阅读说明：本技术 用在组合疗法(睡眠障碍或中枢神经系统障碍)中的nmda受体调节剂(拉帕斯汀)组合 (Combination of NMDA receptor modulators (lapatin) for use in combination therapy (sleep disorders or central nervous system disorders) ) 是由 P·班纳吉 J·唐奈罗 于 2018-12-04 设计创作，主要内容包括：公开了治疗患有(i)认知、神经或心理疾病或障碍以及(ii)睡眠障碍的患者的方法,包括向所述患者给予治疗有效量的N-甲基-D-天冬氨酸(NMDA)受体部分激动剂,特别是拉帕斯汀或其药学上可接受的盐、酯、前药或代谢产物的步骤。(Disclosed is a method of treating a patient suffering from (i) a cognitive, neurological or psychological disease or disorder and (ii) a sleep disorder, comprising the step of administering to said patient a therapeutically effective amount of an N-methyl-D-aspartate (NMDA) receptor partial agonist, in particular lapatin, or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof.)

1. A method of treating a patient suffering from (i) a cognitive, neurological or psychological disease or disorder and (ii) a sleep disorder or sleep disturbance comprising the step of administering to said patient a therapeutically effective amount of a partial N-methyl-D-aspartate (NMDA) receptor agonist.

2. The method according to claim 1, wherein the sleep disorder is selected from insomnia, primary insomnia, idiopathic insomnia; insomnia associated with depression, mood/mood disorders, aging, alzheimer's disease, or cognitive disorders; REM sleep interruption; sleep disorders related to breathing; sleep apnea; periodic limb movement disorder, restless leg syndrome; circadian rhythm sleep disorders; shift work sleep disorder and jet lag syndrome.

3. The method according to any one of claims 1 or 2, wherein the cognitive, neurological or psychological disease or disorder is selected from the group consisting of insufficient memory, intellectual or learning and logical abilities; a reduction in function of any particular individual in one or more cognitive aspects; age-related cognitive decline; dementia; alzheimer's disease; multi-infarct dementia; alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or brain trauma; dementia associated with huntington's disease or parkinson's disease; dementia associated with AIDS; delirium; amnesia; mental retardation; learning disorders including reading disorders, math disorders, or written expression disorders; attention deficit/hyperactivity disorder; schizophrenia, including negative symptoms of schizophrenia; schizophreniform disorder; schizoaffective disorder, delusional schizoaffective disorder, depressive schizoaffective disorder; delusional disorder; substance-induced psychotic disorder; paranoid personality disorder; personality disorder of the schizophrenic type; panic disorder; phobia; obsessive-compulsive disorder; a pressure disorder; generalized anxiety disorder; dyskinesias involving huntington's disease; dyskinesias associated with dopamine agonist therapy; parkinson's disease: restless leg syndrome; including cognitive deficits as a disorder of its symptoms.

4. The method according to any one of claims 1-3, wherein said patient is undergoing treatment with one or more agents that increase the release, production and/or function of 5-hydroxytryptamine, dopamine, epinephrine, norepinephrine and glutamate neurotransmitters for treating said cognitive, neurological or psychological disease or disorder.

5. The method according to any one of claims 1-3, wherein said patient is undergoing treatment with one or more agents selected from the group consisting of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine agonists, antagonists and modulators, Selective Norepinephrine Reuptake Inhibitors (SNRIs).

6. The method according to any one of claims 1-3, wherein the patient is undergoing treatment with one or more agents selected from the group consisting of: opioid agonists, opioid antagonists, opioid partial agonists, calcium channel antagonists, 5HT, 5-HT_1AFull or partial receptor agonists or antagonists, 5-HT_2AFull or partial receptor agonists or antagonists, 5-HT₃A full or partial receptor agonist or antagonist, a sodium channel antagonist, an N-methyl-D-aspartate (NMDA) receptor antagonist, a COX-2 selective inhibitor, a neurokinin receptor 1(NK1) antagonist, a non-steroidal anti-inflammatory drug (NSAID), a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and/or a selective 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SSNRI), a tricyclic antidepressant, a norepinephrine modulator, lithium, valproate, norepinephrine reuptake inhibitor, monoamine oxidase inhibitor (MAOI), monoamine oxidase Reversible Inhibitor (RIMA), a α -adrenoceptor antagonist, an atypical antidepressant, a benzodiazepine, a Corticotropin Releasing Factor (CRF) antagonist, gabapentin, and pregabalin.

