CN115590966A

CN115590966A - Therapeutic combinations of drugs and methods of use thereof

Info

Publication number: CN115590966A
Application number: CN202210967384.9A
Authority: CN
Inventors: 刘爽; 约翰·麦基; P·R·古佐; 崔文革
Original assignee: Kangsheng Boshi Pharmaceutical Co ltd
Current assignee: Harmony Biotechnology Co ltd
Priority date: 2020-01-10
Filing date: 2021-01-10
Publication date: 2023-01-13

Abstract

Therapeutic combinations or formulations of drugs are provided that include triple monoamine reuptake inhibitors, melanin concentrating hormone receptor 1 (MCHR 1) antagonists, and diazoxide or formulations thereof, as well as various combinations thereof, in combination with other drugs or active agents. Methods of treating various conditions, including genetically confirmed syndromes and diseases, using therapeutic combinations and formulations of drugs as provided herein are provided. Methods are provided for administering a triple monoamine reuptake inhibitor (TRI), a melanin concentrating hormone receptor 1 (MCHR 1) antagonist, and diazoxide or a formulation thereof, the dosage of said agents being determined using the methods provided herein, said methods comprising empirical methods for safe and predictable titration and determination of initial therapeutic doses; a model-based method for safe and predictable titration and determination of the initial therapeutic dose and either the lowest therapeutic dose or the optimal effective dose, comprising use of a bayesian pharma-metric model.

Description

Therapeutic combinations of drugs and methods of use thereof

The application is a divisional application of an invention patent application with the application date of 2021, 1 and 10, the application number of 202180008853.8, and the name of the invention is 'combination of medicines and a using method thereof'.

RELATED APPLICATIONS

The present Patent Cooperation Treaty (PCT) International application claims 35 U.S. C. § 119 (e) U.S. provisional application No. USSN 62/959,534 filed on 10/1/2020; USSN No. 62/959,769, filed on

month

1, 10, 2020; USSN No. 62/980,053, filed on 21/2/2020; and priority of USSN No. 63/022,484, filed on day 5, month 9, 2020. The foregoing application is expressly incorporated by reference herein in its entirety and for all purposes. All publications, patents, and patent applications cited herein are expressly incorporated by reference for all purposes.

Technical Field

The present invention relates generally to pharmacology and pharmacokinetics. In alternative embodiments, therapeutic combinations or formulations of drugs are provided that include a triple monoamine reuptake inhibitor (TRI) that inhibits reuptake of serotonin, dopamine, and norepinephrine by blocking central serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), a melanin concentrating hormone receptor 1 (MCHR 1) antagonist, and diazoxide or formulations thereof, as well as various combinations thereof, as well as combinations of these with other drugs or active agents. In an alternative embodiment, there is provided a method for administering a triple monoamine reuptake inhibitor (TRI), a melanin concentrating hormone receptor 1 (MCHR 1) antagonist, or diazoxide or a formulation thereof, the dosage of which is determined using the methods provided herein, comprising empirical methods for safe and predictable titration and determination of initial therapeutic doses; a model-based method for safe and predictable titration and determination of initial therapeutic dose and determination of lowest therapeutic dose or determination of optimal effective dose, comprising the use of a bayesian pharmaometry model. In alternative embodiments, methods of treating various conditions, including genetically confirmed syndromes and diseases, using the therapeutic combinations and formulations of drugs provided herein are provided. In an alternative embodiment, a PK-guided precision dosing method using the pharmacokinetic modeling and simulation method or similar modeling and simulation methods described above and a population PK/PD model of formula I is provided for the treatment of hyperphagia, hyperphagia in PWS, destructive mood disorder (DMDD), oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, and Binge Eating Disorder (BED) in oral doses of formula I or deuterated forms thereof.

Background

Prader-willi syndrome (PWS) is a rare, severe, complex inherited neurodevelopmental disorder that occurs in 1/15,000 to 1/30,000 individuals. PWS is caused by the deletion of a paternally expressed gene on chromosome 15q 11-13. In about 70% of cases, PWS is due to paternal deletion at 15q11-q 13. Approximately 25% of cases of PWS are due to maternal uniparental disomy (meppd), or when both copies of chromosome 15 are inherited from the mother, and 5% are due to translocation or imprinting central mutations.

Today, the only therapy currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of PWS is human growth hormone, which is used to increase linear growth. There is no approved therapy for the treatment of PWS hallmark characteristics, particularly hyperphagia, anxiety, and obsessive compulsive symptoms. There is no approved drug treatment for hyperphagia or related behavioral symptoms associated with PWS.

Hypothalamic obesity or hypothalamic injury-induced obesity (HO or HIO) is caused by hypothalamic injury. The most common cause is associated with a rare non-cancerous tumor known as craniopharyngioma. When such tumors are resected, the hypothalamus is damaged, leading to symptoms of hypothalamic obesity, which is common to many aspects of the PWS phenotype, such as hyperphagia, excessive daytime sleepiness, ADHD, autonomic imbalance; growth hormone, gonadotropin and thyroid stimulating hormone deficiency.

Hypersomnia is a chronic disabling hypersomnia neurological disorder that estimates that 20-67 people are affected per 100,000 people worldwide. Onset of lethargy occurs most often in the second decade of life, but diagnosis is often delayed by years. The symptoms of lethargy include Excessive Daytime Sleepiness (EDS), which, although not specific to lethargy, is a characteristic of the condition present in all patients, as it is a prerequisite for diagnosis. Cataplexy, an involuntary loss of muscle tone while awake, typically caused by intense mood, occurs in up to 60% of patients. Other symptoms are disturbed sleep at night; pre-sleep hallucinations and pre-wake hallucinations occurring at sleep onset and wake up, respectively; and sleep paralysis. Hypersomnia cannot be cured. Various agents that modulate the monoamine system, such as serotonin, dopamine, norepinephrine and histamine, and gamma-aminobutyric acid B (GABA) _B ) Receptors have been used clinically to control symptoms. It is believed that hypersomnia, especially hypersomnia with cataplexy, is due to a deficiency in orexin/hypothalamic secretin.

Achieving optimal doses for individual patients is important to achieve clinical benefit and minimize adverse events. Due to individual differences in body weight, body composition, metabolic enzyme CYP P450 polymorphisms, drug transporter (e.g., PGP) polymorphisms, drug-drug integration, and use of multiple drugs, it is difficult for physicians to prescribe optimal dosages for patients, and empirical titration is often involved, which is not effective in finding optimal dosages. It is more challenging for pediatric, intellectual disability and clinically vulnerable patients.

The case of tesofensine emphasizes the importance of dosing to achieve clinical benefit and minimize adverse events. Preliminary clinical studies using standard doses of tesofensine have shown promise in managing HIO body weight and PWS hyperphagia (saniono Corporation Presentation, 6 months 2020). However, the published data also shows that there may be significant differences in plasma drug concentrations in PWS patients (saniono Corporation Presentation 2019, 3 months). With only the standard mg/day dose, 2/3 of the patients' plasma drug levels exceeded safe levels and were withheld from adverse events (excessive dopamine increase due to DAT inhibition could lead to CNS side effects or exacerbate existing CNS disorders in the patients), while hyperphagia in patients with adequate plasma drug levels was completely controlled. On the other hand, also in the case of tesofensine, using the standard mg/day dose, lowering the dose in all patients resulted in no efficacy.

New paradigms are needed to ensure that safe and effective dosing regimens are provided for these high risk patients.

Disclosure of Invention

In an alternative embodiment, a therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture is provided comprising one or more of any active agent or drug including:

(a) (i) triple monoamine reuptake inhibitors (TRIs) and melanin concentrating hormone receptor 1 (MCHR 1) antagonists or inhibitors,

(ii) Triple monoamine reuptake inhibitors (TRI) and diazoxide (or PROGLYCEM) ^TM ) Or diazoxide choline controlled release agents (DCCR formulations),

(iii) Melanin concentrating hormone receptor 1 (MCHR 1) antagonist or inhibitor and diazoxide (or PROGLYCEM) ^TM ) Or diazoxide choline controlled release agents (DCCR formulations), or

(iv) Triple monoamine reuptake inhibitor (TRI) melanin concentrating hormone receptor 1 (MCHR 1) antagonists or inhibitors and bisAzazine (or progycem) ^TM ) Or diazoxide choline controlled release agents (DCCR formulations); or

(b) (i) triple monoamine reuptake inhibitors (TRIs),

(ii) A melanin concentrating hormone receptor 1 (MCHR 1) antagonist or inhibitor,

(iii) Diazoxide choline controlled release formulations (DCCR formulations), or

(c) The method comprises the following steps (ii) or (b) formulated with any one or more of the following drugs or small molecules:

(1) Non-acylated ghrelin (UAG) analogs and/or livolitides (also known as AZP-531),

(2) Carbetocin, or DURATOCIN ^TM 、PABAL ^TM Or lonaptene ^TM ，

(3) Oxytocin and/or the precursor oxytocin-neurotrophin,

(4) Liraglutide (liraglutide), or Victoza ^TM Or SAXENDA ^TM ，

(5) Exenatide (exenatide), or Byetta ^TM 、BYDUREON ^TM 、 BYDUREON ^TM Or BCISE ^TM ，

(6) Seimelantide (also known as IMCIVREE) ^TM RM-493, BIM-22493, IRC-022493, N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide),

(7) Rimonabant (also known as SR 141716) and/or ACOMPLIA ^TM 、ZIMULTI ^TM ，

(8) A beta adrenergic blocker, wherein optionally, the beta adrenergic blocker is or comprises: metoprolol (or LOPRESSOR) ^TM 、METOLAR XR ^TM 、 TOPROL X ^TM ) Atenolol (or TENORMIN) ^TM ) Propranolol (propranolol) (or INDERAL) ^TM ) And/or nadolol (or CORGARD) ^TM ) Or any combination thereof,

(9) A melatonin receptor agonist, wherein optionally the melatonin receptor agonist is or comprises: melatonin or N-acetyl-5-methoxytryptamineRamelalteon (or ROZEREM) ^TM ) And/or tesimelton (or HETLIOZ) ^TM ) Or any combination thereof,

(10) A histamine receptor 1 antagonist, wherein the histamine receptor 1 antagonist is or comprises: doxepin (or SINEQUAN) ^TM 、QUITAXON ^TM Or APONAL ^TM ) Or a low dose of doxepin (wherein optionally the low dose is 3mg or 6mg, trazodone (or DESYREL) per dose ^TM 、DESYREL DIVIDOSE ^TM Or OLEPTRO ^TM ) Amitriptyline (amitriptyline) (or ELAVIL) ^TM 、PROTANOL ^TM 、QUALITR IPTINE ^TM 、REDOMEX ^TM Or SAROTEN ^TM ) Or amitriptyline and chlorine nitrogen

(chlor diazepoxide)(MORELIN ^TM 、RISTRYL ^TM Or SEDANS ^TM ) And/or mirtazapine (mirtazapine) (or REMERON) ^TM ) Or any combination thereof,

(11) A histamine H3 receptor antagonist or inverse agonist, wherein optionally said H3 receptor antagonist or inverse agonist is or comprises: pitotilisant (or tiproliant), cyprotendine (ciproxidine) or WAKIX ^TM ) Thioperamide (thioperamide), clorproprion (clobenpropert), siprolin (ciproxifan), conricine (concessing) (or nerine), conosidine (roquessing), benemine (wrightine)) and/or betahistine (or SERC) ^TM ) SUVN-G3031 (Suven Life Sciences Ltd), or any combination thereof,

(12) Modafinil (modafinil) (or PROVIGIL) ^TM 、ALERTEC ^TM Or MODAVIGIL ^TM ) And/or armodafinil (or NUVIGIL) ^TM )，

(13) Human growth hormone (hGH) (or somatotropin) or recombinant forms thereof (or OMNITR OPE ^TM 、JINTROPIN ^TM 、NUTROPIN ^TM Or NUTROPIN DEPOT ^TM 、H UMATROPE ^TM 、GENOTROPIN ^TM 、NORDITROPIN ^TM Or SAIZEN ^TM ) Or any of themIn what combination of the components are combined,

(14) Testosterone and/or 17 beta-hydroxyandrost-4-en-3-one,

(15) Progesterone and/or pregn-4-ene-3, 20-dione,

(16) An estrogen, estrone, estradiol or estriol, or any combination thereof,

(17) A thyroid hormone or derivative thereof, wherein optionally the thyroid hormone or derivative thereof is or comprises: triiodothyroxine (T3), thyroxine (T4), levothyroxine or L-thyroxine, or any combination thereof,

(18) Chorionic gonadotropin (hCG) hormone or recombinant forms thereof, or NOVAREL ^TM Or PREGNYL ^TM Or any combination thereof,

(19) Metformin (or GLUCOPHAGE) ^TM ) And/or repaglinide (or PRANDIN) ^TM ，

(20) Insulin or human insulin or recombinant or analogous forms thereof (or ACTRAPID) ^TM 、HUMALOG ^TM 、NOVORAPID ^TM 、APIDRA ^TM 、LANTUS ^TM Or LEVE MIR ^TM ) Or any combination thereof,

(21) Glucocorticoid receptor antagonists or antimorticoids, or mifepristone (or RU-486, or MIFEGYNE) ^TM Or MIFEPREX ^TM ) Metyrapone (or METOPIRONE) ^TM ) Ketoconazole (or NIZORAL) ^TM ) Or aminoglutethimide (or ELIPEN) ^TM 、 CYTADREN ^TM Or ORIMETEN ^TM )，

(22) A histamine receptor 2 antagonist, wherein optionally, said histamine receptor 2 antagonist is or comprises: cimetidine (or tacame) ^TM ) Ranitidine (ranitidine) (or ZANTAC) ^TM ) And/or famotidine (or PEPCID) ^TM ) Or any combination thereof,

(23) A mood stabilizer, wherein optionally the mood stabilizer is or comprises: gabapentin (gabapentin) (or NEURONTIN) ^TM ) (ii) a Clonazepam (clonazepam) (or KLONOPIN) ^TM Or RIVOTRILF ^TM ) (ii) a Valproate, valproic acidSodium or hemi-sodium valproate (or CONVULEX) ^TM 、DEPAKOTE ^TM 、EPILIM ^TM Or STAVZOR ^TM ) (ii) a Oxcarbazepine (or TRILEPTAL) ^TM Or OXTELAR XR ^TM ) (ii) a Lithium or lithium carbonate (or LITHOBID) ^TM Or LITHOMAX ^TM ) (ii) a Topiramate (topiramate) (or TOPAMAX) ^TM 、TROKENDI XR ^TM Or QUDEXY XR ^TM ) And/or lamotrigine (or lamotrigine) ^TM ) Or any combination thereof,

(24) A neuroleptic agent, wherein optionally the neuroleptic agent comprises: risperidone (risperidone) (or Risperdal), aripiprazole (or ABILIFY) ^TM ) Quetiapine (quetiapine) (or SEROQUEL) ^TM ) Olanzapine (or ZYPREXA) ^TM ) Ziprasidone (or GEODON) ^TM ) And/or haloperidol (haloperidol) (or HALDOL) ^TM Or SERENACE ^TM ) Or any combination thereof,

(25) Quetiapine (quetiapine), or SEROQUEL ^TM Or TEMPROLIDE ^TM ，

(26) Naltrexone (or FEBIA) ^TM Or VIVITROL ^TM )，

(27) Gamma-aminobutyric acid (GABA) B (GABA) _B ) Receptor modulators, e.g. sodium oxybate (Xyrem) ^TM ) Or controlled release sodium oxybate (or FT 218), or sodium oxybate minus, optionally JZP-258, or baclofen (baclofen),

(28) Solifenatol (sulrimetol) or SUNOS ^TM ，

(29) A hypothalamic secretin/orexin 2 receptor selective agonist, optionally TAK-925, TAK-994 or TAK-988,

(30) A selective Norepinephrine Reuptake Inhibitor (NRI), or a Selective Serotonin Reuptake Inhibitor (SSRI), or a selective serotonin norepinephrine inhibitor (SNRI), wherein optionally the SSRI or SNRI inhibitor is or comprises reboxetine (or AXS-12, or Edronax) ^TM ) Atomoxetine (or Strattera) ^TM ) Venlafaxine (Effexor) ^TM Or Effexor XR ^TM ) FluocideTins (fluoxetine) (Prozac) ^TM ) Citalopram (citalopram) (Celexa) ^TM ) Escitalopram (Lexapro), paroxetine (pareoxetine) (Paxil) ^TM ) Sertraline (Zoloft) ^TM ) Or duloxetine (duloxetine) (Cymbalta) ^TM )，

