wherein the compound of formula (I) is not a compound of the following formula:

27. The compound of claim 1 wherein the compound of formula (I) is not a compound of the following formula:

28. A compound of formula (II) or (III):

wherein:

each X is independently O, S or NH;

each of R 15 and R 16 is independently hydrogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl; or R 15 and R 16 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or azepino ring;

or a salt thereof.

29. The compound of claim 28 wherein each R 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 11 R 12 , or —C(═O)NR 13 R 14 ; and wherein each aryl or heteroaryl is optionally substituted with one or two substituents selected independently from halo, (C 1 -C 6 )alkyl, NR 11 R 12 , and NR 13 R 14 (C 1 -C 6 )alkyl-.

30. The compound of claim 28 wherein each X is O.

31. The compound of claim 28 wherein each R is H.

32. The compound of claim 1 which is,

or a salt thereof.

33. The compound of claim 1 which is,

or a salt thereof.

34. 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.

35. 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.

Assignments (2)

CONFIRMATORY LICENSE Recorded Jan 13, 2020

From: NIH - DEITR

To: NIH - DEITR

Reel/Frame 051489/0176 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 6, 2011

From: LAVOIE, EDMOND J.; RICE, JOSEPH E.

To: RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

Reel/Frame 027343/0781 →

Continuity (2)

Provisional Application 60953648 · Aug 2, 2007

Related Publication 20120046234A1 · Feb 23, 2012