7. The method according to any one of claims 1-3, wherein said patient is undergoing treatment with lithium or valproate.

8. The method according to any one of claims 1-3, wherein the patient is undergoing treatment with ketamine or esketamine.

9. The method according to any one of claims 1-3, wherein the patient is undergoing treatment with one or more agents selected from the group consisting of: selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs), 5-hydroxytryptamine modulators and stimulators (SMS), 5-hydroxytryptamine antagonists and reuptake inhibitors (SARIs), Norepinephrine Reuptake Inhibitors (NRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), tetracyclics antidepressants (tecas), monoamine oxidase inhibitors (MAOI), and atypical antipsychotics.

10. The method according to claim 9, wherein the SSRI is selected from citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, and sertraline.

11. The method according to claim 9, wherein said SNRI is selected from desvenlafaxine, duloxetine, levomilnacipran, milnacipran and venlafaxine.

12. The method according to claim 9, wherein said SMS is selected from vilazodone and vortioxetine.

13. The method according to claim 9, wherein the SARI is selected from nefazodone and trazodone.

14. The method according to claim 9, wherein the NRI is selected from reboxetine, tinisazine, and viloxazine.

15. The method of claim 9, wherein the NDRI is selected from the group consisting of bupropion, amiptanoic acid, lisdexamfetamine dimesylate and methylphenidate.

16. The method of claim 9, wherein the TCA is selected from the group consisting of amitriptyline, oxaamitriptyline, clomipramine, desipramine, diazepam, diazepine, ditaline, dithiaheptine, doxepin, imipramine, lofelamine, melitracen, nitroxazepine, nortriptyline, norcetirizine, opipramol, pipofezine, protriptyline, and trimipramine.

17. The method according to claim 9, wherein said TeCA is selected from the group consisting of amoxapine, maprotiline, mianserin, mirtazapine, and siprotiline.

18. The method according to claim 9 wherein the atypical antipsychotic is selected from amisulpride, aripiprazole, lurasidone, quetiapine, olanzapine, risperidone and ziprasidone.

19. The method according to any of the preceding claims, wherein the sleep disorder is selected from insomnia, REM sleep disruption, respiratory related sleep disorders, sleep apnea, periodic limb movement disorders, restless leg syndrome, circadian rhythm sleep disorders, and shift work sleep disorders.

20. The method according to claim 19, wherein the insomnia is primary insomnia, idiopathic insomnia or insomnia associated with depression.

21. The method according to any one of claims 1-3, wherein the cognitive disease or disorder is selected from the group consisting of: insufficient memory, intelligence, learning and logic abilities; a reduction in function of any particular individual in one or more cognitive aspects; age-related cognitive decline; dementia; alzheimer's disease; multi-infarct dementia; alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or brain trauma; dementia associated with huntington's disease or parkinson's disease; dementia associated with AIDS; delirium; amnesia; mental retardation; learning disorders including reading disorders, math disorders, or written expression disorders; attention deficit/hyperactivity disorder; schizophrenia, including negative symptoms; schizophreniform disorder; schizoaffective disorder, including delusional schizoaffective disorder or depressive schizoaffective disorder; delusional disorder; substance-induced psychotic disorder; paranoid personality disorder; personality disorder of the schizophrenic type; panic disorder; phobia; obsessive-compulsive disorder; a pressure disorder; generalized anxiety disorder; dyskinesias involving huntington's disease; dyskinesias associated with dopamine agonist therapy; parkinson's disease: restless leg syndrome; including cognitive deficits as a disorder of its symptoms.

22. The method according to any one of the preceding claims, wherein said NMDA receptor partial agonist is a compound of the formula:

23. the method according to claim 22, wherein the compound is administered at a dose of about 5mg/kg or about 10mg/kg or about 15mg/kg weekly or every other week for six to twelve weeks.

