ANALOGS OF CYCLOBENZAPRINE AND AMITRYPTILENE
The present invention relates to cyclobenzaprine analogs and amitryptilene analogs, including deuterated forms useful for treatment or prevention of symptoms associated with post-traumatic stress disorder.
1 . A cyclobenzaprine analog compound of Formula A:
and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from H, C 1-4 -alkyl, and C 1-4 -alkoxy;
R 2 is selected from H, Br, (CH 2 ) n CO 2 R where n=0 to 3 and R═C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;
R 3 is selected from H, C 1-4 -alkoxy, OH, and OCOR where R═C 1-4 -alkyl;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
2 . The compound of claim 1 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF.
3 . The compound of claim 1 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines, optionally further substituted with CD 3 , CD 3 O, CF 3 , or CDF 2 , and with all other positions substituted with D;
The 3 carbons connecting nitrogen to the suberenone are deuterated at all 5 positions (CDCD 2 CD 2 ).
4 . The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is C 1-4 -alkoxy;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
5 . The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OCOR where R═C 1-4 -alkyl;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
6 . The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n=0 and R=methyl;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
7 . The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is C 1-4 -alkoxy;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
R 5 is C 1-4 -alkyl.
8 . The compound of claim 1 , wherein,
R 1 is C 1-4 -alkoxy;
R 2 is H;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
9 . The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OH;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
10 . The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n is 0 and R is C 1-4 -alkyl;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
11 . The compound of claim 1 ,
R 1 is H;
R 2 is C 1-4 -alkoxy;
R 3 is C 1-4 -alkoxy;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
12 . The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is Br;
R 3 is H:
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
13 . A cyclobenzaprine analog compound of Formula A
and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from C 1-4 -alkyl, and C 1-4 -alkoxy;
R 2 is selected from H, Br, (CH 2 ) n CO 2 R where n=0 to 3 and R═C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;
R 3 is selected from H, C 1-4 -alkoxy, OH, and OCOR where R═C 1-4 -alkyl;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
14 . The compound of claim 13 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is C 1-4 -alkoxy;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
15 . The compound of claim 13 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OCOR where R═C 1-4 -alkyl; R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
16 . The compound of claim 13 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n=0 and R=methyl;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
17 . The compound of claim 13 , wherein
R 1 is C 1-4 -alkyl;
R 2 is C 1-4 -alkoxy;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
18 . The compound of claim 13 , wherein,
R 1 is C 1-4 -alkoxy;
R 2 is H;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
19 . The compound of claim 13 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OH;
R 4 is C 1-4 -alkyl; and
R 5 is C 1-4 -alkyl.
20 . The compound of claim 13 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n is 0 and R is C 1-4 -alkyl;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
21 . The compound of claim 13 , wherein
R 1 is C 1-4 -alkyl;
R 2 is Br;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
22 . A cyclobenzaprine analog compound of Formula A
and pharmaceutically acceptable salts thereof, wherein:
R 1 is H
R 2 is selected from H, Br, (CH 2 ) n CO 2 R where n=0 to 3 and R═C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;
R 3 is selected from H, C 1-4 -alkoxy, OH, and OCOR where R═C 1-4 -alkyl;
R 4 is methyl or 2,2-difluoroethyl
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl or methoxy.
23 . The compound of claim 22 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 is methyl
and R 5 is C 1-4 -alkyl.
24 . The compound of claim 22 , wherein
R 1 is H:
R 2 is H;
R 3 is H;
R 4 is 2,2-difluoroethyl
25 . The compound of claim 22 , wherein
R 1 is H;
R 2 , is H;
R 3 is H; and
R 4 and R 5 taken together form a fused 4-membered ring that is optionally substituted with CH 3 or OCH 3
26 . The compound of claim 22 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 and R 5 are CD 3 , or R 4 and R 5 taken together form a 4-membered saturated ring optionally substituted with CD 3 , CD 3 O, CF 3 , or CDF 2 , and with all other positions substituted with D;
The 3 carbons connecting nitrogen to the suberenone are deuterated at all 5 positions (CDCD 2 CD 2 ).
