N-SUBSTITUTED PIPERIDINE DERIVATIVES AS SEROTONIN RECEPTOR AGENTS

• US 20090082342A1
• Filed: 09/19/2008
• Published: 03/26/2009
• Est. Priority Date: 09/21/2007
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Thygesen, Mikkel Boas, Uldam, Henriette Kold
• Application Number:
  US12/234,582
• Publication Number:
  US 20090082342A1
• Time in Patent Office: Days
• US Class Current: 514/221
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 211/58 attached in position 4

Abstract

Disclosed herein are isolated forms of the compounds of Formula (I), (II), (III), (IV) and (V), or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, polymorph, or ester thereof. Also disclosed are methods of inhibiting an activity of a serotonin receptor, methods inhibiting an activation of a serotonin receptor, and methods of alleviating or treating various disease conditions and side effects.

Claims

1. A isolated form of a compound selected from the group consisting of Formulae (I), (II), (III), (IV) and (V), wherein the compounds of Formulae (I), (II), (III), (IV) and (V) have the following structures:

or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, polymorph, or ester thereof.

2. A pharmaceutical composition comprising at least one isolated form of the compound of claim 1, and a pharmaceutically acceptable carrier, diluent, or excipient.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is suitable for oral administration.

4. The pharmaceutical composition of claim 2, further comprising an additional therapeutic agent.

5. The pharmaceutical composition of claim 4, wherein the additional therapeutic agent is selected from the group consisting of a dopaminergic agent, anti-dyskensia agent, anti-dystonia agent, anti-myoclonus agent, anti-tremor agent, anti-psychotic agent, antidepressant, anti-dementia agent and sleep-inducing agent.

6. The pharmaceutical composition of claim 5,

wherein the dopaminergic agent is selected from the group consisting of levodopa, bromocriptine, pergolide, ephenedrine sulfate, pemoline, mazindol, d,1-α

-methylphenethylamine, methylphenydate, pramipexole, modafinil, and ropinirole;

wherein the anti-dyskensia agent, anti-dystonia, anti-myoclonus, or anti-tremor agent is selected from the group consisting of baclofen, botulinum toxin, clonazepam, and diazepam;

wherein the anti-psychotic agent is selected from the group consisting of chlorpromazine, haloperidol, molindone, thioridazine, a phenothiazine, a butyrophenome, a phenylbutylpiperadine, thioxanthine, a substituted benzamide, sertindole, amisulpride, risperidone, clozapine, olanzapine, ziprasidone, a debenzapine, a benzisoxidil, a salt of lithium, Aripiprazole, Etrafon®

, Droperidol, Thioridazine, Thiothixene, Promethazine, Metoclopramide, Chlorprothixene, Triavil®

, Molindone, Sertindole, Amisulpride, Melperone, Paliperidone, Tetrabenazine and their active metabolites;

wherein the phenothiazine is selected from the group consisting of chlorpromazine, mesoridazine, prochlorperazine, thioridazine, Fluphenazine, Perpehnazine, and Trifluoperazine;

wherein the phenylbutylpiperadine is pimozide;

wherein the debenzapine is selected from the group consisting of clozapine, loxapine, olanzapine, and quetiapine;

wherein the benzisoxidil is ziprasidone;

wherein the salt of lithium is lithium carbonate;

wherein the antidepressant is selected from the group consisting of citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, and dapoxetine;

wherein the anti-dementia agent is a cholinesterase inhibitor; and

wherein the sleep-inducing agent is selected from the group consisting of zolpidem, eszopiclone, a benzodiazepine, a melatonin agonist, and an antihistamine.

7. The pharmaceutical composition of claim 6, wherein the cholinesterase inhibitor is selected from the group consisting of are donepezil, galantamine, rivastigmine, tacrine, metrifonate, physostigmine, neostigmine, pyridostigmine, ambenonium, demarcarium, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, chlorbufam, chloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmicarb, pirimicarb, propamocarb, propham, propoxur, edrophonium, phenothiazines, echothiophate, diisopropyl fluorophosphate, dimebon, Huperzine A, T-82 ((2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-one hemifumarate)), TAK-147 (zanapezil), phenserine, quilostigmine, ganstigmine, butyrophenones, imipramines, tropates, phencyclidines, curariforms, ethephon, ethopropazine, iso-OMPA, tetrahydrofurobenzofuran cymserine, N¹phenethyl-norcymserine, N⁸-benzylnorcymserine, N¹, N⁸-bisnorcymserine, N¹-N⁸-bisbenzylnorphysostigmine, N¹,N⁸-bisbenzylnorphenserine and N¹, N⁸-bisbenzylnorcymserine;

wherein the benzodiazepine is selected from the group consisting of temazepam, diazepam, lorazepam, nitrazepam, and midazolam;

wherein the melatonin agonist is ramelteon; and

wherein the antihistamine is diphenhydramine.