24. The method of claim 22, wherein the compound is administered in a dose of about 200mg to about 1000mg weekly or every other week for at least four weeks in one cycle, followed by at least one week, two weeks, three weeks, four weeks, two months or more without the compound.

25. The method of claim 22, wherein the compound is administered in a dose of about 225mg weekly or every other week for at least four weeks during a cycle, followed by at least one week, two weeks, three weeks, four weeks, two months or more without administration of the compound.

26. The method of claim 22, wherein the compound is administered in a dose of about 450mg weekly or every other week for at least four weeks during a cycle, followed by at least one week, two weeks, three weeks, four weeks, two months or more without administration of the compound.

27. The method of claim 22, wherein the compound is administered in a dose of about 900mg weekly or every other week for at least four weeks during a cycle, followed by at least one week, two weeks, three weeks, four weeks, two months or more without the compound.

28. The method according to any one of claims 22-27, wherein said compound is administered intravenously.

29. The method according to any one of claims 1-3, 19-20 or 22-28, wherein the sleep disorder is caused by administration of one or more agents selected from the group consisting of: opioid agonists, opioid antagonists, opioid partial agonists, calcium channel antagonists, 5HT, 5-HT_1AFull or partial receptor agonists or antagonists, 5-HT_2AFull or partial receptor agonists or antagonists, 5-HT₃A full or partial receptor agonist or antagonist, a sodium channel antagonist, an N-methyl-D-aspartate (NMDA) receptor antagonist, a COX-2 selective inhibitor, a neurokinin receptor 1(NK1) antagonist, a non-steroidal anti-inflammatory drug (NSAID), a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and/or a selective 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SSNRI), a tricyclic antidepressant, a norepinephrine modulator, lithium, valproate, norepinephrine reuptake inhibitor, monoamine oxidase inhibitor (MAOI), monoamine oxidase Reversible Inhibitor (RIMA), a α -adrenoceptor antagonist, an atypical antidepressant, a benzodiazepine, a Corticotropin Releasing Factor (CRF) antagonist, gabapentin, and pregabalin.

30. The method according to any one of claims 1-3, 19-20 or 22-28, wherein the sleep disorder is caused by administration of lithium or valproic acid.

31. The method of any one of claims 1-3, 19-20, or 22-28, wherein the sleep disorder is caused by administration of ketamine or esketamine.

32. The method according to any one of claims 1-3, 19-20 or 22-28, wherein the sleep disorder is caused by the administration of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs), 5-hydroxytryptamine modulators and stimulators (SMS), 5-hydroxytryptamine antagonists and reuptake inhibitors (SARIs), Norepinephrine Reuptake Inhibitors (NRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), tetracyclics antidepressants (tecas), monoamine oxidase inhibitors (MAOI) and atypical antipsychotics.

33. The method according to claim 32, wherein the SSRI is selected from citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, and sertraline.

34. The method according to claim 32, wherein said SNRI is selected from desvenlafaxine, duloxetine, levomilnacipran, milnacipran and venlafaxine.

35. The method according to claim 32, wherein said SMS is selected from vilazodone and vortioxetine.

36. The method according to claim 32, wherein the SARI is selected from nefazodone and trazodone.

37. The method according to claim 32, wherein said NRI is selected from reboxetine, tinisazine, and viloxazine.

38. The method of claim 32, wherein the NDRI is selected from the group consisting of bupropion, amiptanoic acid, lisdexamfetamine dimesylate and methylphenidate.

39. The method of claim 32, wherein the TCA is selected from the group consisting of amitriptyline, oxaamitriptyline, clomipramine, desipramine, diazepam, diazepine, ditaline, dithiaheptine, doxepin, imipramine, lofelamine, melitracen, nitroxazepine, nortriptyline, norcetirizine, opipramol, pipofezine, protriptyline, and trimipramine.

40. The method according to claim 32, wherein said TeCA is selected from the group consisting of amoxapine, maprotiline, mianserin, mirtazapine, and siprotiline.

