Analogs of cyclobenzaprine and amitryptilene
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. An amitriptyline 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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
2. 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 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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
3. 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 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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
4. 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 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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally 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 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;
R 5 is C 1-4 -alkyl; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
6. The compound of claim 1 , 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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally 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 H;
R 3 is OH;
R 4 is C 1-4 -alkyl; and
R 5 is C 1-4 -alkyl.
8. The compound of claim 3 , 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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally 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 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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally substituted with methyl, methoxy, CF 3 , or CHF 2 .
10. A amitriptyline analog compound of Formula B,
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; or R 4 and R 5 taken together can form a 4-membered saturated ring optionally substituted with methyl or methoxy; 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 tricyclic ring system of Formula B are deuterated at all 5 positions (CDCD 2 CD 2 ).
11. The compound of claim 10 , 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.
12. The compound of claim 10 , wherein
R 1 is H:
R 2 is H;
R 3 is H; and
R 4 is 2,2-difluoroethyl.
13. The compound of claim 10 , 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 ring that is optionally substituted with Me or OMe.
14. The compound of claim 10 , 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 tricyclic ring system of Formula B are deuterated at all 5 positions (CDCD 2 CD 2 ).