8. A method of inhibiting the activity of a serotonin receptor comprising contacting the monoamine receptor or a system containing a monoamine receptor with at least one isolated form of a compound of claim 1 or a pharmaceutical composition comprising at least one isolated form of said compound of claim 1.

9. The method of claim 8, wherein the serotonin receptor is a subclass selected from the group consisting of in the 5-HT2A subclass and 5-HT2C subclass.

10. The method of claim 8, wherein the serotonin receptor is mutated or modified.

11. A method of inhibiting an activation of a serotonin receptor comprising contacting the monoamine receptor of a system containing a monoamine receptor with at least one isolated form of a compound of claim 1 or a pharmaceutical composition comprising at least one isolated form of said compound of claim 1.

12. The method of claim 11, wherein the serotonin receptor is a subclass selected from the group consisting of in the 5-HT2A subclass and 5-HT2C subclass.

13. The method of claim 11, wherein the serotonin receptor is mutated or modified.

14. A method of alleviating or treating one or more disease condition associated with a serotonin receptor comprising administering a therapeutically effective amount of at least one isolated form of a compound of claim 1 or a pharmaceutical composition comprising at least one isolated form of said compound of claim 1.

15. The method of claim 14, wherein the disease condition is a neuropsychiatric disorder.

16. The method of claim 15, wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, mania, depression, a cognitive disorder, aggressiveness, panic attacks, obsessive compulsive disorder, borderline personality disorder, borderline disorder, multiplex developmental disorder (MDD), a behavioral disorder, psychosis, suicidal tendency, bipolar disorder, sleep disorder, addiction, attention deficit hyperactivity disorder (ADHD), post traumatic stress disorder (PTSD), Tourette'"'"'s syndrome, anxiety, autism, Down'"'"'s syndrome, a learning disorder, a psychosomatic disorder, alcohol withdrawal, epilepsy, pain, a disorder associated with hypoglutamatergia, and serotonin syndrome.

17. The method of claim 16, wherein the psychosis is selected from drug-induced psychosis, treatment-induced psychosis and psychosis associated with a disease.

18. The method of claim 17, wherein the disease is dementia, post traumatic stress disorder, Alzheimer'"'"'s disease, Parkinson'"'"'s disease and schizophrenia.

19. The method of claim 14, wherein the disease condition is a neurodegenerative disorder.

20. The method of claim 19, wherein the neurodegenerative disorder is selected from Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s chorea, sphinocerebellar atrophy, frontotemporal dementia, supranuclear palsy and Lewy body dementia.

21. The method of claim 14, wherein the disease condition is selected from the group consisting of chemotherapy-induced emesis, frailty, on/off phenomena, non-insulin-dependent diabetes mellitus, metabolic syndrome, an autoimmune disorder, sepsis, increased intraocular pressure, glaucoma, a retinal disease, Charles Bonnet syndrome, substance abuse, sleep apnea, pancreatis, anorexia, bulimia, a disorder associated with alcoholism, a cerebral vascular accident, amyotrophic lateral sclerosis, AIDS related dementia, traumatic brain, traumatic spinal injury, tinnitus, a menopausal symptom, sexual dysfunction, low male fertility, low sperm motility, hair loss, hair thinning, incontinence, hemorrhoids, migraine, hypertension, thrombosis, abnormal hormonal activity, a hormonal disorder, a pituitary tumor, a side effect associated with a pituitary tumor, vasospasm, ischemia, cardiac arrhythmia, cardiac insufficiency, asthma, emphysema, and an appetite disorder.

22. The method of claim 14, wherein the disease condition is associated with dysfunction of the serotonin receptor, activation of the serotonin receptor or increased activity of the serotonin receptor.

23. The method of claim 14, wherein the serotonin receptor is a subclass selected from the group consisting of in the 5-HT2A subclass and 5-HT2C subclass.

24. The method of claim 14, wherein the serotonin receptor is mutated or modified.

25. The method of claim 14, comprising administering an additional therapeutic agent.

26. The method of claim 25, wherein the additional therapeutic agent is a dopaminergic agent, anti-dyskensia agent, anti-dystonia agent, anti-myoclonus agent, anti-tremor agent, anti-psychotic agent, antidepressant, anti-dementia agent, or sleep-inducing agent.