(31) Amphetamine, wherein optionally amphetamine or includes amphetamine, dextroamphetamine (or Adderall) ^TM ) Dextro-amphetamine (Mydayis) ^TM ) Or lisdexamfetamine (or Vyvanse) ^TM )，

(32) Methylphenidate or Ritalin, ritalin LA, concerta, metadate CD, methyin ER, daytrana, quillivant XR, quillichew ER, aptensio XR, cotempla XR-ODT, jornay PM or Adhansia XR,

(33) Tricyclic antidepressants (TCAs), wherein optionally TCA is or includes imipramine (Tofranil) ^TM ) Or amitriptyline (Elavil) ^TM ) Clomipramine (Anafranil) ^TM ) Or another TCA, or a combination of TCAs,

(34) Monoamine oxidase inhibitor (MAOI), wherein optionally the MAOI is or comprises selegiline (Emsam) ^TM ) Isocarboxazid (Marplan) ^TM ) Phenelzine (Nardil) ^TM ) And tranylcyclopropylamine (tranylcyclopromine) (parent) ^TM ) Or a further type of MAOI,

(35) THN102, or a combination of modafinil (modafinil) and flecainide (flecainide),

(36) An inhibitor of an astrocyte connexin inhibitor, wherein optionally said inhibitor of an astrocyte connexin inhibitor is or comprises flecainide,

(37) (ii) a prostaglandin DP1 receptor antagonist, wherein optionally the prostaglandin DP1 receptor antagonist is or comprises ONO-4127Na,

(38) Opioids, wherein optionally, the opioids include morphine,

(39) An anti-obesity drug, wherein optionally the anti-obesity drug comprises lorcaserin (belvisq) ^TM )、Orlistat (orlistat) (Alli) ^TM ) Phentermine (phentermine) and topiramate (topiramate) (Qsymia) ^TM ) Or naltrexone hydrochloride (naltrexone HCl) or bupropion hydrochloride (bupropion HCl) (Contrave) ^TM )，

(40) A Farnesoid X Receptor (FXR) agonist, wherein optionally the FXR agonist comprises Obeticholic Acid (OCA), EYP001 (ENYO Pharma), TQA3526, px-102, px-104, or trofexol (tropiferox),

(41) A PPAR agonist, optionally a PPAR α/δ agonist or a PPAR- α/γ agonist, wherein optionally the PPAR- α/γ agonist comprises pioglitazone (pioglitazone), elafinil (elafiniranor) or lanifolin (lanifibrator) (or IVA337, inventiva),

(42) A CC chemokine receptor CCR2/CCR5 inhibitor, wherein optionally said CC chemokine receptor comprises toffexol, a combination of toffexol and cenicriviroc, or cenicriviroc,

(43) A Mitochondrial Pyruvate Carrier (MPC) inhibitor, wherein optionally the MPC inhibitor comprises MSDC-0602K (Cirius Therapeutics),

(44) A fibroblast growth factor 19 (FGF 19) analog, wherein optionally, the FGF19 analog comprises odafmin (aldafermin) (or NGM282, NGM biopharmaceutics)

(45) A fibroblast growth factor 21 (FGF 21) analog, wherein optionally the FGF21 analog comprises a pegylated fibroblast growth factor 21 analog, optionally pebafmin (pegbelfermin),

(46) A thyroid hormone receptor beta (THR-beta) agonist, wherein optionally the THR-beta agonist comprises remeltarone (remetrobom) (MGL-3196, magrigal Pharmaceuticals) or VK-2890,

(47) Inhibitors of stearoyl-CoA desaturase-1 (SCD 1), wherein optionally said SCD1 inhibitor comprises Amcochol (Galmed Pharmaceuticals),

(48) An inhibitor of apoptosis signal-regulating kinase 1 (ASK 1), wherein optionally the ASK1 inhibitor comprises seleonsertib (Gilead Sciences),

(49) An acetyl-CoA carboxylase (ACC) inhibitor, wherein optionally the ACC inhibitor comprises Ficolase (firsocostat) (GS-0976) or MK-4074, or

(50) Any combination of (1) to (49).

In alternative embodiments, the triple monoamine reuptake inhibitor is or comprises:

(a) Tesofensine, tesomel (tesofen) or tesofen (Saniono, ballerup, denmark),

(b) [1,2,4] triazolo [1,5-a ] pyridin-6-yl substituted tetrahydroisoquinoline or salts, solvates, racemates, crystalline forms or derivatives thereof, optionally as described in USPN 8,802,696, or 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline or salts, solvates, racemates, crystalline forms or derivatives thereof, or a compound having the following formula (formula I):

formula I

Or a pharmaceutically acceptable salt thereof, or an S-enantiomer, (+) -stereoisomer or (-) -stereoisomer thereof, or a compound of S or R configuration, or an (S) (+) -stereoisomer or (R) (-) -stereoisomer thereof,

(c) A deuterated form of the compound or drug of (a) or (b), wherein 1,2,3,4, 5,6, 7, 8,9, or 10 or more hydrogen residues are deuterated.

In an alternative embodiment, the melanin concentrating hormone receptor 1 (MCHR 1) antagonist or inhibitor is or comprises:

(a) GW 856464649 (GSK), AZD-1979 (AstraZeneca), AMG-076 (Amgen), BMS-830216 (BMS), ATC-0065 or ATC-0175 (see Chaki et al (2005) CNS Drug Reviews, vol 11 (4): 341-52), GW-803430 or GW-3430 (see Gehlert et al (2009) J Pharm and Experimental Therapeutics, vol 329 (2) 429-38), NGD-4715 (Ligand Pharmaceuticals), SNAP-7941 (see Klemenhagen et al (2007) J Pharm and Experimental Therapeutics, vol 321 (1) 237-48), T-226 or T-296 (see Takeka et al (2002) Eur J phar J438 (35) or any combination thereof,

(b) A compound having the formula (designated formula II):

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) pyridin-2 (1H) -one

Formula II

Or is or

(1-azinone) substituted pyridoindoles as described in USPN 8,716,308, or compounds having the formula:

wherein R is ₁ Is H or optionally substituted alkyl;

R ₂ 、R ₃ 、R ₄ each independently selected from H, -O-alkyl, -S-alkyl, halo, -CF ₃ and-CN;

g is-CR ¹² R ¹³ ------NR ⁵ - -or- -NR ⁵ --CR ¹² R ¹³ ；R ⁵ Is H, optionally substituted alkyl, optionally substituted heterocycle, - -C (= O) - - -R ⁶ 、--C(＝O)--O--R ⁷ Or- -C (= O) - - -NR ¹⁹ R ²⁰ ；R ⁶ And R ⁷ Each is optionally substituted alkyl or optionally substituted heterocycle;

R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₉ and R ₂₀ Each independently selected from H or optionally substituted alkyl; r ¹⁴ And R ¹⁵ Each independently is H or halogen; y is CH; l is-CH ₂ --O--、--CH ₂ CH ₂ - -, - -CH = CH- -or a bond; and B is aryl or heteroaryl or cycloalkyl; with the proviso that when L is a direct bond, B cannot be unsubstituted heteroaryl or heteroaryl monosubstituted by fluorine, or

(c) A deuterated form of the compound or drug of (a) or (b),

and optionally, the therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture further comprises an N-acetyltransferase 2 (NAT 2) or an arylamine N-acetyltransferase inhibitor, optionally acetaminophen, N-acetyl-p-aminophenol (APAP), or acetaminophen (or TYLENOL) ^TM Or PANADOL ^TM ) In combination with any compound of (b) or a deuterated form of a compound or drug of (b), wherein, optionally, in such combination, (b) is formula II.

In alternative embodiments, two or three or more of the drugs or active agents are formulated as separate compositions, or two or three or more of the drugs or active agents are formulated as one composition or pharmaceutical formulation (two or more drugs or active agents are formulated together).

In alternative embodiments, one or two or more of the drugs or active agents are packaged individually, or together, or in any combination in a single package, multiple packages or packets, or blister packs, lidded blisters or blister cards or packets, or shrink wrap.

In an alternative embodiment, one or two or more or all of the drugs or active agents are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a spray, a sachet, an inhalant, a powder, a lyophilized powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository, or any combination thereof, and optionally, the drug delivery device or article of manufacture is or includes an implant.

In alternative embodiments, one or two or more or all of the drugs or active agents are formulated or manufactured together as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a lyophilized powder, a feed, a food product, a food supplement, a pellet, a lozenge, a liquid, an elixir, an aerosol, an inhalant, an adhesive, a spray, a powder, a lyophilized powder, a patch, a tablet, a pill, a capsule, a gel, a geltab, a lozenge, a caplet, a nanosuspension, a nanoparticle, a nanoliposome, a microgel or a suppository.

In an alternative embodiment, one or two or more or all of the drugs or active agents are packaged in dosages that match a timed dosing regimen to match the optimal dosage for the day.

In an alternative embodiment, the drug or active agent comprises:

(a) A triple monoamine reuptake inhibitor or a [1,2,4] triazolo [1,5-a ] pyridin-6-yl substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and a histamine receptor 1 antagonist, optionally doxepin;

(b) A triple monoamine reuptake inhibitor or a [1,2,4] triazolo [1,5-a ] pyridin-6-yl substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and naltrexone;

(c) A triple monoamine reuptake inhibitor or a [1,2,4] triazolo [1,5-a ] pyridin-6-yl substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and a histamine receptor 1 antagonist, optionally doxepin, and naltrexone;

(d) Triple monoamine reuptake inhibitors or [1,2,4]Triazolo [1,5-a ]]Pyridyl-6-substituted tetrahydroisoquinoline derivatives, optionally compounds of formula I, and diazoxide (or PROGLYCEM) ^TM ) Or diazoxide choline controlled release agents (DCCR formulations);

(e) Triple monoamine reuptake inhibitors or [1,2,4]]Triazolo [1,5-a ]]Pyridyl-6-yl substituted tetrahydroisoquinoline derivatives, optionally compounds of formula I, and diazoxide (or PROGLYCEM) ^TM ) Or diazoxide choline controlled release agent (DCCR formulation) and melatonin receptor agonist, optionally melatonin or N-acetyl-5-methoxytryptamine, ranitidine (or ROZEREM) ^TM ) And/or ticocimone (or HETLIOZ) ^TM ) Or any combination thereof,

(f) A triple monoamine reuptake inhibitor or a [1,2,4] triazolo [1,5-a ] pyridin-6-yl substituted tetrahydroisoquinoline derivative, optionally a compound of formula I, and a melanin concentrating hormone receptor 1 (MCHR 1) antagonist or inhibitor, optionally a compound of formula II, or any combination thereof;

(g) Triple monoamine reuptake inhibitors or [1,2,4]]Triazolo [1,5-a ]]Pyridyl-6-yl substituted tetrahydroisoquinoline derivatives, optionally compounds of formula I, and a beta blocker, optionally atenolol (TENORMIN) ^TM ) Bisoprolol (Cardicor) ^TM 、 EMCOR ^TM ) Or metoprolol (betaxoc) ^TM 、LOPRESOR ^TM 、TOPROL XL ^TM ) Or any combination thereof; and/or

(h) Any combination of (a) to (g).

In an alternative embodiment, a pharmaceutical composition, medicament or formulation is provided comprising a compound having the formula:

wherein R is ₁ To R ₁₅ At least one of which is-D (deuterium), or R ₁ To R ₁₅ All of the components are-D,

and optionally, if the carbon atom designated as x is a stereocentre, it is in the R or S configuration.

In an alternative embodiment, provided herein are compounds having the formula:

(a) A 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4,8-d6 compound having the formula:

(b) A 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5 compound having the formula:

(c) A 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2 compound having the formula:

(d) A 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 3-d2 compound having the formula:

(e) A 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-4-d compound having the formula:

(f) A 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-8-d compound having the formula:

or

(g) A 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3 compound having the formula:

in an alternative embodiment, there is provided a pharmaceutical composition, medicament or formulation comprising a compound having the formula:

wherein R is ₁ To R ₁₈ At least one of which is-D (deuterium), or R ₁ To R ₁₈ All are-D.

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl) pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl) pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl) pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-1, 1-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-1, 1-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-1, 1-d ₂ ) Pyridin-2 (1H)) -one,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-1, 1-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-3, 3-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-3, 3-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-3, 3-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-3, 3-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-4, 4-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-4, 4-d ₂ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-4, 4-d 2) pyridin-2 (1H) -one,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-4, 4-d 2) pyridin-2 (1H) -one,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-1, 3-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-1, 3-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-1, 3-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) 1. (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-1, 3-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-1, 4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-1, 4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-1, 4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-1, 4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-3,3,4,4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-3, 4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-3, 4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5- (methyl-d 3) -2,3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-3, 4-d ₄ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-1, 3,4-d ₆ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-1, 3,4-d ₆ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4, 3-b)]Indol-7-yl-1, 3,4-d ₆ ) Pyridin-2 (1H) -ones,

4- ((5-Fluoropyridin-2-yl) methoxy-d ₂ ) -1- (5- (methyl-d) ₃ ) 2,3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indol-7-yl-1, 3,4-d ₆ ) Pyridin-2 (1H) -one, or

4- ((5-Fluoropyridin-2-yl-3, 4, 6-d) ₃ ) Methoxy-d ₂ ) -1- (5- (methyl-d) ₃ ) -2,3,4, 5-tetrahydro-1H-pyrido [4,3-b]Indol-7-yl-1, 3,4,6, 8,9-d ₉ ) Pyridin-2 (1H) -one-3, 5,6-d3.

In alternative embodiments, methods are provided for treating, ameliorating, slowing the progression of, alleviating the symptoms of, reducing adverse events associated with, or preventing a disease or condition, including or associated with:

hyperphagia (optionally assessed by HQ-CT),

moderate to severe Binge Eating Disorder (BED),

the nervous bulimia nervosa is induced,

management of obesity, optionally further including management of weight loss and maintenance of weight loss, or optionally further including increased physical activity as an adjunct to a low calorie diet or for long term weight management,

the early-onset morbid obesity is caused by obesity,

non-alcoholic steatohepatitis (NASH),

non-alcoholic fatty liver disease (NAFLD),

primary Sclerosing Cholangitis (PSC),

primary Biliary Cholangitis (PBC),

inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS),

in the case of type II diabetes mellitus,

obesity induced by hypothalamic injury,

the state of the art for obsessive-compulsive disorder (OCD),

destructive mood disorder (DMDD),

in opposition to contra-sexual disorder (ODD),

the disease of scratching the skin of a patient,

the hair-plucking effect is that the hair-plucking effect,

intermittent rage (IED),

excessive Daytime Sleepiness (EDS),

excessive daytime sleepiness associated with hypersomnia and sleep apnea,

excessive daytime sleepiness associated with hypersomnia,

excessive daytime sleepiness associated with central or obstructive sleep apnea,

in the case of hypersomnia, the symptoms of hypersomnia,

hypersomnia type 1 (NT 1) according to the International sleep disorder Classification-third edition (ICSD-3),

hypersomnia is accompanied by cataplexy,

according to ICSD-3 hypersomnia type 2 (NT 2),

hypersomnia, no cataplexy,

the process of the cataplexy is carried out,

in the case of an idiopathic hypersomnia,

rapid Eye Movement (REM) sleep behavior disorder, epileptic seizure,

an epilepsy, addiction or addictive disorder or behaviour, wherein optionally the addiction, addictive disorder or addictive behaviour is or comprises an Internet Game Disorder (IGD) or a drug addiction, and optionally the drug addiction is or comprises cocaine dependence or alcohol dependence,

in Major Depressive Disorder (MDD),

treatment-resistant depression (TRD),

the negative symptoms of schizophrenia are those of the general type,

the treatment of Parkinson's disease is carried out,

the MDD associated with Parkinson's disease,

the general anxiety of the patient is caused by the general anxiety,

social anxiety disorder (social phobia),

the onset of Fibromyalgia (FM),

in the treatment of diabetic nephropathy, the disease is,

the pain of the lower back is caused by the back pain,

the chronic fatigue syndrome of the human body is shown,

attention Deficit Hyperactivity Disorder (ADHD),

the self-curing disease of the patient is caused by autism,

asperger's lineage, a genetically confirmed disease or Syndrome, wherein optionally the genetically confirmed disease or Syndrome is or includes prader-willi Syndrome, barbie Syndrome (Bardet Biedl Syndrome), smith-Magenis Syndrome (Smith-Magenis Syndrome), 1p36 deficiency Syndrome, 1ip11.2 deficiency Syndrome, fragile X Syndrome, proopiomelanocortin (POMC) deficient obesity, leptin receptor (LEPR) deficient obesity, melanocortin 4 receptor (MC 4R) pathway heterozygous obesity, trisomy 21, rett Syndrome (Rett Syndrome), cyclin dependent kinase-like 5 (cdcdd-5) X linked genetic disease, angelman Syndrome (Angelman's Syndrome), shaff-poplar Syndrome (Schaff-Yang Syndrome), obblet Hereditary osteodystrophy (alberture hercules Syndrome), ostrich-fairy Syndrome (ostrich-14), ostrich Syndrome (ostrich Syndrome), ostrich-gul Syndrome, ostrich Syndrome (ostrich Syndrome)

Syndrome), wilms' Tumor, aniridia, genitourinary system abnormalities, mental retardation or WAGR or WAGRO Syndrome; delaviry Syndrome (Dravet Syndrome), lonnox-Kastokes Syndrome (Lennox-Gastaut Syndrome), gilles-Pieze Syndrome (Gillespie Syndrome) or cerebellar ataxia or Duke Syndrome (Doose Syndrome) or myoclonic dystonia epilepsy (MAE), or Niemann-Pick disease type C, or Norrie disease, or Coffin-Lowry disease,

wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia or postural tachycardia syndrome,

the method comprises the following steps:

(a) (ii) providing or having provided a therapeutic combination, a pharmaceutical dosage form, a drug delivery device or an article of manufacture as provided herein, or a pharmaceutical composition as provided herein, and

(ii) Administering or implanting a therapeutic combination, a pharmaceutical dosage form, a drug delivery device or an article of manufacture to an individual in need thereof, or

(b) Administering or implanting to an individual in need thereof a therapeutically effective dose of a therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture as provided herein.

