Methods of using and compositions comprising tryptophan hydroxylase inhibitors

1. A pharmaceutical composition comprising a first active pharmaceutical ingredient and a second active pharmaceutical ingredient, wherein the first active pharmaceutical ingredient has associated with it a serotonin-mediated adverse effect and the second active pharmaceutical ingredient is a tryptophan hydroxylase inhibitor of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted cycloalkyl, aryl, or heterocycle;

X is a bond, —O—, —S—, —C(O)—, —C(R 4 )═, ═C(R 4 )—, —C(R 3 R 4 )—, —C(R 4 )═C(R 4 )—, —C≡C—,—N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —C(R 3 R 4 )N(R 5 )—, —N(R 5 )C(R 3 R 4 )—, —ONC(R 3 )—, —C(R 3 )NO—,—C(R 3 R 4 )O—, —OC(R 3 R 4 )—, —S(O 2 )—, —S(O 2 )N(R 5 )—, —N(R 5 )S(O 2 )—, —C(R 3 R 4 )S(O 2 )—, or —S(O 2 )C(R 3 R 4 )—;

D is optionally substituted heterocycle;

E is optionally substituted aryl;

R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;

R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl;

each R 5 is independently hydrogen or optionally substituted alkyl or aryl; and

n is 0-3.

2. The composition of claim 1 , wherein the first active pharmaceutical ingredient is a selective serotonin reuptake inhibitor.

3. The composition of claim 2 , wherein the selective serotonin reuptake inhibitor is amitriptyline, citalopram, doxepin, fluoxetine, fluvoxamine, imipramine, norfluoxetine, paroxetine, sertraline, venlafaxine, or zimelidine, or a pharmaceutically acceptable salt or pharmacologically active stereoisomer thereof.

4. The composition of claim 1 , wherein the tryptophan hydroxylase inhibitor is of the formula:

5. The composition of claim 1 , wherein the tryptophan hydroxylase inhibitor is of the formula:

wherein:

each of Z″ 1 , Z″ 2 , Z″ 3 , and Z″ 4 is independently N or CR 10 ;

each R 10 is independently amino, cyano, halogen, hydrogen, OR 11 , SR 11 , NR 12 R 13 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 11 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

each R 13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle.

6. The composition of claim 5 , wherein the tryptophan hydroxylase inhibitor is of the formula:

7. A pharmaceutical composition comprising a selective serotonin reuptake inhibitor and a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted cycloalkyl, aryl, or heterocycle;

X is a bond, —O—, —S—, —C(O)—, —C(R 4 )═, ═C(R 4 )—, —C(R 3 R 4 )—, —C(R 4 )═C(R 4 )—, —C≡C—,—N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —C(R 3 R 4 )N(R 5 )—, —N(R 5 )C(R 3 R 4 )—, —ONC(R 3 )—, —C(R 3 )NO—,—C(R 3 R 4 )O—, —OC(R 3 R 4 )—, —S(O 2 )—, —S(O 2 )N(R 5 )—, —N(R 5 )S(O 2 )—, —C(R 3 R 4 )S(O 2 )—, or —S(O 2 )C(R 3 R 4 )—;

E is optionally substituted aryl or heterocycle;

R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;

R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl;

each R 5 is independently hydrogen or optionally substituted alkyl or aryl; and

each R 10 is independently amino, cyano, halogen, hydrogen, OR 11 , SR 11 , NR 12 R 13 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 11 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

each R 13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle.

n is 0-3; and

q is 1-2.

8. The composition of claim 7 , wherein E is aryl.

9. The composition of claim 7 , wherein X is —O—, —C(R 3 R 4 )O—, or —OC(R 3 R 4 )—.

10. The composition of claim 9 , wherein R 3 is hydrogen or optionally substituted alkyl, and R 4 is hydrogen or optionally substituted alkyl.

11. The composition of claim 9 , wherein R 3 is hydrogen and R 4 is trifluromethyl.

12. The composition of claim 7 , wherein n is 1.

13. The composition of claim 7 , wherein q is 1.

14. The composition of claim 7 , wherein A is optionally substituted biphenyl.

15. The composition of claim 7 , wherein A is substituted biphenyl, E is aryl, X is —C(R 3 R 4 )O—, R 3 is hydrogen, and R 4 is trifluromethyl.

16. The composition of claim 7 , wherein the selective serotonin reuptake inhibitor is fluoxetine.

17. A pharmaceutical composition comprising a selective serotonin reuptake inhibitor and (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl) ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.

18. The composition of claim 17 , wherein the selective serotonin reuptake inhibitor is fluoxetine.