GLYCINE TRANSPORTER-1 INHIBITORS
0 Assignments
0 Petitions
Accused Products
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.
2 Citations
57 Claims
-
1-30. -30. (canceled)
-
31. A method of treating a disease treatable by inhibition of GlyT1 receptor in a patient which method comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):
- View Dependent Claims (32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)
-
32. The method of claim 31 wherein the disease is schizophrenia, bipolar disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome, premenstrual dysphoric disorder, learning disorders, pervasive developmental disorder, attention disorders, autistic disorders, anxiety disorders, cognitive disorders associated with dementia, AIDS dementia, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, spasticity, myoclonus, muscle spasm, tinnitus or hearing impairment and hearing loss.
-
33. The method of claim 31 wherein the disease is Schizophrenia or cognitive disorder associated with Schizophrenia.
-
34. The method of claim 32 wherein:
-
n is 1; Rl and R2 are independently hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein the aforementioned rings are optionally substituted with Ra, Rb, or Rc independently alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, monosubstituted amino, or disubstituted amino;
orR1 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 Rd, Re, or Rf independently alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino;
orRl 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; andAr1 and Ar2 are independently aryl, heteroaryl, cycloalkyl, or heterocyclyl wherein each of the aforementioned ring is optionally substituted with Rg, Rh or Ri wherein Rg 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 Rh 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 Rg, Rh and Ri is optionally substituted with Rj, Rk or Rl 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.
-
-
35. The method of claim 32 wherein R1 and R2 are hydrogen.
-
36. The method of claim 32 wherein R1 is hydrogen and R2 is alkyl.
-
37. The method of claim 32 wherein R1 and R2 are attached to the same carbon atom and are combined to form cycloalkyl optionally substituted with Rd, Re or Rf independently alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino.
-
38. The method of claim 32 wherein R1 and R2 are attached to the same carbon atom and are combined to form monocyclic saturated heterocyclyl which are optionally substituted with Rd, Re or Rf independently alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, monosubstituted amino, or disubstituted amino.
-
39. The method of claim 32 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.
- C1-C2—
-
40. The method of claim 32 wherein R1, R2, R3, R4 and R5 are hydrogen and Ar1 and Ar2 are phenyl, each optionally substituted with Rg, Rh or Ri.
-
41. The method of claim 32 wherein R1, R3, R4, and R5 are hydrogen, R2 is alkyl, and Ar1 and Ar2 are phenyl, each optionally substituted with Rg, Rh or Ri.
-
42. The method of claim 32 wherein R1, R2, R3, R4 and R5 are hydrogen, Ar1 is phenyl optionally substituted with Rg, Rh or Ri and Ar2 is cycloalkyl.
-
43. The method of claim 32 wherein R1, R3, R4, and R5 are hydrogen, R2 is alkyl, Ar1 is phenyl optionally substituted with Rg, Rh or Ri and Ar2 is cycloalkyl.
-
44. The method of claim 32 wherein R1, R2, R3, R4 and R5 are hydrogen, Ar1 is phenyl and Ar2 is heteroaryl, each ring optionally substituted with Rg, Rh or Ri.
-
45. The method of claim 32 wherein R1, R3, R4, and R5 are hydrogen, R2 is alkyl, Ar1 is phenyl and Ar2 is heteroaryl, each ring optionally substituted with Rg, Rh or Ri.
-
46. The method of claim 32 wherein R1, R3, R4 and R5 are hydrogen, R2 is hydrogen or methyl;
- Ar1 is phenyl and Ar2 is phenyl substituted with Rg selected from alkyl, halo, haloalkyl, haloalkoxy, preferably methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy or 2,2,2-trifluoroethoxy.
-
47. The method of claim 32 wherein the compound has the structure:
-
48. The method of claim 32 wherein the compound has the structure:
-
49. The method of claim 32 wherein the compound has the structure:
-
50. The method of claim 32 wherein the compounds 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-(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-l-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.
-
-
51. The method of claim 32 wherein the compound is (R)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid;
- or a pharmaceutically acceptable salt thereof.
-
52. The method of claim 32 wherein the compound is 2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid;
- or a pharmaceutically acceptable salt thereof.
-
53. The method of claim 32 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.
-
54. The method of claim 32 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.
-
55. The method of claim 54 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.
-
56. The method of claim 32 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.
-
57. The method of claim 56 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.
-
32. The method of claim 31 wherein the disease is schizophrenia, bipolar disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome, premenstrual dysphoric disorder, learning disorders, pervasive developmental disorder, attention disorders, autistic disorders, anxiety disorders, cognitive disorders associated with dementia, AIDS dementia, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, spasticity, myoclonus, muscle spasm, tinnitus or hearing impairment and hearing loss.
Specification
- Resources
Thank you for your request. You will receive a custom alert email when the Litigation Campaign Assessment is available.
×
-
Current AssigneeAmgen Inc.
-
Original AssigneeAmgen Inc.
-
InventorsHitchcock, Stephen, Amegadzie, Albert, Qian, Wenyuan, Xia, Xiaoyang, Harried, Scott S.
-
Granted Patent
-
Time in Patent OfficeDays
-
Field of Search
-
US Class Current424/722
-
CPC Class CodesA61K 31/495 having six-membered rings w...A61K 31/551 having two nitrogen atoms, ...A61K 33/00 Medicinal preparations cont...A61P 1/08 for nausea, cinetosis or ve...A61P 13/12 of the kidneysA61P 15/00 Drugs for genital or sexual...A61P 21/00 Drugs for disorders of the ...A61P 25/00 Drugs for disorders of the ...A61P 25/08 Antiepileptics; Anticonvuls...A61P 25/14 for treating abnormal movem...A61P 25/16 Anti-Parkinson drugsA61P 25/18 Antipsychotics, i.e. neurol...A61P 25/20 Hypnotics; SedativesA61P 25/22 AnxiolyticsA61P 25/24 AntidepressantsA61P 25/28 for treating neurodegenerat...A61P 27/02 Ophthalmic agentsA61P 27/16 OtologicalsA61P 29/00 Non-central analgesic, anti...A61P 43/00 Drugs for specific purposes...C07D 213/36 : Radicals substituted by sin...C07D 241/04 : having no double bonds betw...C07D 241/08 : with oxygen atoms directly ...C07D 243/08 : not condensed with other ringsC07D 295/15 : to an acyclic saturated chainC07D 333/20 : by nitrogen atoms nitro, ni...