In alternative embodiments of the methods provided herein:

-the drug or therapeutic combination, the pharmaceutical dosage form is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intracerebrally, epidural, intracranial or rectally, and optionally parenteral administration includes intrathecal, intracerebral or epidural (into intrathecal, intracerebral, epidural space), subcutaneous, intravenous, intramuscular and/or intraarterial administration,

-administering a drug or therapeutic combination, drug dosage form, to achieve a therapeutic level range of steady state plasma concentrations, and wherein:

[1,2,4] triazolo [1,5-a ] pyridin-6-yl substituted tetrahydroisoquinoline derivatives or compounds of formula I at therapeutic levels in plasma concentrations ranging from about: 50 to 4000ng/ml;100 to 3000ng/ml;250 to 1600ng/ml;500 to 1400ng/ml, 600 to 1300ng/ml, 800 to 1250ng/ml, 1000ng/ml to 1250ng/ml, 1250 to 1500ng/ml, 1500 to 2000ng/ml, 2000 to 2500ng/ml;2500 to 3000ng/ml; 3000. to 3500ng/ml; or 3500 to 4000ng/ml;

a therapeutic level of plasma concentration of the (1-azinone) substituted pyridoindole or the compound of formula II ranges from about: 5 to 4000ng/ml, 10 to 1000ng/ml, 10 to 500ng/ml, 25 to 250ng/ml, 50 to 500ng/ml, 50 to 1000ng/ml, 50 to 500ng/ml, 100 to 1000ng/ml, 100 to 500ng/ml, 200 to 1000ng/ml, 500 to 1000ng/ml, 1000 to 2000ng/ml, 2000 to 3000ng/ml or 3000 to 4000ng/ml,

therapeutic levels of tesofensine range from about: 2ng to 50ng/ml, 5 to 20ng/ml, 6.5 to 15ng/ml, 8 to 12ng/ml or about 10ng/ml,

therapeutic levels of diazoxide plasma concentrations range from about: 10ng/ml to 100ng/ml, 20ng/ml to 80ng/ml, 30 to 50ng/ml or about 40ng/ml;

in an alternative embodiment of the method provided herein, the steady state concentration is the time at which the drug concentration in vivo remains consistent; for most drugs, if the drug is administered periodically, the time to reach steady state is three to five half-lives,

in an alternative embodiment of the method provided herein, the plasma concentration of the drug or therapeutic combination, drug dosage form is:

(a) Trough level or trough concentration (C) _Grain ) Or the lowest concentration achieved by the drug or therapeutic combination or drug dosage form prior to administration of the second or next dose, or

(b) Measured from blood samples taken from about 0.5 hours to 24 hours, or 4 to 12 hours, or 1,2,3,4, 5,6, 7, 8,9, or 10 hours or more after the last administration or administration of the drug or therapeutic combination, pharmaceutical dosage form,

-administering a drug, therapeutic combination or pharmaceutical dosage form to achieve a therapeutic level range of steady state plasma concentrations (optionally human plasma concentrations), and wherein:

(a) Therapeutic levels of plasma concentrations of the compound of formula I range from about: 250 to 1600ng/ml;500 to 1400ng/ml, 600 to 1300ng/ml, 800 to 1250ng/ml, 1000ng/ml to 1250ng/ml, 1250 to 1500ng/ml, 1500 to 2000ng/ml, 2000 to 2500ng/ml; or 2500 to 3000ng/ml;

(b) Therapeutic levels of plasma concentrations of the compound of formula I range from about: 600 to 1300ng/ml, 800 to 1250ng/ml, 1000ng/ml to 1250ng/ml, 1250 to 1500ng/ml, 1500 to 2000ng/ml or 2000 to 2500ng/ml; or

(c) Therapeutic levels of plasma concentrations of the compound of formula I range from about: 600 to 1300ng/ml, 800 to 1250ng/ml, 1000ng/ml to 1250ng/ml or 1250 to 1500 ng/ml;

-in an alternative embodiment, the drug or therapeutic combination, drug dosage form, is administered to achieve a daytime therapeutic level range between about 8 to 12 hours time-averaged plasma concentration, wherein the plasma concentration is measured after reaching steady state, and wherein:

[1,2,4] triazolo [1,5-a ] pyridinyl-6-substituted tetrahydroisoquinoline derivatives or compounds of formula I have therapeutic levels at a time-averaged plasma concentration of about 12 hours a day for a range of therapeutic levels: 50. to 4000ng/ml;100 to 3000ng/ml;250 to 1600ng/ml;500 to 1400ng/ml, 600 to 1300ng/ml, 800 to 1250ng/ml, 1000ng/ml to 1250ng/ml, 1250 to 1500ng/ml, 1500 to 2000ng/ml, 2000 to 2500ng/ml;2500 to 3000ng/ml;3000 to 3500ng/ml; or 3500 to 4000ng/ml;

a therapeutic level range of a 12 hour day time-averaged plasma concentration of a (1-azinone) substituted pyridoindole or a compound of formula II is about: 5 to 4000ng/ml, 10 to 1000ng/ml, 10 to 500ng/ml, 25 to 250ng/ml, 50 to 500ng/ml, 50 to 1000ng/ml, 50 to 500ng/ml, 100 to 1000ng/ml, 100 to 500ng/ml, 200 to 1000ng/ml, 500 to 1000ng/ml, 1000 to 2000ng/ml, 2000 to 3000ng/ml or 3000 to 4000ng/ml,

the therapeutic level range for the mean plasma concentration of tesofensine over 12 hours of the day is about: 2ng to 50ng/ml, 5 to 20ng/ml, 6.5 to 15ng/ml, 8 to 12ng/ml or about 10ng/ml, or

The therapeutic levels of diazoxide mean plasma concentrations over a 12 hour day period ranged from about: 10ng/ml to 100ng/ml, 20 to 80ng/ml, 30 to 50ng/ml or about 40ng/ml;

-each drug or active agent of the therapeutic combination, the drug dosage form, the drug delivery device or the manufactured product is delivered to the individual simultaneously or separately, wherein optionally one or each drug or active agent of the therapeutic combination, the drug dosage form, the drug delivery device or the manufactured product is administered in a timed dosing regimen, and/or

-the therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprises formula I or a deuterated derivative of formula I.

In alternative embodiments, there is provided the use of a therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture as provided herein for treating, ameliorating, slowing the progression of, alleviating a symptom of, reducing an adverse event associated with or preventing a disease or condition, including or associated with:

hyperphagia (optionally assessed by HQ-CT),

moderate to severe Binge Eating Disorder (BED),

the symptoms of bulimia nervosa are shown,

the early-onset of the morbid obesity,

nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD),

primary Sclerosing Cholangitis (PSC),

primary Biliary Cholangitis (PBC), inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS),

in the case of type II diabetes mellitus, the disease,

obesity induced by hypothalamic injury,

the state of the art for Obsessive Compulsive Disorder (OCD),

destructive mood disorder (DMDD),

in opposition to contra-sexual disorder (ODD),

the disease of scratching the skin of a patient,

the trichotillomania removal method is adopted,

intermittent rage (IED),

excessive Daytime Sleepiness (EDS),

excessive daytime sleepiness associated with hypersomnia and sleep apnea,

excessive daytime sleepiness associated with hypersomnia,

in the case of hypersomnia, the symptoms of hypersomnia,

the hypersomnia is accompanied by cataplexy,

according to ICSD-3 hypersomnia type 2 (NT 2),

hypersomnia, no cataplexy,

the process of the cataplexy is carried out,

in the case of an idiopathic hypersomnia,

rapid Eye Movement (REM) sleep behavior disorder,

the occurrence of an epileptic seizure is detected,

an epilepsy, addiction or addictive disorder or behavior, wherein optionally the addiction, addictive disorder or addictive behavior is or includes an Internet Gaming Disorder (IGD) or drug addiction, and optionally the drug addiction is or includes cocaine dependence or alcohol dependence,

in Major Depressive Disorder (MDD),

treatment-resistant depression (TRD),

the negative symptoms of schizophrenia are the negative ones,

the treatment of Parkinson's disease is carried out,

the MDD associated with Parkinson's disease,

the general anxiety of the patient is caused by the general anxiety,

social anxiety disorder (social phobia),

the onset of Fibromyalgia (FM),

in the case of diabetic nephropathy, the disease is,

the pain of the lower back is caused by the back pain,

the chronic fatigue syndrome of the human body is shown,

attention Deficit Hyperactivity Disorder (ADHD),

the self-curing disease of the patient is caused by autism,

the system of the Aberger's spectrum,

a gene-confirmed disease or syndrome, wherein optionally said gene-confirmed disease or syndrome is or includes prader-willi syndrome, babybi syndrome, smith-magenis syndrome, 1p36 deletion syndrome, 1ip11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficient obesity, leptin receptor (LEPR) deficient obesity, melanocortin 4 receptor (MC 4R) pathway hybrid obesity, trisomy 21, rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disease, angler syndrome, shaff-poplar syndrome, olblatt genetic osteodystrophy, schirfer-lasel syndrome, maternal 14 disomy, alsetter-rahm syndrome, wilms' tumor, aniridia, genitourinary system abnormalities, mental retardation or WAGR or WAGRO syndrome; delavar syndrome, lorenox-Kastokes syndrome, gilles-Pile syndrome or cerebellar ataxia or Duzier syndrome or myoclonic dystonia epilepsy (MAE), or Niemann-pick disease type C, or Norrin, or Korea-Laudo,

wherein optionally reducing adverse events comprises reducing psychosis, serotonin syndrome, tachycardia, or postural tachycardia syndrome.

In an alternative embodiment, the therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture comprises formula I or a deuterated derivative of formula I.

In alternative embodiments, a therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture as provided herein is provided for treating, ameliorating, slowing the progression of, alleviating the symptoms of, reducing adverse events associated with, or preventing a disease or condition, including or associated with:

hyperphagia (optionally assessed by HQ-CT),

moderate to severe Binge Eating Disorder (BED),

the nervous bulimia nervosa is induced,

the early-onset morbid obesity is caused by obesity,

nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD),

primary Sclerosing Cholangitis (PSC),

primary Biliary Cholangitis (PBC),

inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS),

in the case of type II diabetes mellitus,

obesity induced by hypothalamic injury,

the state of the art for obsessive-compulsive disorder (OCD),

destructive mood disorder (DMDD),

oppositional defiance barrier (ODD),

the disease of scratching the skin of a patient,

the trichotillomania removal method is adopted,

intermittent rage (IED),

excessive Daytime Sleepiness (EDS),

excessive daytime sleepiness associated with hypersomnia and sleep apnea,

excessive daytime sleepiness associated with hypersomnia

in the case of hypersomnia, the symptoms of hypersomnia,

hypersomnia type 1 (NT 1) according to the International Classification of sleep disorders, third edition (ICSD-3)

Hypersomnia with cataplexy

Hypersomnia type 2 (NT 2) according to ICSD-3

Lethargy without cataplexy

Cataplexy

The occurrence of an epileptic seizure is detected,

the occurrence of epilepsy,

an addiction or addiction disorder or behavior, wherein optionally the addiction, addiction disorder or addictive behavior is or comprises an Internet Gaming Disorder (IGD) or a drug addiction, and optionally the drug addiction is or comprises cocaine dependence or alcohol dependence,

in Major Depressive Disorder (MDD),

treatment-resistant depression (TRD),

the negative symptoms of schizophrenia are those of the general type,

the treatment of Parkinson's disease is carried out,

the MDD associated with Parkinson's disease,

the general anxiety of the patient is caused by the general anxiety,

social anxiety disorder (social phobia),

the pain of the Fibromyalgia (FM),

in the case of diabetic nephropathy, the disease is,

the pain of the lower back is caused by the back pain,

the chronic fatigue syndrome of the human body is shown,

attention Deficit Hyperactivity Disorder (ADHD),

the self-curing disease of the patient is caused by autism,

the system of the Aberger's spectrum,

In an alternative embodiment, a method for administering:

(i) Triple monoamine reuptake inhibitors (TRI),

(iii) A diazoxide or a diazoxide preparation which,

(iv) (iv) a therapeutic combination of any one of (i) to (iii),

(iv) A therapeutic combination for use in the methods as provided herein, or

(v) A pharmaceutical composition, medicament, or formulation as provided herein, including a deuterated compound or composition provided herein,

wherein the dosage is determined as follows:

(a) Empirical methods for safe and predictable titration and determination of initial therapeutic dose or determination of minimum therapeutic dose or determination of optimal effective dose; the method comprises the following steps:

1. the test dose (e.g., the dose at which no adverse events were observed or the dose at which minimal adverse events were observed or a safe dose) was administered daily until the patient reached a steady state plasma drug concentration,

2. prior to the next scheduled dose, a blood sample is drawn and the test plasma drug concentration is evaluated,

3. initial treatment dose/day was calculated as follows:

A. for drugs with dose-to-plasma concentration linear relationship, the initial target therapeutic plasma drug concentration is divided by the test plasma drug concentration, and then the dividend is multiplied by the test dose, and

B. for drugs whose dose is non-linear with plasma concentration, the initial target therapeutic plasma drug concentration is divided by the test plasma drug concentration, then the dividend is multiplied by the test dose, and then the product is multiplied by a non-linear exponential factor, optionally the initial target therapeutic plasma drug concentration is a concentration corresponding to: (i) Certain pharmacodynamic efficacy marker levels, such as occupancy of serotonin transporter (SERT or 5-HTT), dopamine transporter (DAT) or norepinephrine transporter (NET) as determined by imaging methods such as Positron Emission Tomography (PET); or, (ii) the lowest effective therapeutic dose as determined by clinical studies.