41. The method according to claim 32 wherein the atypical antipsychotic is selected from amisulpride, aripiprazole, lurasidone, quetiapine, olanzapine, risperidone and ziprasidone.

42. The method according to any of the preceding claims, wherein the sleep disorder is selected from insomnia, REM sleep disruption, respiratory related sleep disorders, sleep apnea, periodic limb movement disorders, restless leg syndrome, circadian rhythm sleep disorders, and shift work sleep disorders.

43. The method according to any of the preceding claims, wherein the sleep disorder or disorder is associated with an increase in synaptic 5-hydroxytryptamine, wherein the increase is caused by the administration of an agent for the treatment of a neurological, psychological or cognitive disorder.

44. The method according to claim 30 or 31, wherein the neurological, psychological or cognitive disease or disorder is depression, MDD or refractory depression.

Background

The N-methyl-D-aspartate (NMDA) receptor is a postsynaptic ionotropic receptor that responds, inter alia, to the excitatory amino acids glutamate and glycine and to the synthetic compound NMDA. NMDA receptors (NMDAR) appear to control the influx of divalent and monovalent ions through receptor-associated channels into post-synaptic neurons and have attracted particular attention because they appear to be involved in a wide range of Central Nervous System (CNS) disorders. NMDAR has been implicated in, for example, neurodegenerative diseases, including stroke-related brain cell death, convulsive disorders, and learning and memory. NMDAR also plays a key role in the regulation of normal synaptic transmission, synaptic plasticity, and excitotoxicity in the central nervous system. NMDAR is further involved in long-term potentiation (LTP), a sustained potentiation of neuronal connections that constitute learning and memory. NMDAR is associated with other diseases ranging from hypoglycemia and cardiac arrest to epilepsy. In addition, there have been preliminary reports indicating that NMDA receptors are involved in chronic neurodegeneration in Huntington's disease, Parkinson's disease and Alzheimer's disease. NMDA receptor activation has been shown to be responsible for post-stroke convulsions, and in certain models of epilepsy, has been shown to be essential for the development of epilepsy. Furthermore, certain properties of NMDA receptors suggest that they may be involved in information processing in the brain that constitutes consciousness itself. In addition, NMDA receptors are also involved in certain types of spatial learning.

In view of the association of NMDAR with various disorders and diseases, NMDA-modulating small molecule agonist and antagonist compounds have been developed for therapeutic use. NMDA receptor compounds can exert dual (agonist/antagonist) effects on NMDA receptors through allosteric sites. These compounds are commonly referred to as "partial agonists". In the presence of a major site ligand, a partial agonist will displace some of the ligand and thus reduce Ca passage through the receptor⁺⁺And (4) flow rate. Partial agonist action in the absence of a major site ligand or in the presence of reduced levels of a major site ligandTo increase Ca through receptor channels⁺⁺And (4) flow rate.

Recently, partial agonists of NMDAR (rapastine or GLYX-13) have been reported with the following structure:

PCT/US2017/015851 describes a method for synthesizing peptide compounds including lapatin.

Major Depressive Disorder (MDD) is associated with abnormal sleep quality, including Slow Wave Sleep (SWS) reduction and rapid eye Rotation (REM) sleep disturbance. Most antidepressants currently approved for marketing disrupt SWS and REM sleep, probably due to elevated synaptic 5-hydroxytryptamine levels (Nutt D, Wilson S, Paterson L.sleep disorders as coresymptoms of depression. Dialogues Clin neurosci.2008; 10 (3): 329) 336). An increase in SWS is associated with an increase in synaptic plasticity and is considered to be an electrophysiological related factor for mood improvement. (Raven F, Van der Zee EA, Meerlo P, havees R. the role of sleep in regulating structural flexibility and synthetic string h: indications for memory and cognitive function. Sleep Med Rev.2017). Methods of treating depression, particularly MDD, without significantly affecting sleep quality would be advantageous.