27 . A amitryptilene analog compound of Formula B
and pharmaceutically acceptable salts thereof wherein:
R 1 is selected from H, C 1-4 -alkyl, and C 1-4 -alkoxy;
R 2 is selected from H, Br, (CH 2 ) n CO 2 R where n=0 to 3 and R═C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;
R 3 is selected from H, C 1-4 -alkoxy, OH, and OCOR where R═C 1-4 -alkyl;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
28 . The compound of claim 27 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
29 . The compound of claim 27 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines, optionally further substituted with CD 3 , CD 3 O, CF 3 , or CDF 2 , and with all other positions substituted with D;
The 3 carbons connecting nitrogen to the suberenone are deuterated at all 5 positions (CDCD 2 CD 2 ).
30 . The compound of claim 27 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is C 1-4 -alkoxy;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
31 . The compound of claim 27 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OCOR where R═C 1-4 -alkyl;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
32 . The compound of claim 27 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n=0 and R=methyl;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
33 . The compound of claim 27 , wherein
R 1 is C 1-4 -alkyl;
R 2 is C 1-4 -alkoxy;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
R 5 is C 1-4 -alkyl.
34 . The compound of claim 27 , wherein,
R 1 is C 1-4 -alkoxy;
R 2 is H;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
35 . The compound of claim 27 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OH;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
36 . The compound of claim 27 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n is 0 and R is C 1-4 -alkyl;
R 3 is H;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
37 . The compound of claim 27 ,
R 1 is H;
R 2 is C 1-4 -alkoxy;
R 3 is C 1-4 -alkoxy;
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
38 . The compound of claim 27 , wherein
R 1 is C 1-4 -alkyl;
R 2 is Br;
R 3 is H:
R 4 and R 5 taken together form a 4-membered saturated ring substituted with 1 or more fluorines and optionally further substituted with methyl, methoxy, CF 3 , or CHF 2 .
39 . A amitryptilene analog compound of Formula B
and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from C 1-4 -alkyl, and C 1-4 -alkoxy;
R 2 is selected from H, Br, (CH 2 ) n CO 2 R where n=0 to 3 and R═C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;
R 3 is selected from H, C 1-4 -alkoxy, OH, and OCOR where R═C 1-4 -alkyl;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
40 . The compound of claim 39 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is C 1-4 -alkoxy;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
41 . The compound of claim 39 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OCOR where R═C 1-4 -alkyl; R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
42 . The compound of claim 39 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n=0 and R=methyl;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
43 . The compound of claim 39 , wherein
R 1 is C 1-4 -alkyl;
R 2 is C 1-4 -alkoxy;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
44 . The compound of claim 39 , wherein,
R 1 C 1-4 -alkoxy;
R 2 is H;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
45 . The compound of claim 39 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OH;
R 4 is C 1-4 -alkyl; and
R 5 is C 1-4 -alkyl.
46 . The compound of claim 39 , wherein
R 1 is C 1-4 -alkyl;
R 2 is (CH 2 ) n CO 2 R where n is 0 and R is C 1-4 -alkyl;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
47 . The compound of claim 39 , wherein
R 1 is C 1-4 -alkyl;
R 2 is Br;
R 3 is H;
R 4 is C 1-4 -alkyl wherein if R 4 is ethyl the terminus carbon can be optionally substituted by fluorine one to three times; and
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
48 . A amitryptilene analog compound of Formula B,
pharmaceutically acceptable salts thereof, wherein:
R 1 is H
R 2 is selected from H, Br, (CH 2 ) n CO 2 R where n=0 to 3 and R═C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;
R 3 is selected from H, C 1-4 -alkoxy, OH, and OCOR where R═C 1-4 -alkyl;
R 4 is methyl or 2,2-difluoroethyl
R 5 is C 1-4 -alkyl; R 4 and R 5 taken together can form a fused 4-membered saturated ring optionally substituted with methyl or methoxy.
49 . The compound of claim 48 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 is methyl
and R 5 is C 1-4 -alkyl.
50 . The compound of claim 48 , wherein
R 1 is H:
R 2 is H;
R 3 is H;
R 4 is 2,2-difluoroethyl
51 . The compound of claim 48 , wherein
R 1 is H;
R 2 , is H;
R 3 is H; and
R 4 and R 5 taken together form a fused 4-membered ring that is optionally substituted with Me or OMe
52 . The compound of claim 48 , wherein
R 1 is H;
R 2 is H;
R 3 is H;
R 4 and R 5 are CD 3 , or R 4 and R 5 taken together form a 4-membered saturated ring optionally substituted with CD 3 , CD 3 O, CF 3 , or CDF 2 , and with all other positions substituted with D;
wherein, the 3 carbons connecting nitrogen to the suberenone are deuterated at all 5 positions (CDCD 2 CD 2 ).