4. Optionally including:

i. the initial therapeutic dose is administered daily until the patient reaches a steady state plasma drug concentration,

prior to the next scheduled dose, drawing a blood sample and evaluating the current therapeutic plasma drug concentration,

calculating the next treatment target dose/day as follows:

A. for drugs whose dose is linear with plasma concentration, the next target therapeutic plasma drug concentration is divided by the current therapeutic plasma drug concentration, and then the dividend is multiplied by the current therapeutic dose, and

B. for drugs whose dose is non-linear with plasma concentration, the next target therapeutic plasma drug concentration is divided by the current therapeutic plasma drug concentration, then the dividend is multiplied by the current therapeutic dose, and then the product is multiplied by a non-linear exponential factor, and

optionally, reaching steady state after two subsequent measured plasma drug concentration results that are at least one week apart and within the next therapeutic plasma drug concentration target range,

v. and optionally continuing the procedure until a minimum therapeutic dose or an optimally effective dose is reached; or

(b) A model-based method for safe and predictable titration and determination of an initial therapeutic dose and determination of a minimum therapeutic dose or determination of an optimal effective dose, and the method comprises:

1. administering the test dose daily for about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day,

2. withdrawing a first blood sample from about 1 hour to 3 days, 6 hours to 2 days, or about 1 day after administration of the first test dose,

3. withdrawing a second or subsequent blood sample about 1 hour to 28 days, 6 hours to 14 days, 1 day to 7 days, or about 2 days after withdrawing the first or subsequent blood sample,

4. initial treatment start dose/day was calculated as follows:

i. using the initial target treatment plasma drug concentration, test dose administration time, plasma concentration of the blood sample and time at which the blood sample was drawn and a pharmaco-metric model,

and optionally, using the initial target therapeutic plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample, the time at which the blood sample was drawn, the human PK data and the Bayesian pharmacogenomics model,

and optionally including:

i. an initial treatment-initiating dose is administered daily until the individual or patient reaches a steady state plasma drug concentration,

calculating the next treatment target dose/day:

B. for drugs whose dose is non-linear with plasma concentration, the next target therapeutic plasma drug concentration is divided by the current therapeutic plasma drug concentration, and then the dividend is multiplied by the current therapeutic dose, and then the product is multiplied by a non-linear exponential factor, and

continuing the procedure until a minimum therapeutic dose or an optimal effective dose is reached, or

(c) A model-based bayesian adaptive control method for safe and predictable titration and determination of initial treatment dose and determination of minimum treatment dose or determination of optimal effective dose, and the method comprising:

1. administering the test dose once or twice daily for about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day,

2. withdrawing a first blood sample about 1/2 hour to 28 days, 1 hour to 3 days, 6 hours to 2 days, and 1 day after administration of the first test dose,

3. optionally, a second or subsequent blood sample is drawn about 1 hour to 28 days, 6 hours to 14 days, 1 day to 7 days, or about 2 days after the first or subsequent blood sample is drawn,

4. initial treatment start dose/day was calculated as follows:

i. selecting an initial target trough plasma drug concentration or other corresponding PK parameters, e.g., CMAX and other plasma concentrations prior to trough, AUC, etc.),

recording information which may include, but is not limited to, the test dose, the time at which the test dose was administered (recorded in a medical record or electronic diary), the measured plasma drug concentration and the time at which the blood sample was drawn, patient information (e.g., age, weight, height, sex, genetic information of the patient (e.g., CYP450 profile), non-genetic information of the patient, the patient's drug, the patient's health, etc.), the dose strength available,

developing a population PK model as follows:

A. using data from a human population PK study, and

B. using nonlinear mixed effects modeling software (e.g., NONMEM (version 7.2, ICON, ellicott City, MD), phoenix NLME (version 8.1, CERTARA, st. Louis, MO), or other modeling software),

C. estimation methods, such as first order conditional estimation and interaction methods (FOCE-I), bayesian and other similar estimation methods,

D. exploring different structures, growth at different rates and other types of models,

E. selecting a model defined as fully descriptive data of a goodness-of-fit diagnostic map, a comparison based on minimum Objective Function Values (OFV), and an evaluation of estimates of population-fixed and random effect parameters,

F. parameterizing the PK model according to values of clearance rate (CL), distribution volume (V) and absorption rate constant (Ka),

inputting information from i, ii and iii into appropriate portions of pharmacokinetic clinical decision support software, such as MWPharm + + (Mediware, prague, czech Republic), insight Rx (InsightRx, san Francisco, calif.), doseMeRx (DoseMe, queenland, australia) and other software systems),

v. using Bayesian estimation, generating a single parameter estimate and selecting the available dose intensity closest to the initial trough plasma drug concentration target, or optionally, other PK parameter targets that characterize the target therapeutic plasma drug concentration target,

optionally, reaching a steady state for the current dose defined by two subsequently measured plasma drug concentration results, optionally about one week apart, within the current target plasma concentration range,

5. optionally, the next and subsequent doses are calculated as follows:

i. selecting the next target trough plasma drug concentration or other corresponding PK parameters, e.g., CMAX and other plasma concentrations prior to trough, AUC, etc.),

record information that may include, but is not limited to, the current dose, the time at which the test dose was administered (recorded in a medical record or electronic diary), the measured plasma drug concentration and the time at which the blood sample was drawn, patient information (e.g., age, weight, height, sex, genetic information of the patient (e.g., CYP450 profile), non-genetic information of the patient, the drug of the patient, the health of the patient, the dose intensity available

inputting the above i and ii into pharmacokinetic clinical decision support software, such as MWPharm + + (Mediware, prague, czech Republic), insightRx (InsightRx, san Francisco, calif.), doseMeRx (DoseMe, queenland, australia), and appropriate parts of other software systems, using Bayesian estimation to generate a single parameter estimate and selecting the available dose intensity that is closest to the next trough plasma drug concentration target, or optionally, other PK parameter targets that characterize the target therapeutic plasma drug concentration,

optionally, reaching a steady state after two subsequently measured plasma drug concentration results, optionally separated by about one week, within a target range,

optionally, continuing the process until a minimum therapeutic dose or an optimally effective dose at steady state is reached.

In an alternative embodiment, provided are methods of delivering or administering a triple monoamine reuptake inhibitor (TRI) to a subject in need thereof, wherein TRI comprises formula I or a deuterated derivative of formula I, and optionally, TRI comprises tesofensine.

In an alternative embodiment, methods are provided for administering and maintaining an effective dose of:

(i) Triple monoamine reuptake inhibitors (TRI),

(iii) A diazoxide or diazoxide preparation which is,

(iv) (iv) a therapeutic combination of any one of (i) to (iii), or

(iv) A therapeutic combination for use in the methods as provided herein, or

wherein the dose is determined by a method comprising:

(a) Recording the maintenance dose and maintenance therapy plasma drug concentration associated with the lowest effective therapeutic dose or the optimal therapeutic dose, and

(b) At an early stage of about 1 to 12 months, 3 to 9 months, 4 to 8 months or 6 months, or when a change in body weight, medication or health status occurs:

prior to the next scheduled dose, a blood sample is drawn and the current plasma drug concentration is evaluated,

and optionally, if the current plasma drug concentration differs from the maintenance treatment plasma drug concentration by more than about 20%, optionally more than about 50%, calculating a new treatment dose/day by a method comprising:

i. for drugs with a linear dose to plasma concentration relationship, the maintenance treatment plasma drug concentration is divided by the current plasma drug concentration, and then the dividend is multiplied by the maintenance dose,

A. optionally, a steady state is reached after two subsequently measured plasma drug concentration results that are at least one week apart and within about 20% of the maintenance therapeutic plasma concentration, or

B. Optionally, the process is continued until a steady state maintenance therapeutic dose is reached, and

for drugs whose dose is non-linear with plasma concentration, dividing the maintenance treatment plasma drug concentration by the current plasma drug concentration, then multiplying the dividend by the maintenance dose, and then multiplying the product by a non-linear index; or

And optionally using a bayesian adaptive model based method comprising:

(A) Recording the maintenance treatment trough plasma drug concentration, the actual dose, the time of administration of the dose, the current trough plasma concentration of the blood sample measured and/or the time at which the blood sample was withdrawn, patient factors,

(B) Inputting the above into an appropriate section of pharmacokinetic clinical software, and

(C) Using bayesian estimation and generating a single parameter and selecting the dose that will most closely achieve the maintenance treatment trough plasma drug concentration, or

D. Optionally, a steady state is reached after two subsequently measured plasma drug concentration results that are at least one week apart and within about 20% of the maintenance therapeutic plasma concentration, or

E. Optionally, the process is continued until a steady state maintenance therapeutic dose is reached.

In alternative embodiments, TRI comprises formula I or a deuterated derivative of formula I, or TRI comprises tesofensine.

In an alternative embodiment, there is provided a method for treating hyperphagia, hyperphagia in PWS, destructive mood disorder (DMDD), oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, or Binge Eating Disorder (BED), comprising administering formula I or a deuterated derivative of formula I to a subject in need thereof.

In an alternative embodiment, methods are provided for administering formula I or a deuterated derivative of formula I for treating hyperphagia, hyperphagia in PWS, destructive mood disorder (DMDD), oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, or Binge Eating Disorder (BED).

In an alternative embodiment, there is provided a method for treating hyperphagia, hyperphagia in PWS, destructive mood disorder (DMDD), oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, and Binge Eating Disorder (BED) with an oral dosage form of formula I or a deuterated derivative of formula I of the preceding claims, said method comprising administering an oral dosage form that, when administered once or twice daily, provides a trough plasma concentration, a 24 hour mean plasma concentration, a 24 hour time mean plasma concentration, or a 12 hour time-of-day mean plasma concentration of a deuterated derivative of formula I or formula I of the preceding claims of 250ng/mL to 500ng/mL, 500 to 1000ng/mL, 1000 to 1500ng/mL, 1500 to 2000ng/mL, or 1500 to 2500ng/mL, when measured at about one week, about two weeks, or steady state.

In an alternative embodiment, there is provided a method for treating hyperphagia, hyperphagia in PWS, destructive mood disorder (DMDD), oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, and Binge Eating Disorder (BED) with an oral dosage form of formula I or a deuterated derivative of formula I of the preceding claims, said method comprising administering an oral dosage form that when administered once or twice daily provides 150 to 3000ng/ml of the trough plasma concentration, the 24 hour time-averaged plasma concentration, or the 12 hour day time-averaged plasma concentration of a deuterated derivative of formula I or of formula I of the preceding claims when measured at about one week, about two weeks, or steady state.

The details of one or more exemplary embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

All publications, patents, and patent applications cited herein are hereby expressly incorporated by reference in their entirety for all purposes.

Brief Description of Drawings

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the office upon request and payment of the necessary fee.

The drawings set forth herein are illustrative of exemplary embodiments provided herein and are not meant to limit the scope of the invention as encompassed by the claims.

The drawings are described in detail herein.

FIG. 1 illustrates an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5, as described in example 2 below.

FIG. 2 illustrates an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2, as described in example 3 below.

FIG. 3 illustrates an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3, as described in example 4 below.

FIG. 4 illustrates an exemplary scheme for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-1, 1-d 2) pyridin-2 (1H) -one, as described in example 5 below.

FIG. 5 illustrates an exemplary scheme for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-1, 3-d 4) pyridin-2 (1H) -one, as described in example 6 below.

FIG. 6 illustrates an exemplary scheme for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-3, 3-d 2) pyridin-2 (1H) -one, as described in example 7 below.

Fig. 7 illustrates: relationship between plasma concentration of compound of formula I and striatal occupancy of dopamine transporter (DAT) after multiple doses of 10 to 60mg of compound of formula I.

FIGS. 8 and 9 illustrate the relationship between plasma concentration of the compound of formula I and the occupancy of serotonin transporter (SERT) in the striatum and thalamus following multiple doses of 3-60mg of the compound of formula I. Like reference symbols in the various drawings indicate like elements.

FIG. 10 schematically illustrates an exemplary alternative for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-1, 3-d 4) pyridin-2 (1H) -one.

Fig. 11 schematically illustrates an exemplary alternative for the synthesis of exemplary compound P, as discussed in detail in example 8 below.

Figure 12 schematically illustrates the proton NMR spectrum of compound P, as discussed in detail in example 8 below.

Figure 13 schematically illustrates the LCMS spectrum of compound P, as discussed in detail in example 8 below.

FIG. 14 illustrates an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5, 8A and 8B, as described in example 4.1 below.

FIG. 15 schematically illustrates the proton NMR spectrum of compound 8-Boc, as discussed in detail in example 4.1 below.

Figure 16 schematically illustrates the proton NMR spectrum of compound 8A, as discussed in detail in example 4.1 below.

FIG. 17 illustrates an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2, 12A and 12B, as described in example 5.1 below.

Fig. 18 schematically illustrates the proton NMR spectrum of compound 12, as discussed in detail in example 5.1 below.

Figure 19 schematically illustrates the proton NMR spectrum of compound 12A, as discussed in detail in example 5.1 below.

Figure 20 illustrates an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3, 16A and 16B, as described in example 6.1 below.

Fig. 21 schematically illustrates the proton NMR spectrum of compound 16B, as discussed in detail in example 6.1 below.

Figure 22 illustrates summary statistics of the pharmacokinetic parameters of formula I from a single ascending dose PK study in healthy humans.

Figure 23 illustrates a dose scale plot of Cmax for formula I from a single ascending dose PK study in healthy humans.

Figure 24 illustrates a dose scale plot of formula I AUC (0-T) from a single ascending dose PK study in healthy humans.

Figure 25 illustrates the PK profile in a phase I single ascending dose study of formula I.

Fig. 26 illustrates the 3-chamber PK model for formula I.

FIG. 27 illustrates a goodness of fit plot for the population PK model of formula I.

Fig. 28 illustrates the consistency of PK results for the PK model with those determined from data from the human SAD study of formula I.

FIG. 29 illustrates visual predictive examination (VPC) of the layers from the dosage component of formula I

FIG. 30 illustrates Emax model fitting using PK-PD data from example 12.

FIG. 31 illustrates PK/PD model parameters used to model formula I.

FIG. 32 illustrates the C trough levels of formula I required to 30, 45 and 60% DAT receptor occupancy, as discussed in example 16 below.

Figure 33 illustrates a simulation of formula I with respect to the relationship between receptor occupancy and time post-dose (in hours), as discussed in example 16 below.

Figure 34 illustrates simulating personalized dosing based on day 7C trough to estimate day 14 dose change to achieve 30%dat receptor occupancy, as discussed in example 16 below.

Figure 35 illustrates a simulation of achieving 60% dat receptor occupancy of personalized dosing for a 160kg patient, as discussed in example 16 below.

Like reference symbols in the various drawings indicate like elements.

Detailed Description

In an alternative embodiment, novel deuterated [1,2,4] triazolo [1,5-a ] pyridin-6-yl substituted tetrahydroisoquinoline derivatives triple monoamine reuptake inhibitors are provided. In an alternative embodiment, there are provided novel deuterated (1-azzinone) substituted pyridoindole melanin-concentrating hormone receptor 1 (MCHR 1) antagonists or inhibitors.

In alternative embodiments, therapeutic combinations or formulations of drugs are provided that include various combinations of a triple monoamine reuptake antagonist or inhibitor, a melanin concentrating hormone receptor 1 (MCHR 1) antagonist or inhibitor, and a diazoxide or diazoxide choline controlled release agent (DCCR) formulation, in combination with other drugs or active agents. In alternative embodiments, methods of treating various conditions, including genetically confirmed syndromes and diseases, using the therapeutic combinations and formulations of drugs provided herein are provided.

Although the embodiments provided herein are not limited by any particular mechanism of action, there is evidence that although TRI, MCHR1 antagonists and diazoxide target different regions and pharmacological targets in the brain, their effects are complementary, and thus, the discovery described herein for the first time is that administration of TRI, MCHR1 antagonists and diazoxide, or a combination of all three, can provide synergistic benefits to an individual in need thereof, for example, in the treatment of hyperphagia and/or related eating disorders.

Pharmaceutical compositions and formulations

In alternative embodiments, provided herein are medicaments or compounds, or provided herein are medicaments or compounds for use in practicing the methods, formulated for administration by any one or more means, including orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intracerebrally, epidural, intracranial, or rectally. Provided herein are drugs or compounds, or provided herein for use in practicing methods, that may further comprise pharmaceutically acceptable carriers, adjuvants, and excipients. In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, is formulated for parenteral administration, including intrathecal, intracerebral or epidural (into the intrathecal, intracerebral, epidural space), subcutaneous, intravenous, intramuscular, and/or intraarterial administration; for example, by injection routes but also including a variety of infusion techniques. Intra-arterial, intrathecal, intracranial, epidural, intravenous and other injections as used in some embodiments may include administration through a catheter or pump, such as an intrathecal pump or an implantable medical device (which may be an intrathecal pump or catheter).