Disclosure of Invention

There is provided a method of treating a patient suffering from (i) a cognitive, neurological or psychological disease or disorder and (ii) a sleep disorder or disorder, comprising the step of administering to said patient a therapeutically effective amount of a partial N-methyl-D-aspartate (NMDA) receptor agonist. In some embodiments, the NMDA receptor partial agonist is a compound of the formula:

in some embodiments, methods of treating a patient suffering from a cognitive, neurological or psychological disease or disorder are provided, wherein the patient suffers from a sleep disorder or disorder. In some embodiments, sleep disorders and disorders result from the administration of one or more non-NMDA receptor partial agonists for the treatment of cognitive, neurological or psychological diseases or disorders.

Drawings

FIG. 1 Effect of lapatin, Ketamine (Ketamine) and Zolpidem (Zolpidem) on the latency of SWS and REM sleep. Fig. 1 (a): baseline and mean latency to SWS after treatment. FIG. 1 (B): baseline and mean latency to REM sleep after treatment. P05, P01, P001 to the base line; REM, rapid eye movement; SWS, slow wave sleep.

FIG. 2 the effect of lapatin, ketamine and zolpidem on the duration (A) and depth (B) of the SWS. Fig. 2 (a): average duration of SWS during the light and dark periods. Fig. 2 (B): average depth of SWS during the light and dark periods. P05, P01, P001 to the base line; SWS, slow wave sleep.

Figure 3 effect of lapatin, ketamine and zolpidem on duration of REM sleep. P < 05, P < 001 to baseline; REM, rapid eye movement.

FIG. 4 the effect of lapatin, ketamine and zolpidem on insomnia. Fig. 4 (a): baseline and mean duration of wakefulness after treatment. Fig. 4 (B): baseline and mean percentage of active wake after treatment. P05, P01 and P001 are compared with the base line.

Detailed Description

Provided herein are methods of treating a patient suffering from (i) a cognitive, neurological or psychological disease or disorder and (ii) a sleep disorder or disorder, comprising the step of administering to the patient a therapeutically effective amount of a partial N-methyl-D-aspartate (NMDA) receptor agonist. In some embodiments, the NMDA receptor partial agonist is a compound of the formula:

in some embodiments, methods of treating a patient suffering from a cognitive, neurological or psychological disease or disorder are provided, wherein the patient suffers from a sleep disorder or disorder. In some embodiments, sleep disorders and disorders result from the administration of one or more non-NMDA receptor partial agonists for the treatment of cognitive, neurological or psychological diseases or disorders. Methods of treating a patient undergoing treatment for depression while also suffering from sleep disorders and sleep disturbances caused by the treatment for depression are provided. In some embodiments, the patient is treated for major depression or refractory depression.

In some embodiments, the patient is undergoing treatment with one or more agents selected from the group consisting of: selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs), 5-hydroxytryptamine modulators and stimulators (SMS), 5-hydroxytryptamine antagonists and reuptake inhibitors (SARIs), Norepinephrine Reuptake Inhibitors (NRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (tecas), monoamine oxidase inhibitors (MAOI) and atypical antipsychotics.

For example, the SSRI may be selected from SSRIs selected from citalopram (citalopram), escitalopram (escitalopram), paroxetine (parooxetine), fluoxetine (fluooxetine), fluvoxamine (fluvoxamine) and sertraline (sertraline). In some embodiments, the patient suffers from a sleep disorder or sleep disorder as a result of treatment with an SSRI.

For example, the SNRI may be selected from desvenlafaxine (desvenlafaxine), duloxetine (duloxetine), levomilnacipran (levomilnacipran), milnacipran (milnacipran), and venlafaxine (venlafaxine). In some embodiments, the patient suffers from a sleep disorder or sleep disorder as a result of treatment with the SNRI.

For example, the SMS may be selected from vilazodone (vilazodone) and vortioxetine (vortioxetine). In some embodiments, the patient suffers from a sleep disorder or sleep disorder as a result of treatment with SMS.

For example, an atypical antipsychotic may be selected from amisulpride, aripiprazole, lurasidone, quetiapine, olanzapine, risperidone and ziprasidone. In some embodiments, the patient suffers from a sleep disorder or sleep disorder as a result of treatment with an atypical antipsychotic.

