Analogs of cyclobenzaprine and amitriptyline
The present invention relates to cyclobenzaprine analogs and amitriptyline 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, or deuterated variants thereof, wherein:
R 1 is selected from H, C 1-4 -alkyl, and C 1-4 -alkoxy;
R 2 is selected from 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; 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; 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.
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; and
the 3 carbons connecting nitrogen to the tricyclic ring system of Formula A 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; 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 .
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; 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 .
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; 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 .
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 ; and
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; 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 .
9. The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is H;
R 3 is OH; 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 .
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; 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 .
11. The compound of claim 1 ,
R 1 is H;
R 2 is C 1-4 -alkoxy;
R 3 is C 1-4 -alkoxy; 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 .
12. The compound of claim 1 , wherein
R 1 is C 1-4 -alkyl;
R 2 is Br;
R 3 is H; 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 .
13. A cyclobenzaprine analog compound of Formula A
and pharmaceutically acceptable salts, or deuterated variants 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, CF3, or CHF2.
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;
R 5 is C 1-4 -alkyl; and
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;
R 5 is C 1-4 -alkyl; and
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 .