In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, may be formulated according to conventional procedures appropriate for the desired route of administration. In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, are formulated or manufactured as lyophilizates, powders, lozenges, liposomes, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, may be formulated as preparations for implantation or injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., a sparingly soluble salt). Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. For example, suitable alternative and exemplary formulations for each of these methods of administration can be found, for example, in Remington: the Science and Practice of Pharmacy, eds. Gennaro, 20 th edition, lippincott, williams & Wilkins, philadelphia, pa.

In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, may be formulations for parenteral administration comprising any common excipient, for example, sterile water or saline, polyalkylene glycols such as polyethylene glycol, synthetic or vegetable oils, hydrogenated naphthalenes, and the like. In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, can be biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers, and can be excipients suitable for controlling the release of the active compound.

In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, are administered using parenteral delivery systems, such as ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, intrathecal catheters, pumps, and implants, and/or using liposomes. Formulations for parenteral administration may also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. Formulations for inhalation administration may contain, for example, lactose as excipient, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops or as a gel for intranasal use.

In alternative embodiments, a drug or compound as provided herein, or a composition for performing a method as provided herein, is administered intranasally. When administered by this route, examples of suitable dosage forms are nasal sprays or dry powders, as known to those skilled in the art. For example, nasal formulations may contain conventional surfactants, typically nonionic surfactants. When a surfactant is used in the nasal formulation, the amount present will vary depending on the particular surfactant selected, the particular mode of administration (e.g., drops or spray), and the effect desired.

In alternative embodiments, the drugs or compounds provided herein, or compositions for use in practicing the methods provided herein, are in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol or as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, and isotonic sodium chloride solution. In an alternative embodiment, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In alternative embodiments, fatty acids such as oleic acid find use in the preparation of injectables. Formulations for intravenous administration may comprise solutions in sterile isotonic aqueous buffer. If necessary, the formulation may further comprise a solubilizing agent and a local anesthetic to relieve pain at the injection site. Typically, the ingredients are provided separately or mixed together in unit dosage form, e.g., as a dry lyophilized powder or water free concentrate, in a sealed container such as an ampoule (ampoule/ampoule) or sachet indicating the quantity of active agent. In the case of administration of the compound by infusion, it may be dispensed as a formulation with an infusion bottle containing sterile medical grade water, saline or dextrose/water. When the compounds are administered by injection, an ampule of sterile water for injection or saline may be provided to allow for mixing of the ingredients prior to administration.

In alternative embodiments, the medicaments or compounds provided herein, or compositions for practicing the methods provided herein, further comprise aqueous and non-aqueous sterile injection solutions, which may contain (include) antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and/or aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.

In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, are formulated for topical administration, e.g., in the form of a liquid, lotion, cream, or gel. Topical application may be accomplished by direct application to the treatment area. Such application may be accomplished, for example, by rubbing the formulation (e.g., lotion or gel) onto the skin of the treatment area, or by spray applying a liquid formulation to the application or treatment area.

In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, comprises a bioimplant or bioimplant material, and may also be coated with a compound of the invention or other compounds to improve the interaction between cells and the implant.

In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, comprises a small amount of a wetting or emulsifying agent, or a pH buffering agent.

In an alternative embodiment, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, are formulated as suppositories with conventional binders and carriers such as triglycerides.

In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, comprise oral formulations, such as tablets, pills, lozenges, troches (see, e.g., as described in USPN 5,780,055), aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or gelcaps, gels, jellies, syrups, and/or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, taste masking agents, flavouring agents, colouring agents and preserving agents in order to provide palatable preparations. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate, and the like. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax.

In alternative embodiments, formulations for oral use are hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

In alternative embodiments, a drug or compound provided herein, or a composition for use in practicing a method provided herein, comprises an aqueous suspension comprising an active material in admixture with an excipient suitable for use in the manufacture of aqueous suspensions. Exemplary excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents, for example naturally-occurring phosphatides (for example lecithin), condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (for example heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (for example polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

In alternative embodiments, the medicaments or compounds provided herein, or compositions for practicing the methods provided herein, comprise an oil suspension, which may be formulated by suspending the active ingredient (e.g., a compound of the invention) in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil, such as liquid paraffin. Oral suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

In alternative embodiments, the drugs or compounds provided herein, or compositions for use in practicing the methods provided herein, include agents that control the release of the compounds, thereby providing for timed or sustained release of the compounds.

In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, is formulated or formulated into a multiparticulate and/or solid dispersion formulation, e.g., as described in, e.g., U.S. patent application publication No. 20080118560, e.g., comprising a hydrophobic matrix former, which is a water-insoluble, non-swelling amphiphilic lipid; and a hydrophilic matrix former, which is a meltable water-soluble excipient. In one embodiment, a drug or compound provided herein, or a composition for practicing a method provided herein, is contained in a tablet, pill, capsule, lozenge, etc., comprising any combination of: binders, for example in the form of starch, polyvinylpyrrolidone, gum tragacanth or gelatin; fillers, such as microcrystalline cellulose or lactose; disintegrants, such as crospovidone, sodium starch glycolate, corn starch, and the like; lubricants, such as magnesium stearate, stearic acid, glyceryl behenate; glidants, such as colloidal silicon dioxide and talc; sweetening agents, such as sucrose or saccharin, aspartame, acesulfame potassium; and/or a flavoring agent, such as peppermint, methyl salicylate, or orange flavor. When the dosage unit form is a capsule, it may also contain a liquid carrier, for example, a fatty oil.

In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, comprise (or are contained in or packaged in) a unit dose formulation having a coating, e.g., a coating comprising sugar, shellac, sustained release agents and/or other enteric coating agents, or any pharmaceutically pure and/or non-toxic agent.

In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, comprises a unit dose formulation (or contained or packaged therein), wherein each different compound of the composition or article of manufacture is contained in a different layer of a pill, tablet or capsule, e.g., as described in USPN 7,384,653, e.g., having an outer alkali-soluble layer and an inner acid-soluble layer. In an alternative embodiment, a drug or compound provided herein, or a composition for practicing a method provided herein, comprises a unit dose formulation (or contained or packaged therein), wherein each of the different compounds of the composition or article of manufacture is contained in a liquid or gel of different viscosity, such as described in U.S. patent application publication No. 20050214223. In alternative embodiments, the drugs or compounds provided herein, or compositions for practicing the methods provided herein, comprise (or are contained or packaged in) unit dose formulations having a reduced potential for abuse, e.g., as described in U.S. patent application publication No. 20040228802, e.g., comprising a bittering agent, a bright deterrent/indicator dye, or a fine insoluble particulate matter.

Carrier

In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, comprises or is formulated with or as an aqueous or non-aqueous solution, suspension, emulsion, and solid. Examples of non-aqueous solvents suitable for use as disclosed herein include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. In alternative embodiments, the aqueous carrier may comprise water, ethanol, an alcohol/water solution, glycerol, an emulsion, and/or a suspension, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.

In alternative embodiments, liquid carriers are used in the manufacture or formulation of the drugs or compounds provided herein, or compositions for use in practicing the methods provided herein, including carriers for preparing solutions, suspensions, emulsions, syrups, elixirs, and pressurized compounds. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers or osmo-regulators.

In alternative embodiments, liquid carriers for making or formulating the compounds of the present invention include water (partially containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier may also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers in the form of sterile liquids are useful which contain the compounds for parenteral administration. The liquid carrier for the pressurized compounds disclosed herein may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

In alternative embodiments, solid carriers are used in the manufacture or formulation of a drug or compound provided herein, or compositions for use in practicing methods provided herein, including solid carriers comprising materials such as lactose, starch, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, mannitol, and the like. Solid carriers may also include one or more substances that act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it may also be an encapsulating material. In powders, the carrier may be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression characteristics in suitable proportions and compacted in the shape and size desired. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine (polyvinylpyrrolidine), low melting waxes, and ion exchange resins. Tablets may be prepared by compression or moulding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, crospovidone, croscarmellose sodium), surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating to provide release in parts of the intestinal tract other than the stomach.

In alternative embodiments, parenteral carriers are used in the manufacture or formulation of the medicaments or compounds provided herein, or compositions for use in practicing the methods provided herein, including parenteral carriers suitable for use as disclosed herein, including but not limited to sodium chloride solution, ringer's dextrose, dextrose and sodium chloride, ringer's lactate, and fixed oils. Intravenous carriers may include fluid and nutrient supplements, electrolyte supplements such as those based on ringer's dextrose, and the like. Preservatives and other additives may also include, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

In alternative embodiments, the carrier used to manufacture or formulate a drug or compound provided herein, or a composition for practicing a method provided herein, can be mixed with disintegrants, diluents, granulating agents, lubricants, binders, and the like as desired using conventional techniques known in the art. The carrier may also be sterilized by methods that do not deleteriously react with the compound, as is generally known in the art.

The invention also provides compositions, including pharmaceutical compositions and formulations, and kits containing (comprising) a drug or compound provided herein or for use in practicing methods provided herein. By way of example only, a kit or article of manufacture may comprise a container (e.g., a bottle) with a desired amount of a compound (or pharmaceutical composition of a compound) described herein. Such kits or articles of manufacture may further comprise instructions for using the compounds (or pharmaceutical compositions of compounds) described herein. The instructions may be attached to the container or may be included in a package (e.g., a box or plastic or aluminum foil bag) that holds the container.

The drugs or compounds provided herein, or compositions for practicing the methods provided herein, can be delivered to the body or targeted to a particular tissue or organ (e.g., muscle or brain) by any method or protocol, including, for example, ex vivo "cell loading" with a drug or compound provided herein or a composition for practicing the methods provided herein, wherein the "loaded cells" are administered intramuscularly, or intrathecally, intracerebrally, or epidurally, into the Central Nervous System (CNS), e.g., as described in U.S. patent application publication No. 20050048002.

In an alternative embodiment, a drug or compound provided herein, or a composition for performing a method provided herein, is first lyophilized and then suspended in a hydrophobic medium, e.g., comprising aliphatic, cyclic, or aromatic molecules, e.g., as described in U.S. patent application publication No. 20080159984.

In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, comprises or is formulated into a pharmaceutically acceptable salt. Pharmaceutically acceptable salts may include suitable acid addition or base salts thereof. In an alternative embodiment, the compounds may be formulated as described in Berge et al, J Pharm Sci,66,1-19 (1977).

In alternative embodiments, a drug or compound provided herein, or a composition for practicing a method provided herein, is formulated as a salt, for example, formed with: strong mineral acids such as mineral acids, for example hydrohalic acids such as hydrochlorides, hydrobromides and hydroiodides, sulfuric acid, phosphoric acid sulfates, hydrogen sulfates, hemisulfates, thiocyanates, persulfates and sulfonic acids; strong organic carboxylic acids, such as unsubstituted or substituted (e.g. by halogen) alkane-carboxylic acids of 1 to 4 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, e.g. unsubstituted or substituted (e.g. by halogen) ₁ -C ₄ ) Alkyl or aryl sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. The compounds of the invention also include pharmaceutically unacceptable salts, for example, salts may still be of value as intermediates in synthetic or analytical processes or protocols.

In alternative embodiments, the compounds, active agents or medicaments provided herein or for use in the practice of the methods provided herein include any acceptable salt, such as acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cypionate, glucoheptonate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmitate, pectate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivalate (pivalate), camphorate, undecanoate and succinate, organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric acid and sulfonic acid. Pharmaceutical compositions as disclosed herein may be prepared according to methods well known and routinely practiced in the art. See, e.g., remington, the Science and Practice of Pharmacy, mack Publishing Co., 20 th edition, 2000; and Sustained and Controlled Release Drug Delivery Systems, eds. J.R. Robinson, marcel Dekker, inc., new York,1978.

In some embodiments, the compounds, active agents, or medicaments provided herein or for use in performing the methods provided herein are provided in the form of pharmaceutically acceptable salts, including amines that are basic in nature and can be reacted with inorganic or organic acids to form pharmaceutically acceptable acid addition salts; for example, such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, and organic acids such as p-toluenesulfonic, methanesulfonic, oxalic, p-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acids, and related inorganic and organic acids; <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -1,4- , -1,6- , , , , , , , , , , , , , , , , β. - , , , , , , -1- , -2- , , , , , - -b- , , , - , , , , , . </xnotran>

In alternative embodiments, the compounds, active agents, or drugs provided herein or used in the practice of the methods provided herein include compositions manufactured under "good manufacturing practice" or GMP or "current good manufacturing practice" (cGMP) conditions.

Derivatized and deuterated compounds

In alternative embodiments, the compounds, active agents, or drugs provided herein or used to practice the methods provided herein are derivatized analogs, such as metabolic blocking or otherwise altered derivatives, including deuterated, hydroxylated, fluorinated, or methylated analogs or derivatives, or any combination thereof.

With respect to the deuterated compounds provided herein or used in the practice of the methods provided herein, it will be recognized that some variation in the abundance of natural isotopes will occur in the synthetic compounds depending on the source of the chemical materials used in the synthesis. Thus, a preparation of the compound will inherently contain a small amount of deuterated isotopologues. For compounds, including pharmaceutical preparations and formulations, provided herein or for use in practicing the methods provided herein, when a particular position is designated as having deuterium ("-D"), it is understood that the abundance of deuterium at that position is greater than or significantly greater than the natural abundance of deuterium (which is 0.015%). For example, alternative embodiments of the invention include a drug or compound provided herein, or an analog of a drug or compound for use in practicing the methods provided herein, said analog having deuterium of greater than 0.02% or greater than about 0.1%. In one embodiment, deuterium substitution or "enrichment" occurs at one or more specific positions. In one embodiment, deuterium enrichment is not less than about 1%, 10%, 20%, 50%, 70%, 80%, 90% or 95% or more or between about 1% and 100%.

In one embodiment, a deuterated (or otherwise substituted) compound provided herein or used to practice a method provided herein has a slower metabolic rate, e.g., a slower rate of hydroxylation, than a corresponding protonated (non-deuterated, non-substituted) compound.

With respect to providing a new site for deuteration of formula II, it was found that an important metabolic pathway of formula II includes its N-acetylation by N-acetyltransferase 2 (NAT-2), which produces 1- (2-acetyl-5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl) -4- ((5-fluoropyridin-2-yl) methoxy) pyridin-2 (1H) -one, i.e. the following structure:

in phase I clinical trials, the amount of this metabolite was found to be very large compared to the parent compound of formula II in healthy volunteers. This metabolite does not contribute to the pharmacology of MCHR1 antagonism. It is expected that combining formula II with a NAT-2 inhibitor (e.g., acetaminophen) can reduce this metabolite and increase the effective concentration of formula II in the patient, thereby reducing the required dose. By replacing the hydrogen with deuterium on the carbon adjacent to the nitrogen being acetylated (see, e.g., examples 5-7), the acetylation process can be slowed to reduce the formation of this metabolite.

Stereoisomers

In alternative embodiments, a compound, active agent, or drug provided herein or used in the practice of the methods provided herein exists as a separate, corresponding stereoisomer (including the stereoisomers) substantially free of another possible stereoisomer. In alternative embodiments, the term "substantially free of other stereoisomers" as used herein means that less than about 15%, 20%, 25%, 30%, 35%, 40%, 50%, or 55% of the other stereoisomers, or less than about 10% of the other stereoisomers, or less than about 5% of the other stereoisomers, or less than about 2% of the other stereoisomers, or less than about 1% or less of the other stereoisomers, or less than "X"% of the other stereoisomers (where X is a number between 0 and 100, inclusive). Methods of obtaining or synthesizing individual enantiomers of a given compound are known in the art and may be applied, where applicable, to the final compound or starting materials or intermediates.

Application method

In alternative embodiments, provided herein are drugs or compounds, or provided herein are drugs or compounds for use in practicing the methods, administered by any one or more means, including orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intracerebrally, epidural, intracranial, or rectally. Provided herein are drugs or compounds, or for use in practicing methods, that are administered with pharmaceutically acceptable carriers, adjuvants, and vehicles. In alternative embodiments, a drug or compound provided herein, or a composition for performing a method provided herein, is administered intrathecally, intracerebrally, or epidurally (into the intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly, and/or intraarterially; for example, by injection routes but also including various infusion techniques. Intra-arterial, intrathecal, intracranial, epidural, intravenous and other injections may include administration through a catheter or pump, such as an intrathecal pump or an implantable medical device (which may be an intrathecal pump or catheter).

In alternative embodiments, the therapeutic combination of the medicament, pharmaceutical composition, preparation and kit may be administered by any known method or route, including by intranasal, intramuscular, intravenous, topical or oral routes, or combinations thereof.

