Neuroactive substituted cyclopenta[b]phenanthrenes as modulators for GABA type-A receptors

Patent metadata

Field	Value
Publication number	US-9365502-B2
Application number	US-201414200219-A
Country	US
Kind code	B2
Filing date	Mar 7, 2014
Priority date	Mar 11, 2013
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

The present disclosure is generally directed to neuroactive substituted cyclopenta[b]phenanthrenes as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H, ═O, ═CHCN, ═CHCO 2 R z , where R z is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, β-CN, β-OH, β-OR y , where R y is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, β-NO 2 , spiroepoxy, or C(O)R x , where R x is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 2 is H, ═O, ═CHCN, ═CHCO 2 R w , where R w is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, β-CN, β-OH, β-OR v , where R v is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, β-NO 2 , spiroepoxy, or C(O)R u , where R u is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 3 is H, ═O, ═CHCN, ═CHCO 2 R t , where R t is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, —CN, β-OH, β-OR s , where R s is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, β-NO 2 , spiroepoxy, or C(O)R r , where R r is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 4 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 5 is H, CO 2 R q , where R q is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl, CH 2 OR p , where R p is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl, C(O)R o , where R o is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl, C(O)NHR n , where R n is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl, CH 2 NHR m , where R m is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl, CH 2 N(CH 3 ) 2 , or CH 2 N(CH 2 CH 3 ) 2 ;
R 6 is H, ═O, N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , OR l , where R l is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl, or NR k , where R k is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl;
R 7 is H, ═O, N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , OR j , where R j is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl, or NR i , where R i is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl;
R 8 is H, N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , optionally substituted morpholinyl, or OR h , where R h is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl;
R 9 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl;
R 10 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 11 is H or C(O)R g , where R g is optionally substituted C 1 -C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, or optionally substituted C 2 -C 20 alkynyl;
- - - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between, C 1 -C 2 , C 4 -C 4a , C 4a -C 5 , C 8 -C 9 , or C 9 -C 10 , with the provisos that when present between: (i) C 4 -C 4a , the C 4a —H substituent is not present; (ii) C 4a -C 5 , the C 4a —H substituent is not present and R 7 is other than ═O; (iii) C 9 -C 10 , R 1 is other than ═O, ═CHCN or ═CHCO 2 R z , and R 2 is other than ═O, ═CHCN or ═CHCO 2 R w ; and, (iv) C 8 -C 9 , R 2 is other than ═O, ═CHCN or ═CHCO 2 R w , and R 3 is other than ═O, ═CHCN or ═CHCO 2 R t ; and,
with the proviso that:
when C 4a —H is in the α-configuration, R 4 =methyl and R 1 =R 2 =R 5 =R 6 =R 7 =R 8 =R 9 =R 10 =R 11 is H, R 3 is other than ═O or spiroepoxy.

2. The compound of claim 1 , wherein R 11 is H.

3. The compound of claim 1 , wherein R 10 is selected from the group consisting of H and methyl.

4. The compound of claim 1 , wherein R 3 is selected from the group consisting of ═CHCN, β-NO 2 , ═O, spiroepoxy, β-CN and C(O)CH 3 .

5. The compound of claim 1 , wherein a double bond is present between C 8 -C 9 .

6. The compound of claim 1 , wherein R 9 is H.

7. The compound of claim 1 , wherein R 1 is H.

8. The compound of claim 1 , wherein R 2 is H.

9. The compound of claim 1 , wherein R 4 is methyl.

10. The compound of claim 1 , wherein R 5 is H.

11. The compound of claim 1 , wherein R 6 is H.

12. The compound of claim 1 , wherein R 7 is H and R 8 is H.

13. The compound of claim 1 , wherein the C 4a —H is in the alpha configuration.

14. The compound of claim 1 , wherein the C 4a —H is in the beta configuration.

15. The compound of claim 1 , of structure (I-a):

wherein R 3 is H, ═O, ═CHCN, ═CHCO 2 R t , where R t is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, —CN, β-OH, β-OR s , where R s is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl, β-NO 2 , spiroepoxy, or C(O)R r , where R r is optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 10 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl; and,
- - - denotes an optional C—C bond, resulting in a C═C bond between C 8 -C 9 , with the proviso that when present, R 3 is other than ═O, ═CHCN or ═CHCO 2 R t ;
with the proviso that when C 4a —H is in the α-configuration, R 4 =methyl and R 1 =R 2 =R 5 =R 6 =R 7 =R 8 =R 9 =R 10 =R 11 is H, R 3 is other than ═O or spiroepoxy.

16. The compound of claim 1 selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

Assignees

• Univ Washington

Inventors

• Covey Douglas

Classifications

• C07C255/47

  to carbon atoms of rings being part of condensed ring systems · CPC title

• C07C49/513

  a keto group being part of a condensed ring system · CPC title

• C07C255/31 Primary

  having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings · CPC title

• C07C49/345

  polycyclic · CPC title

• C07C205/05

  having nitro groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title