27. The method of claim 26, wherein the dopaminergic agent is selected from the group consisting of levodopa, bromocriptine, pergolide, ephenedrine sulfate, pemoline, mazindol, d,1-α

-methylphenethylamine, methylphenydate, pramipexole, modafinil, and ropinirole;

wherein the anti-dyskensia agent, anti-dystonia agent, anti-myoclonus agent, or anti-tremor agent is selected from the group consisting of baclofen, botulinum toxin, clonazepam, and diazepam;

wherein the anti-psychotic agent selected from the group consisting of chlorpromazine, haloperidol, molindone, thioridazine, a phenothiazine, a butyrophenome, a phenylbutylpiperadine, thioxanthine, sulpiride, sertindole, amisulpride, risperidone, clozapine, olanzapine, ziprasidone, a debenzapine, a benzisoxidil, a salt of lithium, Aripiprazole, Etrafon®

, Droperidol, Thioridazine, Thiothixene, Promethazine, Metoclopramide, Chlorprothixene, Triavil®

, Molindone, Sertindole, Amisulpride, Melperone, Paliperidone, Tetrabenazine and their active metabolites;

wherein the antidepressant is selected from the group consisting of citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, and dapoxetine;

wherein the anti-dementia agent is a cholinesterase inhibitor; and

wherein the sleep-inducing agent is selected from the group consisting of zolpidem, eszopiclone, a benzodiazepine, a melatonin agonist, and an antihistamine.

28. The method of claim 27, wherein the phenothiazine is selected from the group consisting of chlorpromazine, mesoridazine, prochlorperazine, thioridazine, Fluphenazine, Perpehnazine, and Trifluoperazine;

wherein the phenylbutylpiperadine is pimozide;

wherein the debenzapine is selected from the group consisting of clozapine, loxapine, olanzapine, and quetiapine;

wherein the benzisoxidil is ziprasidone;

wherein the salt of lithium is lithium carbonate;

wherein the cholinesterase inhibitor is selected from the group consisting of are donepezil, galantamine, rivastigmine, tacrine, metrifonate, physostigmine, neostigmine, pyridostigmine, ambenonium, demarcarium, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, chlorbufam, chloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmicarb, pirimicarb, propamocarb, propham, propoxur, edrophonium, phenothiazines, echothiophate, diisopropyl fluorophosphate, dimebon, Huperzine A, T-82 ((2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinolin-1-one hemifumarate)), TAK-147 (zanapezil), phenserine, quilostigmine, ganstigmine, butyrophenones, imipramines, tropates, phencyclidines, curariforms, ethephon, ethopropazine, iso-OMPA, tetrahydrofurobenzofuran cymserine, N¹phenethyl-norcymserine, N⁸-benzylnorcymserine, N¹, N⁸-bisnorcymserine, N¹-N⁸-bisbenzylnorphysostigmine, N¹, N⁸-bisbenzylnorphenserine and N¹, N⁸-bisbenzylnorcymserine;

wherein the benzodiazepine is selected from the group consisting of temazepam, diazepam, lorazepam, nitrazepam, and midazolam;

wherein the melatonin agonist is ramelteon; and

wherein the antihistamine is diphenhydramine.

29. A method of alleviating or treating a condition induced by the administration of an anti-psychotic compound comprising administering a therapeutically effective amount of at least one isolated form of a compound of claim 1 or a pharmaceutical composition comprising at least one isolated form of said compound of claim 1 to a subject being administered the anti-psychotic compound.

30. The method of claim 29, wherein the condition is a side effect selected from the group consisting of an extrapyramidal side effect, a histaminic side effect, an alpha adrenergic side effect, and an anticholinergic side effect.