One embodiment includes an article of manufacture comprising a pharmaceutical composition or formulation, a blister pack, a lidded blister or blister card or pack, a flip, tray or shrink wrap or kit comprising: a therapeutic combination of a medicament, pharmaceutical composition or preparation for oral administration as provided herein.

In alternative embodiments, the individual ingredients may be formulated, for example for topical application, for oral or topical application, although all of the ingredients may be in a blister pack, lidded blister or blister card or pack, flip, tray or shrink wrap, or kit. Each component may be packaged individually or may be formulated as a unit dose, for example, as a tube (e.g., with gel, lotion, etc.), ampoule, blister pack, or the like.

Dosage form

In alternative embodiments, the drugs or compounds provided herein, or compositions for use in practicing The methods provided herein, are formulated and administered in a variety of different dosages and treatment regimens depending on The disease or condition to be ameliorated, the condition of The individual to be treated, the goals of The treatment, and The like, as routinely determined by The clinician, see, e.g., the latest edition of Remington: the Science and Practice of Pharmacy, mack Publishing co.

In alternative embodiments, an effective amount of a drug or compound provided herein, or a composition for practicing a method provided herein, including stereoisomers, salts, hydrates, or solvates, is from about 0.1mg to about 20.0mg per kg of body weight of an individual or subject (e.g., patient). In another variation, the effective amount is from about 0.1mg to about 10.0mg per kg of body weight of the individual or subject (e.g., patient) or from about 0.1mg to about 5.0mg per kg of body weight of the patient. Alternatively, the effective amount is from about 0.2mg to about 2mg per kg body weight of the individual or subject (e.g., patient).

In alternative embodiments, an effective amount of a drug or compound provided herein, or a composition for practicing a method provided herein (e.g., as a solid dose, such as a pill, tablet, or lozenge), is from about 0.1mg to about 2.0mg per kg body weight of the individual, subject, or patient; or from about 0.1mg to about 1.0mg per kg body weight; or about 0.1mg, about 0.15mg, about 0.2mg, about 0.25mg, about 0.3mg, about 0.35mg, about 0.4mg, about 0.45mg, about 0.5mg, about 0.55mg, about 0.6mg, about 0.65mg, about 0.7mg, about 0.75mg, about 0.8mg, about 0.85mg, about 0.9mg, about 0.95mg, or about 1.0mg per kg body weight; or an effective amount of a drug or compound provided herein, or a composition for practicing a method provided herein, is about 0.1mg, about 0.15mg, about 0.2mg, about 0.25mg, or about 0.3mg per kg body weight.

In alternative embodiments, an effective amount of a drug or compound provided herein, or a composition for practicing a method provided herein (e.g., as a solid dose, such as a pill, tablet, or lozenge) is from about 1mg to about 400mg; or a solid dosage form comprising from about 1mg to about 250 mg; or the solid dosage form comprises from about 5mg to about 150mg; or a solid dosage form (e.g., as a pill, tablet, or lozenge) comprising from about 1mg to about 75mg; or the solid dosage form comprises about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70 mg, or about 75mg.

Method for safe and predictable titration to effective doses

In an alternative embodiment, an empirical method is provided for safe and predictable titration and determination of an initial therapeutic dose for any single drug used in the methods provided herein (e.g., when the drugs are used alone), or for any combination of drugs provided herein, or for determining a minimum therapeutic dose, or for determining an optimal effective dose; the method comprises the following steps:

a. daily administration of a test dose (e.g., a dose at which no adverse event is observed or a dose at which minimal adverse event is observed or a safe dose) until the patient reaches a steady state plasma drug concentration,

b. prior to the next scheduled dose, a blood sample is drawn and the test plasma drug concentration is evaluated,

c. initial treatment dose/day was calculated as follows:

1. for drugs with dose-to-plasma concentration linear relationship, the initial target therapeutic plasma drug concentration is divided by the test plasma drug concentration, and then the dividend is multiplied by the test dose, and

2. for drugs whose dose is non-linear with plasma concentration, the initial target therapeutic plasma drug concentration is divided by the test plasma drug concentration, then the dividend is multiplied by the test dose, and then the product is multiplied by a non-linear exponential factor, optionally the initial target therapeutic plasma drug concentration is a concentration corresponding to: (i) Certain pharmacodynamic efficacy marker levels, such as occupancy of serotonin transporter (SERT or 5-HTT), dopamine transporter (DAT) or norepinephrine transporter (NET) as determined by imaging methods such as Positron Emission Tomography (PET); or, (ii) the lowest effective therapeutic dose as determined by clinical studies.

d. Optionally comprising:

calculating the next treatment target dose/day as follows:

1. for drugs whose dose is linear with plasma concentration, the next target therapeutic plasma drug concentration is divided by the current therapeutic plasma drug concentration, and then the dividend is multiplied by the current therapeutic dose, and

2. for drugs whose dose is non-linear with plasma concentration, the next target therapeutic plasma drug concentration is divided by the current therapeutic plasma drug concentration, then the dividend is multiplied by the current therapeutic dose, and then the product is multiplied by a non-linear exponential factor, and

continuing the procedure until a minimum therapeutic dose or an optimal effective dose is reached.

In an alternative embodiment, a model-based method for safe and predictable titration and determination of initial therapeutic dose and determination of lowest therapeutic dose or determination of optimal effective dose is provided and comprises:

a. administering the test dose daily for about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day,

b. withdrawing a first blood sample from about 1 hour to 3 days, 6 hours to 2 days, or about 1 day after administration of the first test dose,

c. withdrawing a second or subsequent blood sample about 1 hour to 28 days, 6 hours to 14 days, 1 day to 7 days, or about 2 days after withdrawing the first or subsequent blood sample,

d. initial treatment initiation dose/day was calculated as follows:

i. using the initial target treatment plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample and the time at which the blood sample was drawn and a pharmaco-metric model,

and optionally, using the initial target therapeutic plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample, the time at which the blood sample was drawn, the human PK data and the Bayesian pharmaco-metric model,

and optionally, using the initial target treatment plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample, the time at which the blood sample was drawn, the human PK data, the patient's genetic information, the patient's non-genetic host factors, the patient's other drugs, and a Bayesian pharmaco-metric model,

e. and optionally including:

i. an initial treatment-initiating dose is administered daily until the patient reaches a steady state plasma drug concentration,

calculating the next treatment target dose/day:

2. for drugs whose dose is non-linear with plasma concentration, the next target therapeutic plasma drug concentration is divided by the current therapeutic plasma drug concentration, and then the dividend is multiplied by the current therapeutic dose, and then the product is multiplied by a non-linear exponential factor, and

In an alternative embodiment, there is provided a method of maintaining an effective dose, wherein the method comprises:

(a) Recording the maintenance dose and maintenance therapy plasma drug concentration associated with the lowest effective therapeutic dose or the optimal therapeutic dose,

(b) At an early stage of about 1 to 12 months, 3 to 9 months, 4 to 8 months or 6 months or when a change in body weight, medication or health status occurs:

1. before the next scheduled dose, a blood sample is drawn and the current plasma drug concentration is evaluated

2. If the current plasma drug concentration differs from the maintenance treatment plasma drug concentration by more than about 20%, optionally more than about 50%, a new treatment dose/day is calculated by a method comprising:

i. for drugs whose dose is linear with plasma concentration, dividing the maintenance therapy plasma drug concentration by the current plasma drug concentration, and then multiplying the dividend by the maintenance dose, and

for drugs whose dose is non-linear with plasma concentration, dividing the maintenance treatment plasma drug concentration by the current plasma drug concentration, then multiplying the dividend by the maintenance dose, and then multiplying the product by a non-linear index, or

Optionally, a steady state is reached after two subsequently measured plasma drug concentration results that are at least one week apart and within about 20% of the maintenance treatment plasma concentration, or

Optionally, continuing the process until a steady state maintenance therapeutic dose is reached.

In alternative embodiments, it may be desirable to round the lowest therapeutic or optimally effective dose to the nearest available dose. For example, a calculation may determine that the optimal effective dose is 23 mg/day, but the closest available dose may be only 20mg. Thus, the patient will only be administered 20 mg/day.

In an alternative embodiment, a pharmacokinetic modeling and modeling method of formula I is provided that includes using human PK data, as described sequentially in fig. 25-29. The 3-chamber model best describes human PK data. The inter-patient variability in healthy volunteers was 20.2%. Visual predictive inspection (VPC) charts indicate that the final model is unbiased. In an alternative embodiment, is a population PK/PD model of formula I using human PK data as described in figure 30 and figure 31.

In an alternative embodiment, a PK-guided precision dosing method using the pharmacokinetic modeling and simulation method described above or a similar modeling and simulation method and a population PK/PD model of formula I is provided for treating hyperphagia, hyperphagia in PWS, destructive mood disorder (DMDD), oppositional Defiant Disorder (ODD), obesity in hypothalamic injury-induced obesity, and Binge Eating Disorder (BED) in oral doses of formula I.

Packaging and drug delivery system

In alternative embodiments, therapeutic combinations, preparations, formulations and/or kits are provided comprising a combination of ingredients as described herein. In one aspect, each member of the combination of ingredients is manufactured in a separate package, kit, or container; alternatively, all or a portion of the ingredients are combined and manufactured in separate packages or containers. In alternative aspects, the package, kit or container comprises a blister pack, flip, tray, shrink wrap, or the like.

In one aspect, the package, kit or container comprises a "blister pack" (also referred to as a blister pack or foam pack). In alternative embodiments, therapeutic combinations, preparations, formulations and/or kits are provided that are manufactured as "blister packs" or as a plurality of packets, including lidded blister packs, lidded blister or blister cards or packages or packets, or shrink-wrap.

In one aspect, the blister package is made up of two separate elements: a clear or closed plastic cavity shaped to fit the product, and a blister foil backing therefor. The two components are then sealed together to form a blister strip of one or more blisters, each blister having a unit dose protected from the environment (e.g., moisture, pathogens, light). One or more blister strips may be further connected to a sheet material that allows the product to be packaged, handled, hung, displayed or transported without damaging the blister seal and providing child-resistance. Exemplary types of "blister packs" include: face seal blister pack, combination (gang run) blister pack, simulated blister pack, interactive blister pack, slide blister pack.

Blister packs, flaps or trays are a form of packaging for goods; thus, there is provided a blister pack, flip, or tray comprising a composition as provided herein (e.g., a combination of active ingredients (such as a multi-component combination of medicaments as provided herein)). The blister pack, flip cover or tray may be designed to be non-reclosable so that the consumer can determine whether the package has been opened. They are used to package goods for sale where product tampering is a consideration, such as pharmaceutical products provided herein. In one aspect, the blister pack provided herein comprises a molded PVC substrate having a raised area ("blister") to accommodate a tablet, pill, etc. comprising the combination provided herein, covered by a foil laminate. The tablets, pills, etc. are removed from the pack by peeling the foil back or by pushing the blister to force the tablets to break the foil. In one aspect, a particular form of blister pack is a stick pack. In one aspect, in the uk, the blister pack conforms to uk standard 8404.

In an alternative embodiment, laminated aluminum foil blister packs are used, for example, to prepare medicaments that are designed to dissolve immediately in the mouth of a patient. This exemplary method includes preparing the pharmaceutical combinations, therapeutic combinations, and pharmaceutical dosage forms provided herein as aqueous solutions that are dispensed (e.g., in measured doses) into the aluminum (e.g., aluminum foil) laminate tray portion of the blister pack. This tray was then freeze dried to form tablets having a blister pocket shape. The aluminium foil laminate of both the tray and the lid completely protects any individual dose which is highly hygroscopic and/or sensitive. In one aspect, the package comprises a child resistant security laminate. In one aspect, the system provides an identifying mark for a tablet by embossing a design into an aluminum foil pouch that is occupied by the tablet as it changes from an aqueous state to a solid state. In one aspect, separate 'push-in' blister packs/sachets are used, for example using a hard tempered aluminium (e.g. aluminium foil) lidding material. In one aspect, a hermetic high barrier aluminum (e.g., aluminum foil) laminate is used. In one aspect, any of the articles of manufacture provided herein, including kits or blister packs, use the foil laminates and stick packs, pouches and bags, combination foils, papers, and films for the peelable and non-peelable laminates of the high barrier packages.

In alternative embodiments, any of the articles of manufacture provided herein, including kits or blister packs, include memory aids that help remind patients when and how to take medications. This preserves the efficacy of the drug by protecting each pill prior to administration; the product or the kit has portability and is convenient to take at any time and any place.

In alternative embodiments, the pharmaceutical combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices, and articles of manufacture provided herein use child-resistant and geriatric friendly packaging, such as packaging that complies with U.S. government minimum finger and grip strength child-resistant packaging regulations. For example, in an alternative embodiment, foil-only pill packaging is used.

In an alternative embodiment, the pharmaceutical combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices, and articles of manufacture provided herein place tablets, capsules, pills, or equivalents on a blister card or equivalent to track usage. By tracking usage, the blister card monitor can remind the patient and/or primary care giver to take (or have taken) medication at the correct time, such as in the morning and/or afternoon; and may facilitate discussion with healthcare professionals to determine and overcome compliance barriers.

In alternative embodiments, patient usage is monitored by using a custom made blister card or using an Electronic Compliance Monitor (ECM) system (Intelligent Devices secc inc. (IDI), grand Cayman, cayman island) or equivalent. For example, in an alternative embodiment, the blister card or equivalent contains electronic components that detect, record, protect and/or transmit the removal of the medication from the blister card or equivalent. For example, a sensor detects the removal of a medication from a blister card or equivalent, and this information may be transmitted to a remote location for review by, for example, a medication provider and/or a primary care facility or individual. Data transmission data may be downloaded to a transmission and/or storage device through hard contact, and the data may be remotely scanned and downloaded using a Radio Frequency Identification (RFID) chip, tag or device or equivalent operatively connected to a computer and/or cell phone or other device. Radio frequency identification uses electromagnetic fields to automatically identify and track tags attached to objects, where the tags contain electronically stored information, in this embodiment, whether and/or when to remove medication from each compartment of a blister card or equivalent, or to a Near Field Communication (NFC) enabled mobile device or handset. NFC is a set of communication protocols that enables two electronic devices, one of which is typically a portable device such as a smartphone, to establish communication by keeping them within 4 centimeters (1.6 inches) of each other.

In alternative embodiments, the multi-drug delivery system used in the methods provided herein may comprise the use of a cartridge to house or enclose a drug delivery device or package, blister pack, flip, or tray provided herein, wherein in this exemplary delivery system, one week of drug dosage forms (e.g., one, two, or three or more tablets, pills, capsules, gelcaps, or equivalents) are stored in four rows, two administration rows (for opening and self-administration by a user, e.g., a patient) for morning or breakfast or morning administration, and two rows for evening, evening or afternoon administration; morning or breakfast or morning administration lines are clearly separated from evening, dinner time or afternoon administration lines, and the daily and ready-to-use doses are arranged in columns. In an alternative embodiment, the blister pack, flap or tray is physically connected to the storage box, wherein the blister pack, flap or tray slides into and out of the storage box, and in an alternative embodiment, the afternoon group in the row may be folded over the morning group in the row for reinserting the blister pack, flap or tray into the storage box, if necessary. In an alternative embodiment, the storage case includes a sensor to detect the removal of the medication from each compartment (e.g., which compartment is open and when) and this information can be transmitted to a remote location, such as by Near Field Communication (NFC) to an NFC enabled mobile device or handset, for example for review by a medication provider and/or primary care facility or individual.

In any embodiment of the methods provided herein, the plasma concentration of the drug or therapeutic combination, drug dosage form is: (a) Trough level or trough concentration (C) _Grain ) Or in application ofThe lowest concentration reached with the drug or therapeutic combination or pharmaceutical dosage form prior to the second dose or the next dose, or (b) as determined from a blood sample taken from about 0.5 to 24 hours, or 4 to 12 hours, or 1,2,3,4, 5,6, 7, 8,9, or 10 or more hours after the last administration or administration of the drug or therapeutic combination, pharmaceutical dosage form.

In alternative embodiments, "individualized dosing" and "PK-directed dosing," "precision dosing" are interchangeable terms, meaning that each patient is administered according to the PK profile of the drug in the patient.