In a preferred embodiment, a method of treating major depression or refractory depression is provided, wherein the patient suffers from a sleep disorder or sleep disturbance. In some embodiments, the patient is undergoing treatment with esketamine (esketamine), and has terminated treatment with esketamine and suffered from a sleep disorder or sleep disorder.

"treating" includes any effect, e.g., reduction, modulation, or elimination, that results in an improvement in the condition, disease, disorder, etc. An "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

The term "effective amount" refers to the amount of a component of interest (e.g., GLYX-13 (or a composition containing GLYX-13)) that is sought by a researcher, veterinarian, medical doctor or other clinician to elicit the biological or medical response of a tissue, system, animal or human.

GLYX-13 can be obtained by recombinant or synthetic methods, such as those described in U.S. Pat. Nos. 5,763,393 and 4,086,196, which are incorporated herein by reference. Polymorphs, hydrates, homologs, solvates, free bases and/or suitable salt forms of GLYX 13, such as, but not limited to, acetate salts, are also contemplated. The peptide may be in cyclized or non-cyclized form, as further described in US 5,763,393. In some embodiments, GLYX-13 analogs can include insertions or deletions of a moiety on one or more of the Thr or Pro groups, e.g., CH₂OH or NH₂Deletion of a portion. In other embodiments, GLYX-13 may optionally be substituted with one or more halogens, C₁-C₃Alkyl (optionally substituted with halogen or amino), hydroxy and/or amino.Other compounds contemplated for use herein include partial glycine site agonists of NMDAR disclosed in US 5,763,393, US 6,107,271 and Wood et al, neuro. report, 19, 1059-.

In some embodiments, such as within an induction period, a therapeutically effective amount of GLYX-13 administered for treatment of an adult human is from about 0.01mg/kg to about 1000mg/kg per administration (e.g., from about 0.01mg/kg to about 100mg/kg, from about 0.01mg/kg to about 50mg/kg, from about 0.01mg/kg to about 25mg/kg, from about 0.01mg/kg to about 10mg/kg, from about 0.1mg/kg to about 100mg/kg, from about 0.1mg/kg to about 50mg/kg, from about 0.1mg/kg to about 10mg/kg, from about 1mg/kg to about 100mg/kg, from about 1mg/kg to about 50mg/kg per administration, e.g., once a week, twice a week, or three times a week and/or as described herein). The dose of GLYX-13 can be any dose, including but not limited to about 1ug/kg, 25ug/kg, 50ug/kg, 75ug/kg, 100 ug/kg, 125ug/kg, 150ug/kg, 175ug/kg, 200ug/kg, 225ug/kg, 250ug/kg, 275ug/kg, 300ug/kg, 325ug/kg, 350ug/kg, 375ug/kg, 400ug/kg, 425ug/kg, 450ug/kg, 475ug/kg, 500ug/kg, 525ug/kg, 550ug/kg, 575ug/kg, 600ug/kg, 625ug/kg, 650ug/kg, 675ug/kg, 700ug/kg, 725ug/kg, 750ug/kg, 775ug/kg, 800ug/kg, 825ug/kg, 850ug/kg, 875ug/kg, 900ug/kg, 925ug/kg, 950ug/kg, 975ug/kg, 1mg/kg, 2.5mg/kg, 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg or 100 mg/kg. In certain embodiments, GLYX-13 can be therapeutically effective for depression in a range (e.g., an intravenous dose range) of about 1 to about 10mg/kg, for example about 5 to about 10mg/kg, such as about 1mg/kg, about 5mg/kg, or 10 mg/kg.

In some embodiments, a therapeutically effective amount of GLYX-13 administered for adult human treatment may be a fixed dose, e.g., from about 1000mg to about 200mg, or 900mg to about 100mg, e.g., from about 200mg to about 500mg, e.g., 50mg, 100mg, 225mg, 250mg, 200mg, 300mg, 350mg, 450mg, 500mg, 600mg, 700mg, 750mg, and/or 900mg unit dose, e.g., over an induction period (administration period). It is understood that the maintenance dose may be lower than the induction dose.