31. The method of claim 29, wherein the condition is selected from the group consisting of stroke, tremors, sedation, gastrointestinal problems, neurological problems, increased risk of death, a cerebrovascular event, a movement disorder, dystonia, akathisia, a parkinsoniam movement disorder, dyskinesia, tardive dyskinesia, a cognitive disorder, prolactinemia, catalepsy, psychosis, neuroleptic malignant syndrome, a heart problem, a pulmonary problem, diabetes, liver failure, suicidality, sedation, orthostatic hypotension, choking, dizziness, tachycardia, blood abnormalities, an abnormal triglyceride level, an increased cholesterol level, dyslipidemia, hyperglycemia, syncope, a seizure, dysphagia, priapism, thrombotic thrombocytopenic purpura, disruption of body temperature regulation, insomnia, agitation, anxiety, somnolence, aggressive reaction, headache, constipation, nausea, dyspepsia, vomiting, abdominal pain, saliva increase, toothache, rhinitis, coughing, sinusitis, pharyngitis, dyspnea, back pain, chest pain, fever, rash, dry skin, seborrhea, increased upper respiratory infection, abnormal vision, arthralgia, hypoaesthesia, manic reaction, concentration impairment, dry mouth, pain, fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, diarrhea, confusion, asthenia, urinary incontinence, sleepiness, increased duration of sleep, accommodation disturbance, palpitations, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, lassitude, increased pigmentation, increased appetite, automatism, increased dream activity, diminished sexual desire, nervousness, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia, emotional liability, a nightmare, delirium, yawning, dysarthria, vertigo, stupor, paraesthesia, aphasia, hypoesthesia, tongue paralysis, a leg cramp, torticollis, hypotonia, coma, migrain, hyperreflexia, choreoathetosis, anorexia, flatulence, stomatitis, melena, hemorrhoids, gastritis, fecal incontinence, erutation, gastroeophageal reflux, gastroenteritis, esophagitis, tongue discoloration, choleithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, gastrointestinal hemorrhage, hematemesis, edema, rigors, malaise, pallor, enlarged abdomen, ascites, sarcoidosis, flushing, hyperventilation, bronchospasm, pneumonia, tridor, asthma, increased sputum, aspiration, photosensitivity, increased sweating, acne, descreased sweating, alopecia, hyperkeratosis, skin exfoliation, bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria, ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversion, a ventricular extrasystole, ST depression, AV block, myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation, hyponatremia, creatine phosphokinase increase, thirst, weight decrease, decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertrigylceridemia, hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia, dysuria, urinary retention, cystitis, renal insufficiency, arthrosis, synostosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurperal lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal hemorrhage, increased SGOT, increased SGPT, cholestatic hepatitis, cholecystitis, choleithiasis, hepatitis, hepatocellular damage, epistaxis, superficial phlebitis, thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, decreased hearing, anemia, hypochromic anemia, normocytic anemia, granulocytopenia, leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, male breast pain, antiduretic hormone disorder, bitter taste, micturition disturbances, oculogyric crisis, abnormal gait, involuntary muscle contraction, increased injury, a pituitary tumor, galactorrhea, bradykinesia, myoclonus, hiccups, uncontrolled gambling, a drug craving, rigidity, psychomotor slowing, tics, Friedrich'"'"'s ataxia, Machado-Joseph'"'"'s disease, restless legs syndrome, and a hallucinogenic effect.

32. The method of claim 31, wherein the dyskinesia is induced by treatment of Parkinson'"'"'s disease.

33. The method of claim 31, wherein the akathisia is induced by administration of a neuroleptic agent or selective serotonin reuptake inhibitor.

34. The method of claim 29, wherein the subject is being treated for a disease or disorder selected from the group consisting of schizophrenia, bipolar disorder, agitation, psychosis, behavioral disturbances in Alzheimer'"'"'s disease, depression with psychotic features or bipolar manifestations, obsessive compulsive disorder, post traumatic stress syndrome, anxiety, personality disorders (borderline and schizotypal), dementia, dementia with agitation, dementia in the elderly, Tourette'"'"'s syndrome, restless leg syndrome, insomnia, social anxiety disorder, dysthymia, ADHD, and autism.

35. A method for alleviating or treating a condition associated with dopaminergic therapy comprising administering a therapeutically effective amount of at least one isolated form of a compound of claim 1 or a pharmaceutical composition comprising at least one isolated form of said compound of claim 1 to a subject receiving dopaminergic therapy.

36. A method of alleviating or treating schizophrenia comprising administering a therapeutically effective amount of at least one isolated form of a compound of claim 1 or a pharmaceutical composition comprising at least one isolated form of said compound of claim 1 to a subject suffering from schizophrenia.

37. A method of alleviating or treating psychosis comprising administering a therapeutically effective amount of at least one isolated form of a compound of claim 1 or a pharmaceutical composition comprising at least one isolated form of said compound of claim 1 to a subject suffering from psychosis.

38. The method of claim 37, wherein the psychosis is selected from drug-induced psychosis, treatment-induced psychosis and psychosis associated with a disease

39. The method of claim 38, wherein the disease is selected from Alzheimer'"'"'s disease and schizophrenia.