IP Library › Granted Patent US 9,944,644

Granted Patent B2

US 9,944,644 · App. 14/775,565 · Granted Apr 17, 2018

Octahydropyrrolopyrroles their preparation and use

Inventors: Konstantin Petrukhin (New Windsor, NY); Christopher Cioffi (Albany, NY); Graham Johnson (Sanbornton, NH); Nicoleta Dobri (New York, NY); Emily Freeman (Albany, NY); Ping Chen (Albany, NY); Michael Conlon (Albany, NY); Lei Zhu (Albany, NY)

Assignee: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

C07D487/04 C07D209/52 C07D401/12 C07D403/04 C07D403/06 C07D403/12 C07D471/04 C07D498/04 C07D519/00

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,944,644
App. No.: 14/775,565
Granted: Apr 17, 2018
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides compounds comprising variously substituted octahydropyrrolopyrroles, their synthesis, methods of making, methods of using, compositions and formulations thereof.

Claims (133)

1. A compound of the structure:

wherein

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl;

A is absent or present, and when present is

B is substituted or unsubstituted heterobicycle of the structure:

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and ϕ are each independently absent or present, and when present each is a bond;

Z 1 is S, O or N;

Z 2 is S, O, N or N—R 7 ,

wherein R 7 is H, C 1 -C 10 alkyl, or oxetane;

X is C or N;

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently CR 8 , C(R 9 ) 2 , N—R 10 , O, N, SO 2 , or C═O,

wherein

R 8 is H, halogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 10 alkyl), C(O)OH, C(O)O(C 1 -C 10 alkyl), C(O)—NH 2 , C(O)—NH(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , NHC(O)—NH(C 1 -C 10 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 , SO 2 —NH (C 1 -C 10 alkyl), SO 2 —N(C 1 -C 10 alkyl) 2 , CN, or CF 3 ;

R 9 is H or C 1 -C 10 alkyl; and

R 10 is H, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 10 alkyl)-CF 3 , (C 1 -C 10 alkyl)-OCH 3 , (C 1 -C 10 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 10 alkyl)-CF 3 , SO 2 —(C 1 -C 10 alkyl)-OCH 3 , SO 2 —(C 1 -C 10 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 10 alkyl)-CF 3 , C(O)—(C 1 -C 10 alkyl)-OCH 3 , C(O)—(C 1 -C 10 alkyl)-halogen, C(O)—NH—(C 1 -C 10 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 10 alkyl)-C(O)OH, C(O)—NH 2 or oxetane,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of the structure:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 of the structure:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein B has the structure

wherein

n is an integer from 0-2;

α, β, χ, δ, ε, and ϕ are each independently absent or present, and when present each is a bond;

Z 1 is S, O or N;

Z 2 is S, O, N or N—R 7 ,

wherein R 7 is H, C 1 -C 10 alkyl, or oxetane;

X is C or N;

Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are each independently CR 8 , C(R 9 ) 2 , N—R 10 , O, N, SO 2 , or C═O,

wherein

R 8 is H, halogen, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 10 alkyl), C(O)OH, C(O)O(C 1 -C 10 alkyl), C(O)—NH 2 , C(O)—NH(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , NHC(O)—NH(C 1 -C 10 alkyl), NHC(O)—N(C 1 -C 4 alkyl) 2 , SO 2 —NH(C 1 -C 10 alkyl), SO 2 —N(C 1 -C 10 alkyl) 2 , CN, or CF 3 ;

R 9 is H or C 1 -C 10 alkyl;

R 10 is H, C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 10 alkyl)-CF 3 , (C 1 -C 10 alkyl)-OCH 3 , (C 1 -C 10 alkyl)-halogen, SO 2 —(C 1 -C 10 alkyl), SO 2 —(C 1 -C 10 alkyl)-CF 3 , SO 2 —(C 1 -C 10 alkyl)-OCH 3 , SO 2 —(C 1 -C 10 alkyl)-halogen, C(O)—(C 1 -C 10 alkyl), C(O)—(C 1 -C 10 alkyl)-CF 3 , C(O)—(C 1 -C 10 alkyl)-OCH 3 , C(O)—(C 1 -C 10 alkyl)-halogen, C (O)—NH—(C 1 -C 10 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 10 alkyl)-C(O)OH, C(O)—NH 2 or oxetane, and

wherein

when α is present, then Z 1 and Z 2 are N, X is N, β is present, and χ and δ are absent, or when α is present, then Z 1 is O or S, Z 2 is N, X is C, χ is present, and β and δ are absent;

when α is absent, then Z 1 is N, Z 2 is N—R 7 , X is C, β and δ are present, and χ is absent, or when α is absent, then Z 1 is N, Z 2 is O or S, X is C, β and δ are present, and χ is absent;

when ε and ϕ are each present, then n=1, and each of Y 1 , Y 2 , Y 3 , and Y 4 are independently C—R 8 or N; and

when ε and ϕ are each absent, then n=0, 1 or 2, each of Y 1 , Y 2 , Y 3 , and each occurrence of Y 4 are independently C(R 9 ) 2 , N—R 10 , O, or SO 2 ,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 of the structure:

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

7. The compound of claim 4 , wherein B has the structure:

wherein

n is 0;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 and Y 3 are each CH 2 or C(CH 3 ) 2 ; and

Y 2 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 4 alkyl), SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O)OH, C(O)—NH 2 or oxetane,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 4 , wherein B has the structure:

wherein

n is 1;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 2 and Y 4 are each CH 2 or C(CH 3 ) 2 ; and

Y 3 is O, SO 2 , or N—R 10 ,

wherein

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 4 , wherein B has the structure:

wherein

n is 1;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 3 and Y 4 are each CH 2 or C(CH 3 ) 2 ; and

Y 2 is O, SO 2 , or N—R 10 ,

wherein

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 4 , wherein B has the structure:

wherein

n is 2;

R 7 is H, C 1 -C 4 alkyl, or oxetane;

Y 1 , Y 3 and each occurrence of Y 4 are each CH 2 or C(CH 3 ) 2 ; and

Y 2 is O, SO 2 , or N—R 10 ,

wherein

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 4 , wherein B has the structure:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 4 wherein B has the structure:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 4 , wherein B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 4 , wherein B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein B has the structure:

wherein

R 7 is H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , or

and

each R 10 is H or CH 3 ,

or a pharmaceutically acceptable salt thereof.

16. The compound of 4 , wherein B has the structure:

wherein

R 7 is H, C 1 -C 4 alkyl, or oxetane; and

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN or CF 3 , or

B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein R 8 is H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O—(C 1 -C 4 alkyl), C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN or CF 3 ,

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 4 , wherein B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 4 alkyl), CN, CF 3 , C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 or NHC(O)—N(CH 3 ) 2 , or

B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, O—(C 1 -C 4 alkyl), CN or CF 3 ,

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier.

Assignments (1)

CONFIRMATORY LICENSE Recorded Sep 28, 2016

From: COLUMBIA UNIV NEW YORK MORNINGSIDE

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 040166/0537 →

Continuity (2)

Provisional Application 61785334 · Mar 14, 2013

Related Publication 20160046632A1 · Feb 18, 2016