Glycine transporter-1 inhibitors

• US 8,735,383 B2
• Filed: 03/21/2012
• Issued: 05/27/2014
• Est. Priority Date: 06/28/2006
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Amegadzie, Albert, Qian, Wenyuan, Xia, Xiaoyang, Harried, Scott S., Stephen, Hitchcock
• Primary Examiner(s): LEESER, ERICH A
• Application Number:
  US13/426,539
• Publication Number:
  US 20120195985A1
• Time in Patent Office: 797 Days
• Field of Search: 514/183, 514/218, 514/255.04
• US Class Current: 514/183
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/36 : Radicals substituted by singly-bound nitrogen atoms nitro radicals C07D213/26
• CPC Class Codes: C07D 241/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 241/08 : with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 243/08 : not condensed with other rings
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12

Abstract

The present invention provides compounds that are glycine transporter 1 (hereinafter referred to as GlyT-1) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of GlyT-1 such as cognitive disorders associated with Schizophrenia, ADHD (attention deficit hyperactivity disorder), MCI (mild cognitive impairment), and the like. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Claims

1. A method of treating Schizophrenia or cognitive disorder associated with Schizophrenia in a patient which method comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):

2. The method of claim 1 wherein:

n is 1;

R¹ and R² are independently hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aforementioned rings are optionally substituted with R^a, R^b, or R^c independently alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino;

or

R¹ and R², when attached to the same carbon atom, can combine to form cycloalkyl or monocyclic saturated heterocyclyl to give a spiro ring wherein the cycloalkyl or monocyclic saturated heterocyclyl can be optionally substituted with R^d, R^e, or R^f independently alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino;

or

R¹ and R², when attached to carbon atoms 2 and 5 or 3 and 6 positions of the piperazine ring, can combine to form —

C₁-C₃—

alkylene chain wherein one of the carbon atoms in the alkylene chain is optionally replaced by a —

NR—

, —

O—

, —

S(O)n1- (wherein R is hydrogen or alkyl and n1 is 0-2) and further wherein one or two hydrogen atoms in the alkylene chain can be optionally substituted with one or two alkyl; and

Ar¹ and Ar² are independently aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein each of the aforementioned ring is optionally substituted with R^g, R^h or Rⁱ wherein R^g is alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino and R^h and Rⁱ are independently alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aromatic or alicyclic ring in R^g, R^h and Rⁱ is optionally substituted with R^j, R^k or R^l which are independently alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino provided that;

the compound of Formula (I) is not 2-(4-benzhydrylpiperazin-1-yl)acetic acid or 2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid.

3. The method of claim 1 wherein R¹ and R² are hydrogen.

4. The method of claim 1 wherein R¹ is hydrogen and R² is alkyl.

5. The method of claim 1 wherein R¹ and R² are attached to the same carbon atom and are combined to form cycloalkyl optionally substituted with R^d, R^e or R^f which is independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino.

6. The method of claim 1 wherein R¹ and R² are attached to the same carbon atom and are combined to form monocyclic saturated heterocyclyl which are optionally substituted with R^d, R^e or R^f which is independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino.

7. The method of claim 1 wherein R¹ and R² are attached to carbon atoms 2 and 5 or 3 and 6 positions of the piperazine ring, and are combined to form —

C₁-C₂-alkylene chain wherein one or two hydrogen atoms in the alkylene chain can be optionally substituted with one or two alkyl.

8. The method of claim 1 wherein R¹, R², R³, R⁴ and R⁵ are hydrogen and Ar¹ and Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ.

9. The method of claim 1 wherein R¹, R³, R⁴, and R⁵ are hydrogen, R² is alkyl, and Ar¹ and Ar² are phenyl, each optionally substituted with R^g, R^h or Rⁱ.

10. The method of claim 1 wherein R¹, R², R³, R⁴ and R⁵ are hydrogen, Ar¹ is phenyl optionally substituted with R^g, R^h or Rⁱ and Ar² is cycloalkyl.

11. The method of claim 1 wherein R¹, R³, R⁴, and R⁵ are hydrogen, R² is alkyl, Ar¹ is phenyl optionally substituted with R^g, R^h or Rⁱ and Ar² is cycloalkyl.

12. The method of claim 1 wherein R¹, R², R³, R⁴ and R⁵ are hydrogen, Ar¹ is phenyl and Ar² is heteroaryl, each ring optionally substituted with R^g, R^h or Rⁱ.

13. The method of claim 1 wherein R¹, R³, R⁴, and R⁵ are hydrogen, R² is alkyl, Ar¹ is phenyl and Ar² is heteroaryl, each ring optionally substituted with R^g, R^h or Rⁱ.

14. The method of claim 1 wherein R¹, R³, R⁴ and R⁵ are hydrogen, R² is hydrogen or methyl and Ar¹ and Ar² are independently phenyl, each ring optionally substituted with R^g or R^h wherein R^g and R^h are independently methyl, fluoro, trifluoromethyl, trifluoromethoxy or 2,2,2-trifluoroethoxy.