In an alternative embodiment, the terms "plasma concentration", "plasma drug concentration", "serum drug concentration", "plasma level", "level" in the context of drug concentration are interchangeable and mean the drug concentration in humans or animals and are measured and interpreted by a person skilled in the art, see Loftsson t.

In alternative embodiments, the "target therapeutic plasma drug concentration" or similar term is within the therapeutic plasma range, optionally near the midpoint of the therapeutic level range of plasma concentrations. For example, if the treatment used to treat PWS, i.e., the effective or productive plasma concentration range, is between 1000ng/ml to 1400ng/ml, the target therapeutic plasma drug concentration may be the midpoint of about 1000ng/ml, about 1300ng/ml, or optionally about 1200 ng/ml.

In an alternative embodiment, treatment in the context of plasma concentrations means effective or effective treatment of a medical condition.

Any of the above aspects and embodiments may be combined with any of the other aspects or embodiments disclosed herein in the summary, figures, and/or the detailed description section.

As used in this specification and the claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, the term "or" is understood to be inclusive and encompasses both "or" and "unless specifically stated or apparent from the context.

Unless otherwise indicated or apparent from the context, the term "about" as used herein is understood to be within the normal tolerance of the art, e.g., within 2 standard deviations of the mean. About (using the term "about") can be understood to be within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. All numerical values provided herein are modified by the term "about," unless the context clearly dictates otherwise.

As used herein, the terms "substantially all," "substantially most," "substantially all," or "most" encompass at least about 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% or more of the reference amount of the composition, unless specifically stated or apparent from the context. For example, in alternative embodiments, the term "substantially pure" refers to a chemical purity, e.g., a "substantially pure" compound (e.g., comprising formula I) as provided or used in a therapeutic formulation or combination provided herein is at least about 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% pure or free of contaminants or other forms, e.g., free of any form other than the S-enantiomer of formula I.

Each patent, patent application, publication, and document cited herein is hereby incorporated by reference in its entirety. The citation of the above patents, patent applications, publications and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of such publications or documents. The incorporation of these documents by reference alone should not be construed as an assertion or admission that any portion of the contents of any document is deemed to be essential material for meeting the statutory disclosure requirements of any country or region for a patent application. Nevertheless, the right to rely on any such documents, where appropriate, is retained to provide material that is deemed essential to the claimed subject matter by the reviewing authorities or courts.

Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the present invention has been described in considerable detail with reference to one or more specific embodiments, those of ordinary skill in the art will recognize that changes can be made to the embodiments specifically disclosed in this application, and that such modifications and improvements are within the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element which is not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," consisting essentially of, \8230; … "consisting of, \8230; consisting of" can be replaced by either of the other two terms. Accordingly, the terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims.

The invention will be further described with reference to the examples described herein; however, it should be understood that the invention is not limited to such embodiments.

Examples

Example 1: exemplary methods of treating prader-willi syndrome by administering formula I or a deuterated analog thereof

This example describes exemplary methods and compositions for treating prader-willi syndrome by administering pharmaceutical compositions comprising formula I or 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline.

Male and female patients (4 years and older) with a history of PWS confirmed by genetic testing were selected for treatment.

The patient is administered a low (optionally sub-therapeutic) dose of the pharmaceutical composition of 1mg to 20mg per day for one day, one week, two weeks, three weeks or four weeks. Periodically collecting blood samples to determine the drug concentration at steady state and to determine the latest target dose required to achieve dopamine transporter (DAT) occupancy between 15% and 75%, whether or not by means of a pharmaco-metric modeling method that also utilizes pharmacokinetic/pharmacodynamic (PK/PD) data; optionally, determining the most recent target dose by reaching a plasma drug concentration value between 100ng/ml and 4000ng/ml at steady state; optionally, determining the most recent target dose by reaching a plasma drug concentration value between 200ng/ml and 2000ng/ml at steady state; optionally, the most recent target dose is determined by reaching a plasma drug concentration value between 400ng/ml and 2000ng/ml at steady state. Every 3 or 6 months, or when there are significant changes in patient medication, body weight and other physical changes that affect drug absorption and metabolism, the blood level will be re-measured to adjust the dosage as necessary; optionally, the patient will start a low dose of between 5mg and 20mg per day and gradually increase the dose at 5mg or 10mg or 20mg intervals until efficacy on hyperphagia and/or neuropsychiatric and behavioral symptoms is safely achieved. The clinician can accelerate the titration, slow the titration if necessary, and later re-accelerate the titration depending on the patient's tolerance.

Example 2: treatment of hypothalamic obesity or hypothalamic injury induction by administering formula I or any deuterated analog thereof Exemplary method of obesity

This example describes exemplary methods and compositions for treating hypothalamic obesity or hypothalamic injury-induced obesity by administering a pharmaceutical composition comprising formula I or 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline.

Male and female patients (4 years and older) diagnosed with hypothalamic injury-induced obesity were selected for treatment.

The patient is administered a low (optionally sub-therapeutic) dose of the pharmaceutical composition of 1mg to 20mg per day for one, two, three or four weeks. Periodically collecting blood samples to determine the drug concentration at steady state and to determine the latest target dose required to achieve a DAT occupancy between 15% and 75%, whether or not by means of a pharmaco-metric modeling method that also utilizes PK/PD data; optionally, determining the most recent target dose by reaching a plasma drug concentration value of between 100ng/ml and 4000ng/ml at steady state; optionally, determining the most recent target dose by reaching a plasma drug concentration value of between 200ng/ml and 2000ng/ml at steady state; optionally, the most recent target dose is determined by achieving a plasma drug concentration value of between 400ng/ml and 2000ng/ml at steady state, optionally, between about 400ng/ml and 2000ng/ml at steady state. Every 3 or 6 months, or when there are significant changes in patient medication, body weight and other physical changes that affect drug absorption and metabolism, the blood level will be re-measured to adjust the dosage as necessary; optionally, the patient will start a low dose of between 5mg and 20mg per day and gradually increase the dose at 5mg or 10mg or 20mg intervals until efficacy on hyperphagia and/or neuropsychiatric and behavioral symptoms is safely achieved. The clinician can accelerate the titration, slow the titration if necessary, and later re-accelerate the titration depending on the patient's tolerance.

Example 3: exemplary methods for treating Binge Eating Disorder (BED) by administering formula I or any deuterated analog thereof

This example describes exemplary methods and compositions for treating Binge Eating Disorder (BED)

The following were selected for treatment: male and female patients with BED diagnosed according to DCM-IV (DSM-IV: manual for diagnosis and statistics of psychiatric disorders, fourth edition), optionally male and female patients with BED diagnosed according to DCM-IV and Major Depressive Disorder (MDD) diagnosed according to DCM-IV; optionally, the BED is a refractory BED, optionally, the MDD is a refractory MDD, optionally, the diagnosis of the MDD involves an interview of video recordings.

The patient is administered a low (optionally sub-therapeutic) dose of the pharmaceutical composition of 1mg to 20mg per day for one day, one week, two weeks, three weeks or four weeks. Periodically collecting blood samples to determine the drug concentration at steady state and to determine the latest target dose required to achieve a DAT occupancy between 15% and 75%, whether or not by means of a pharmaco-metric modeling method that also utilizes PK/PD data; optionally, determining the most recent target dose by reaching a plasma drug concentration value between 100ng/ml and 4000ng/ml at steady state; optionally, determining the most recent target dose by reaching a plasma drug concentration value between 200ng/ml and 2000ng/ml at steady state; optionally, the most recent target dose is determined by reaching a plasma drug concentration value between 400ng/ml and 2000ng/ml at steady state. Every 3 or 6 months, or when there are significant changes in patient medication, body weight and other physical changes that affect drug absorption and metabolism, the blood level will be re-measured to adjust the dosage as necessary; optionally, the patient will start a low dose of between 5mg and 20mg per day and gradually increase the dose at 5mg or 10mg or 20mg intervals until efficacy on BED is safely achieved. The clinician can accelerate the titration, slow the titration if necessary, and later re-accelerate the titration depending on the patient's tolerance.

Example 4:

this example describes an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5, as schematically illustrated in figure 1.

Ketone 4, 2-amino-1- (3, 4-dichlorophenyl) ethan-1-one hydrochloride is converted to intermediate 5 under active proton deuteration conditions. Intermediate 5 is reduced by sodium borodeuteride to form alcohol 6. By reduction of the intermediate 2,3- ([ 1,2,4] with DIBAL-D (diisobutylaluminumdeuteroide)]Triazolo [1,5-a ]]Deuterated aldehydes 3,3- ([ 1,2, 4) prepared from pyridin-6-yl) benzonitrile]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde- α -d1 was reductively aminated with deuterated amine 6 via sodium borodeuteride to afford intermediate 7. The intermediate 7 is cyclized under acidic conditions to obtain a target molecule 8, - ([ 1,2,4]]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5.Example 4.1:7- ([1,2,4]Triazolo [1,5-a ]]Pyridine-6- Preparation of yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d 5A and 8B

2- (amino-d) ₂ ) Preparation of (E) -1- (3, 4-dichlorophenyl) ethan-1-one-2, 2-d2 DCl salt 5:

2-amino-1- (3, 4-dichlorophenyl) ethan-1-one hydrochloride 4 (3.0 g, 12.5 mmol), D in a sealed tube ₂ O (20 mL), THF (20 mL) and DCl (20%,8 mL) was stirred at 95 ℃ for 24 hours. Isotopic purity was determined by mass spectrometry (91% D). The volatiles were removed in vacuo. The procedure was repeated. The product was obtained as an off-white solid by concentration in vacuo (>99％D)。ESI-MS(M+1)m/z:206

Preparation of 2- (amino-d 2) -1- (3, 4-dichlorophenyl) ethane-1, 2-d 3-1-ol-d 6:

at 0 ℃ to 2- (amino-d) ₂ ) -1- (3, 4-dichlorophenyl) ethan-1-one-2, 2-d ₂ DCl salt 5 (367mg, 1.50mmol) in CH ₃ To the solution in OD (2.8 mL) was added NaBD ₄ (61 mg, 1.46mmol). The mixture was stirred at room temperature overnight. Adding a few drops of D ₂ O to quench the reaction. The mixture was concentrated to dryness in vacuo to give the crude title compound 6.

Preparation of 2- (((3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) phenyl) methyl-d 2) amino-d) -1- (3, 4-dichlorophenyl) ethan-1, 2-d 3-1-ol-d 7:

to the above residue 6 (1.50 mmol) in CH ₃ To a solution in OD (2.8 mL) was added (3- ([ 1,2,4] C)]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde

3 (336mg, 1.50mmol) and DCM (1.5 mL). The mixture was stirred at room temperature for 2 hours, followed by addition of NaBD ₄ (61 mg, 1.46mmol). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue partitioned between DCM and 4N NH ₄ Between OH groups. The aqueous phase was extracted with DCM (2 ×). Subjecting the combined extracts to Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product (610 mg).

Preparation of 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester-1, 3,4-d 5-Boc:

to cold sulfuric acid (2.15 mL) was added 2- (((3- ([ 1,2, 4) dropwise at 0 deg.C]Triazolo [1,5-a ]]Pyridin-6-yl) phenyl) methyl-d 2) amino-d) -1- (3, 4-dichlorophenyl) ethan-1, 2-d 3-1-ol-d 7 (610 mg) in DCM (1.9 mL). The mixture was stirred and allowed to warm to room temperature overnight. Adding ice water to the reaction mass, and passingAdding NaOH 20% to adjust pH to 9-10. The mixture was extracted with DCM (3 ×), and the combined extracts were taken over Na ₂ SO ₄ Drying, filtering and vacuum concentrating to obtain the product containing 7- ([ 1,2,4] D]Triazolo [1,5-a ]]Pyridine-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5. The crude residue containing 8 was dissolved in DCM (20 mL). Di-tert-butyl dicarbonate (360mg, 1.65mmol) was added to the solution. The resulting mixture was stirred at room temperature overnight, and then purified by column chromatography (H: etOAc 2]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester-1, 3,4-d 5-Boc (180mg, 24% three steps). ESI-MS (M + 1) M/z:500; ¹ HNMR(400MHZ,CDCl3)δ8.80(s,1H),8.39(s,1H),7.93-7.69(m, 2H),7.47-7.30(m,3H),7.20(s,1H),7.12-6.77(m,2H),1.64-1.14(m, 9H)。

chiral SFC separation:

racemic 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester-1, 3,4-d 5-Boc (165 mg) was dissolved in 5mL MeOH and 5mL dichloromethane, and then resolved by chiral SFC (Regis Whelk-O1 (S, S) 21X mm; mobile phase: 45-2-propanol +0.25DEA/CO2;254 nM) to give enantiomers A8A-Boc (88mg, RT =2.35min,100 ee) and enantiomer B8B-Boc (69mg, RT =2.77min,100 ee).

Preparation of enantiomer 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5 HCl salt 8A:

a mixture of 8A-Boc and 4N HCl in dioxane (1 mL) above was stirred at room temperature for 1 hour. After removal of volatiles, the residue was wet milled with EtOAc (2 mL). The product enantiomer 7- ([ 1,2, 4) was obtained]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5 HCl salt 8B (60 mg); ESI-MS (M + 1) M/z:400; ¹ HNMR(400MHz,DMSO)δ9.8(bs,2H),9.34(s,1H),8.56 (s,1H),7.68(m,4H),7.37-7.27(m,1H),6.90(d,J＝7.80Hz,1H)。

preparation of enantiomer 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5 HCl salt 8B:

a mixture of 8B-Boc and 4N HCl in dioxane (1 mL) above was stirred at room temperature for 1 hour. After removal of volatiles, the residue was wet milled with EtOAc (2 mL). The product enantiomer 7- ([ 1,2, 4) was obtained]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 3,4-d5 HCl salt 8B (50 mg); ESI-MS (M + 1) M/z:400; ¹ HNMR: same as 8A

Example 5:

this example describes the synthesis of exemplary compound 7- ([ 1,2, 4)]Triazolo [1,5-a ]]An exemplary scheme for pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2, as schematically illustrated in fig. 2. Compound 5 is reduced via sodium borohydride to compound alcohol 9, which is then converted to deuterated amine 10. By reduction of the intermediate 2,3- ([ 1,2,4] with DIBAL-D (diisobutylaluminumdeuteroide)]Triazolo [1,5-a ]]Deuterated aldehydes 3,3- ([ 1,2, 4) prepared from pyridin-6-yl) benzonitrile]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde

Reductive amination with deuterated amine 10 via sodium borodeuteride affords intermediate 11. The intermediate 11 is cyclized under acidic condition to obtain the target molecule 12,7- ([ 1,2,4] B]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2.

Example 5.1:7- ([1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3,4- Preparation of tetrahydroisoquinoline-1, 1-d 2A and 12B

Preparation of 2- (amino-d 2) -1- (3, 4-dichlorophenyl) ethan-1-ol-d 10:

to a solution of 2-amino-1- (3, 4-dichlorophenyl) ethan-1-one hydrochloride 4 (288mg, 1.2mmol) in 2mL of methanol at 0 deg.C was added NaBH ₄ (33mg, 0.79mmol). The mixture was stirred at 0 ℃ for 30 minutes and then concentrated in vacuo. By D ₂ O/MeOD (0.5 mL/1.5 mL) treated the residue. After stirring at room temperature for 20 minutes, the mixture was concentrated in vacuo. The residue is directly used inAnd (4) carrying out the next reaction.

Preparation of (3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) phenyl) met-a-d-ol 3 b:

to 3- ([ 1,2,4] at 0 deg.C]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde 3a (2.51 g, 11.2 mmol) in CH ₃ To the solution in OD (22 mL) was added NaBD ₄ (265mg, 6.33 mmol). The mixture was stirred at 0 ℃ for 30 minutes, and then water (40 mL) was added. Filtration gave (3- ([ 1,2, 4) as a white solid]Triazolo [1,5-a ]]Pyridin-6-yl) phenyl) methyl-d-ol 3b (1.65g, 65% yield).

Preparation of (3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) benzaldehyde-a-d 1:

at room temperature to (3- ([ 1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) phenyl) methyl-d-ol 3b (1.65g, 7.37mmol) in CH ₂ Cl ₂ To the solution (30 mL) was added dess-martin periodinane (3.75g, 8.84mmol). The mixture was stirred at room temperature overnight. Column chromatography purification afforded (3- ([ 1,2, 4) as an off-white solid]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde- α -d1 (1.64g, 99%,74% by weight). ESI-MS (M + 1) M/z:225.