In some embodiments, any of the GLYX-13 doses described herein may be administered less than a daily baseline, such as every other day (e.g., every third day); once or twice a week; once, twice or three times a week; twice or three times a week; twice weekly (e.g., every 3 days, every 4 days, every 5 days, every 6 days, or, e.g., about 2 days to about 3 days apart between doses); once every three to four days; once per week; once every two weeks (every two weeks); twice a month; once a month or even less. In certain embodiments, GLYX-13 is administered at a frequency of once per week, twice per week, once per two weeks, or any combination thereof.

In certain embodiments, GLYX-13 (lapatin) is administered in a range of about 1 to about 10mg/kg, such as about 5 to about 10mg/kg, such as about 1mg/kg, about 5mg/kg, or about 10mg/kg (e.g., an intravenous dose range); and/or GLYX-13 is administered at a frequency of once per week, once per two weeks, or any combination thereof.

In some embodiments, the methods and regimens include two or more treatment cycles (e.g., consecutive cycles), wherein each cycle includes an induction period and a rest period. As will be appreciated by those skilled in the art, each treatment cycle may vary independently of one another in terms of dose, frequency, duration of induction period, duration of rest period, and the like.

Administration and formulation

As is well known in the art, GLYX-13 of the present invention, as well as any other pharmacological agent (e.g., one or more other antidepressants), may be administered in a variety of ways depending on the intended use. For example, if the compositions of the present invention are administered orally, they may be formulated as tablets, capsules, granules, powders or syrups. Alternatively, the formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), instillation formulations or suppositories. For administration by the ocular mucosal route, the compositions of the invention may be formulated as eye drops or eye ointments. These preparations can be prepared by conventional methods, and-if desired-the composition can be mixed with any conventional additives, such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension aids, emulsifiers, or coating agents.

In some embodiments, GLYX-13 herein may be administered to a patient parenterally, including but not limited to subcutaneous, intramuscular, and intravenous administration. In some embodiments, one or more of the components of the compositions described herein may also be administered via slow controlled intravenous infusion or by release from an implant device.

In the formulations of the present invention, wetting agents, emulsifying agents, and lubricating agents (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can be present in the formulated medicament.

The compositions of the present invention may be suitable for oral, intranasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. The amount of composition that can be combined with the carrier material to produce a single dose will vary depending upon the subject being treated and the particular mode of administration.

The method of making these formulations comprises the step of bringing into association the composition of the invention with a carrier and optionally one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the medicament with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a composition of the invention as the active ingredient. The compositions of the present invention may also be administered as a bolus, an lick, or a paste.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compositions of the present invention, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan; cyclodextrins, and mixtures thereof.

Suspensions, in addition to the compositions of the present invention, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Pharmaceutical compositions of the invention suitable for parenteral administration comprise a composition of the invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

"pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or human, as appropriate. For human administration, the formulations should meet sterility, pyrogenicity, overall safety and purity standards as required by the FDA Office of Biologics standards. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents and the like, which are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. The compositions described herein may also comprise other active compounds that provide supplemental, additional, or enhanced therapeutic functions. Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof; vegetable oils, such as olive oil; and injectable organic esters such as ethyl oleate and cyclodextrins. Proper fluidity can be maintained, for example, by the use of a coating material (e.g., lecithin), by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The disclosed compounds can be provided as part of a liquid or solid formulation (e.g., aqueous or oily suspensions, solutions, emulsions, syrups and/or elixirs). The compositions may also be formulated as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid formulations may contain additives including, but not limited to, suspending agents, emulsifying agents, non-aqueous carriers, and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Non-aqueous carriers include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Preservatives include, but are not limited to, methyl or propyl hydroxybenzoate and sorbic acid. Contemplated compounds may also be formulated for parenteral administration, including but not limited to administration by injection or continuous infusion. Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents including, but not limited to, suspending, stabilizing, and dispersing agents. The compositions may also be provided in powder form for constitution with a suitable vehicle, including but not limited to sterile, pyrogen-free water. For example, pharmaceutical formulations of lapatine are disclosed in U.S. patent publication nos. 20170296616 and 20170049844, which are incorporated herein by reference.

The invention has a number of aspects which are illustrated by the following non-limiting examples.