15. The method of claim 1 wherein the compound has the structure:

16. The method of claim 1 wherein the compound has the structure:

17. The method of claim 1 wherein the compound has the structure:

18. The method of claim 1 wherein the compound is selected from a group consisting of:

(R)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((3-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((3,5-dichlorophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((4-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-benzhydrylpiperazin-1-yl)acetic acid;

2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((2-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((3-biphenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-((4-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(R)-2-(4-((4-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-((3-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

(R)-2-(4-((3-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((3-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-benzhydryl-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-iodophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((S)-(3-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(biphenyl-3-yl-phenyl-methyl)-piperazin-1-yl)-acetic acid;

2-((R)-2-methyl-4-((S)-phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((4-chlorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(biphenyl-4-yl-phenyl-methyl)-piperazin-1-yl)-acetic acid;

2-((R)-4-((4-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((4-cyanophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((3-chlorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

[(R)-4-((R)-biphenyl-3-yl-phenyl-methyl)-2-methyl-piperazin-1-yl]-acetic acid;

2-((R)-2-methyl-4-((3-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((S)-(2-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(2-bromophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(m-tolyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-isopropylphenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((4-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((3-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(thiophen-2-yl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-(3-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((S)-(3-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-(4-(methylthio)phenyl)(phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-((S)-(2-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(2-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((S)-phenyl(3-(trifluoromethoxy)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-phenyl(3-(trifluoromethoxy)phenyl)methyl)piperazin-1-yl)acetic acid;

[(R)-4-((R)-biphenyl-4-yl-phenyl-methyl)-2-methyl-piperazin-1-yl]-acetic acid;

{(R)-2-methyl-4-[(R)-(2′

-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazin-1-yl]-acetic acid;

{(R)-2-methyl-4-[(R)-(3′

-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazin-1-yl]-acetic acid;

{(R)-2-methyl-4-[(R)-(4′

-methyl-biphenyl-4-yl)-phenyl-methyl]-piperazin-1-yl]-acetic acid;

2-((R)-4-((S)-(2,4-difluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(2,4-difluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((S)-(4-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(4-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((S)-(3-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((R)-(3-fluorophenyl)(phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(S)-2-(4-benzhydryl-2-methylpiperazin-1-yl)acetic acid;

2-((S)-2-methyl-4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

(S)-2-(4-benzhydryl-3-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-benzhydryl-3-methylpiperazin-1-yl)acetic acid;

2-((2,5-trans)-4-benzhydryl-2,5-dimethylpiperazin-1-yl)acetic acid;

2-((2,5-cis)-4-benzhydryl-2,5-dimethylpiperazin-1-yl)acetic acid;

2-((R)-3-methyl-4-(phenyl(4-diphenyl)methyl)piperazin-1-yl)acetic acid;

(R)-2-(4-(bis(3-chlorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(3-fluorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-(4-((3-(trifluoromethyl)phenyl)(4-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-(4-((4-fluorophenyl)(3-(diphenyl)methyl))-(R)-2-methylpiperazin-1-yl)acetic acid

(R)-2-(4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-((R)-4-((3-bromophenyl)(4-fluorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(4-fluorophenyl)methyl)-3-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(4-fluorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

2-(4-(bis(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-(thiophen-2-yl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((R)-thiophen-2-yl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-2-methyl-4-((S)-thiophen-2-yl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(R)-2-(4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

(S)-2-((R)-4-(bis(4-chlorophenyl)methyl)-3-methylpiperazin-1-yl)propanoic acid;

(S)-2-((R)-4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)propanoic acid;

(R)-2-((R)-4-(bis(4-chlorophenyl)methyl)-2-methylpiperazin-1-yl)propanoic acid;

2-((2R,6S)-4-(bis(4-chlorophenyl)methyl)-2,6-dimethylpiperazin-1-yl)acetic acid;

2-(4-(bis(4-chlorophenyl)methyl)-2,2-dimethylpiperazin-1-yl)acetic acid;

2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)propanoic acid;

(R)-2-(4-(bis(4-chlorophenyl)methyl)-2-isopropylpiperazin-1-yl)acetic acid;

2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)acetic acid; and

2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)-1,4-diazepan-1-yl)-acetic acid;

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 wherein the compound is (R)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 wherein the compound is 2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;

or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 wherein the compound is 2-((R)-2-methyl-4-((R)-phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;

or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 wherein the compound of formula (I) is administered in combination with an agent which is sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, or PDE10 antagonists.

23. The method of claim 22 wherein said agent is adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazopam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazopam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazopam, thioridazine, thiothixene, tracazolate, kanylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, or combinations thereof.

24. The method of claim 1 wherein the compound of formula (I) is administered in combination with an agent which is an anti-depressant or anti-anxiety agent, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase, serotonin and noradrenaline reuptake inhibitors, corticotropin releasing factor antagonists, adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazopines, 5-HTA agonists, 5-HTA antagonists, or corticotropin releasing factor antagonists.

25. The method of claim 24 wherein said agent is amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, fluoxetine, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, venlafaxine, duloxetine, aprepitant, bupropion, lithium, nefazodone, trazodone, viloxazine, alprazolam, chlordiazepoxide, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam, prazepam, buspirone, flesinoxan, gepirone, ipsapirone, or combinations thereof.