Preparation of (3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) phenyl) met-d 2-ol 3 c:

to 3 (3- ([ 1,2,4] C) at 0 deg.C]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde-a-d 1 (1.64g, 7.37mmol) in CH ₃ Add NaBD to OD (20 mL) ₄ (310 mg, 7.37 mmol). The mixture was stirred at 0 ℃ for 30 minutes, and then water (30 mL) was added. Filtration gave (3- ([ 1,2,4] as a white solid]Triazolo [1,5-a ]]Pyridin-6-yl) phenyl) methyl-d 2-ol 3c (1.40g, 84% yield, 95% D).

at room temperature to (3- ([ 1,2, 4)]Triazolo [1,5-a ]]Pyridin-6-yl) phenyl) methyl-d 2-ol 3c (1.40g, 6.25mmol) in CH ₂ Cl ₂ To the solution (30 mL) was added dess-Martin periodinane (3.18g, 7.50mmol). The mixture was stirred at room temperature overnight. Purification by column chromatography gives (3- ([ 1,2, 4) as an off-white solid]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde

3(1.39g，99％，92％D)。ESI-MS(M+1)m/z:225

Preparation of 2- (((3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) phenyl) methyl-d 2) amino) -1- (3, 4-dichlorophenyl) ethan-1-ol 11:

2- (amino-d 2) -1- (3, 4-dichlorophenyl) ethan-1-ol-d 10 (210mg, 0.99mmol), (3- ([ 1,2,4] methyl ethyl phenyl) ethyl acetate]Triazolo [1,5-a ]]Pyridin-6-yl) benzaldehyde

3 (220mg, 0.99mmol), DCM (1 mL) and CH ₃ A mixture of OD (1.4 mL) was stirred at room temperature for 4 hours. Addition of NaBD ₄ (41mg, 0.90mmol) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue partitioned between DCM and 4N NH ₄ Between OH groups. The aqueous phase was extracted with DCM (2 ×). Subjecting the combined extracts to Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product (about 440mg,>99％D)。

preparation of 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d 2:

to cold sulfuric acid (1.72 mL) was added 2- (((3- ([ 1,2, 4) dropwise at 0 deg.C]Triazolo [1,5-a ]]A solution of pyridin-6-yl) phenyl) methyl-d 2) amino) -1- (3, 4-dichlorophenyl) ethan-1-ol 11 in DCM (1.5 mL). The mixture was stirred and allowed to warm to room temperature and then maintained overnight. Ice water was added to the reaction and the pH was brought to 9-10 by adding 20% NaOH. The mixture was extracted with DCM (3 ×), and the combined extracts were taken over Na ₂ SO ₄ Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound 12 (177 mg, 45%, two steps). ESI-MS (M + 1) M/z:397; ¹ HNMR(400MHz,CDCl3)δ8.79(s,1H),8.39(s,1H),7.88-7.73(m,2H),7.47-7.27(m,3H), 7.25-7.22(s,1H),7.05-6.97(m,2H),4.32-4.25(m,1H),3.58-3.50(m, 1H),3.18-3.10(m,1H)。

preparation of 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester-1, 1-d 2-Boc:

to 7- ([ 1,2,4] at room temperature]Triazolo [1,5-a ]]Boc was added to a solution of pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2 (177mg, 0.446mmol) in DCM (4 mL) ₂ O (107mg, 0.490mmol). The mixture was stirred at room temperature overnight. The mixture was purified by column chromatography to give the title compound 12-Boc (160 mg).

Chiral SFC (supercritical fluid chromatography) separation:

rac 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester-1, 1-d 2-Boc (139 mg) was dissolved in 5mL MeOH and 5mL dichloromethane and then resolved by chiral SFC (Regis Whelk-O1 (S, S) 21X 250mm; mobile phase: 45-2-propanol +0.25DEA/CO2;254 nM) to yield enantiomer a 12A-Boc (56mg, rt =2.35min,100 ee) and enantiomer B12B-Boc (56mg, rt =2.77min,100 ee).

Preparation of enantiomer (7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2 HCl salt 12A:

a mixture of the above 12A-Boc and 4N HCl in dioxane (1 mL) was stirred at room temperature (rt) for 1 hour. After removal of volatiles, the residue was wet milled with EtOAc (2 mL). The product enantiomer (7- ([ 1,2, 4) was obtained]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2 HCl salt 12A (50 mg); ESI-MS (M + 1) M/z:397; ¹ HNMR(400MHz,DMSO)δ9.8(bs,2H),9.34(s,1H),8.56(s, 1H),7.68(m,4H),7.37-7.27(m,1H),6.90(d,J＝7.80Hz,1H), 4.61-4.39(m,1H),3.76-3.62(m,1H),3.50-3.45(m,1H)。

preparation of enantiomer (7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2 HCl salt 12B:

a mixture of 12B-Boc and 4N HCl above in dioxane (1 mL) was stirred at room temperature for 1 hour. After removal of volatiles, the residue was wet milled with EtOAc (2 mL). The product enantiomer (7- ([ 1,2, 4) was obtained]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-1, 1-d2 HCl salt 12B (50 mg); ESI-MS (M + 1) M/z:397; ¹ HNMR: same as 12A.

Example 6:

this example describes an exemplary scheme for the synthesis of the exemplary compound 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3, as schematically illustrated in fig. 3.

Ketone 5, 2-amino-1- (3, 4-dichlorophenyl) ethan-1-one hydrochloride is converted to intermediate 13 under active proton deuteration conditions. Intermediate 13 is reduced by sodium borodeuteride to form alcohol 14. Aldehyde 3a,3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) benzonitrile prepared by reduction of intermediate 2,3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) benzonitrile with DIBAL (diisobutylaluminum hydride) was reductively aminated with deuterated intermediate 14 via sodium borodeuteride to give intermediate 15. Cyclizing the intermediate 15 under acidic condition to obtain the target molecule 16,7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3.

Example 6.1:7- ([1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3,4- Preparation of tetrahydroisoquinoline-3, 4-d 3A and 16B:

preparation of 2- ((3- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) benzyl) amino) -1- (3, 4-dichlorophenyl) ethan-1, 2-d 3-1-ol 15:

to the above residue 14 (1.50 mmol) in CH ₃ To a solution of OH (2.2 mL) was added aldehyde 3a (336mg, 1.50mmol) and DCM (1.5 mL). The mixture was stirred at room temperature for 2 hours, followed by the addition of NaBH ₄ (57mg, 1.50mmol). The resulting mixture was stirred at room temperature overnight. The mixture was washed with DCM and 4N NH ₄ And (4) distributing among OH groups. The aqueous phase was extracted with DCM (2 ×). Subjecting the combined extracts to Na ₂ SO ₄ Dried, filtered and concentrated in vacuo to give the crude product (580 mg).

Preparation of 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester-3, 4-d 3-Boc:

to cold sulfuric acid (2.15 mL) was added 2- ((3- ([ 1,2, 4) dropwise at 0 deg.C]Triazole compounds and 21,5-a]A solution of pyridin-6-yl) benzyl) amino) -1- (3, 4-dichlorophenyl) ethan-1, 2-d 3-1-ol 15 (580 mg) in DCM (1.9 mL). The mixture was stirred and allowed to warm to room temperature overnight. Adding ice water to the reaction, and adjusting the pH to 9-10 by adding 20% NaOH. The mixture was extracted with DCM (3 ×), and the combined extracts were taken over Na ₂ SO ₄ Drying, filtering and vacuum concentrating to obtain the product containing 7- ([ 1,2,4] D]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3. The residue containing 16 was dissolved in DCM (20 mL). To the solution was added di-tert-butyl dicarbonate (360 mg,1.65 mmol). The resulting mixture was stirred at room temperature overnight, and then purified by column chromatography (H: etOAc 2]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate-3, 4-d 3-Boc (168mg, 22%, three steps). ESI-MS (M + 1) M/z:498;

chiral SFC separation:

rac 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester-3, 4-d 3-Boc (101 mg) was dissolved in 5mL MeOH and 5mL dichloromethane and then resolved by chiral SFC (Regis wheelk-O1 (S, S) 21X 250mm, mobile phase: 45% 2-propanol +0.25DEA/CO2;254 nM) to yield enantiomer a16A-Boc (30mg, rt =2.35min,100 ee) and enantiomer B16B-Boc (33mg, rt =2.77min,100 ee).

Preparation of enantiomer 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3 HCl salt 16A:

a mixture of 16A-Boc and 4N HCl in dioxane (1 mL) above was stirred at room temperature for 1 hour. After removal of volatiles, the residue was wet milled with EtOAc (2 mL). The product enantiomer 7- ([ 1,2, 4) was obtained]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3 HCl salt 16A (26 mg); ESI-MS (M + 1) M/z:398; ¹ HNMR: same as 16B

Preparation of enantiomer 7- ([ 1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3 HCl salt 16B:

a mixture of 16B-Boc and 4N HCl in dioxane (1 mL) above was stirred at room temperature for 1 hour. After removal of volatiles, the residue was wet milled with EtOAc (2 mL). The product enantiomer 7- ([ 1,2, 4) was obtained]Triazolo [1,5-a ]]Pyridin-6-yl) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydroisoquinoline-3, 4-d3 HCl salt 16B (27 mg); ESI-MS (M + 1) M/z:398; ¹ HNMR(400MHz,DMSO)δ9.8(bs,2H),9.34(s,1H),8.56 (s,1H),7.68(m,4H),7.37-7.27(m,1H),6.90(d,J＝7.80Hz,1H), 4.58-4.50(m,1H),4.41-3.99(m,1H)。

example 7:

this example describes an exemplary scheme for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-1, 1-d 2) pyridin-2 (1H) -one, as schematically illustrated in fig. 4.

Cyclization of indoleamine a with deuterated carboxaldehyde forms intermediate B, which is protected with Boc to give intermediate C. Compound D is obtained by methylation of indole C. Ullman coupling of bromide D and pyridine F affords compound G, and subsequent deprotection under acidic conditions affords the target compound H as the HCl salt.

Example 8:

this example describes an exemplary scheme for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-1, 3-d 4) pyridin-2 (1H) -one, as schematically illustrated in fig. 5.

Indole acid I is converted to indole amide J. Reaction of indoleamide J with CD2O Pictet-Spinger gives lactam K. Lactam K is reduced with deuterated borane to give amine L, which is protected with Boc to give indole M. Compound N is obtained by methylation of indole M. Pyridone F is obtained from compound E by treatment with ammonium formate acetate. Ullman coupling of bromides N and F affords compound O. Deprotection of O under acidic conditions gives the target compound P as the HCl salt.

An alternative scheme for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-1, 3-d 4) pyridin-2 (1H) -one is schematically illustrated in figure 10.

Benzylamine W is reacted with allyltrimethylsilane X in the presence of deuterated formaldehyde to form 1-benzylpiperidine-2, 6-d 4-4-ol Y. Y removes the benzyl group and then Boc protects to give alcohol Z. After oxidation of alcohol Z with N-methylmorpholine N-oxide (NMO) and tetrapropylammonium perruthenate (TPAP), followed by reaction of ketone AA with (3-bromophenyl) hydrazine AB, deuterated indole L is obtained, which is protected with Boc to give indole M. Compound N is obtained by methylation of indole M. Compound E was treated with formic acid and ammonium acetate to give compound F. Ullman coupling of bromide N and pyridine F affords compound O, and subsequent deprotection under acidic conditions affords the target compound P.

Compound P was synthesized according to the route described in figure 11. Nitrosamines AD obtained from hydroxypiperidines AC are treated with sodium/deuterium oxide to form 2,2,6,6-d 4N-nitrosopiperidines AE. The N-nitroso group was removed by Ni/Al reduction to give piperidine AF, which was Boc protected to give compound Z. Hydroxypiperidine Z is oxidized to form ketone AA. Fisher indole synthesis of ketone AA and 3-bromophenylhydrazine gave indole L, which was protected with Boc to form compound M. Compound N is obtained by methylation of indole M. Ullman coupling of bromide N and pyridone F affords compound O, and subsequent deprotection under acidic conditions, yields more than 50mg of the target compound P as the HCl salt. Proton NMR and LCMS spectra are included in fig. 12 and 13, respectively.

Example 9:

this example describes an exemplary scheme for the synthesis of the exemplary compound 4- ((5-fluoropyridin-2-yl) methoxy) -1- (5-methyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indol-7-yl-3, 3-d 2) pyridin-2 (1H) -one, as schematically illustrated in fig. 6.

Indole acid I is converted to indole amide J. The Pictet-Spinger reaction of indoleamide J with formaldehyde gives lactam Q. The lactam Q is reduced with deuterated borane to give amine R, which is protected with Boc to give indole S. Compound T is obtained by methylation of indole S. Pyridone F was obtained from compound E by treatment with ammonium formate acetate. Ullman coupling of bromides T and F affords compound U. Deprotection of U under acidic conditions affords the target compound V as the HCl salt.

Example 10:

this embodiment describes a new algorithm provided herein for calculating an initial dose, and then safely titrating and maintaining an effective dose. Central transporter occupancy is a powerful pharmacodynamic marker to assess target involvement of transporter inhibitors and to guide dosing in efficacy clinical trials. The occupancy of several reuptake inhibitors as measured by Positron Emission Tomography (PET) has been reported. SERT occupancy was reported to be 65-85% at the efficacious doses of SSRI and SSNRI (Meyer JH et al, am J Psychiatry.2004, 5.2004; 161 (5): 826-35 Herold N et al, J Neural Transm (Vienna). 2006, 5.113 (5): 659-70 Klein N et al, psychopharmacology (Berl). 2007, 4.2007; 191 (2): 333-9.). Interestingly, the moderate amount of SERT occupancy at clinical doses, 25-46%, means that inhibition of serotonin reuptake may be necessary, but not sufficient to be efficacious in humans, supporting preclinical data that low phagocytosis requires co-inhibition of SERT and NET (Talbot PS et al, neuropsychopharmacology, 2 months 2010; 35 (3): 741-51). DAT occupancy of bupropion (14-26%), modafinil (51-57%) and methylphenidate (40-74%) at various approved doses is reported (

Volkow ND et al, am J Psychiatry.1998, 10 months; 155 1325-31; kim W et al, int J neuropsychopharmacol.2014, 5 months; 17 697-703, kim W et al, int J neuropsychopharmacol, 5 months 2014; 17 (5):697-703.). Tesofensine is reported to have a DAT occupancy of 50% -70% and is recommended as an optimal weight loss dose (Appel L et al, eur Neuropychophharmacol.2014.2 months; 24 (2): 251-61). Radioligands for NET were recently developed, which allowed assessment of NET occupancy. It is reported that, at a potent dose, the NET occupancy of duloxetine ranges from about 30-50% (Moriguchi S et al, int J Neuropsychopharmacol.2017, 12.1.12; 20 (12): 957-962) and venlafaxine is 8-61% (Arakawa 2014). For ease of review, table 9 summarizes the reported transporter occupancy ranges for the approved monoamine reuptake inhibitors described above.

Table 1: reported transporter occupancy ranges for approved monoamine reuptake inhibitors at efficacious doses

The PET study was part of a previous clinical development strategy for compounds of formula I to assess safety, tolerability and pharmacokinetics as well as DAT and SERT occupancy in healthy male volunteers.

In the study, SERT occupancy at steady state of multiple 30-60mg doses of the compound of formula I reached 65-75%. After multiple 60mg doses of the compound of formula I, a significant and dose-dependent DAT occupancy of up to about 60% was achieved. Using a single value, an approximately linear relationship between plasma compound concentration of formula I and DAT occupancy is presented in fig. 7. Using the respective values, the relationship between plasma concentrations of the compound of formula I and SERT occupancy is presented in fig. 8 and fig. 9. The individual SERT and DST occupancy values and corresponding plasma concentrations are listed in example 12.

Although significant variability in plasma concentrations versus dose for the compound of formula I was observed in several cohorts, as shown in figures 5 and 6, in general, the magnitude of the plasma concentrations closely matched the magnitude of the estimated occupancy. This PK/PD relationship established will be used to guide dosing in future studies.

When starting the PET study, there is not enough method to estimate NET occupancy in the human brain. However, NET occupancy was expected to be nearly identical to DAT occupancy after administration of the compound of formula I, based on ex vivo occupancy data in mouse brain.

Combining the results of this PET study with preclinical results, it was concluded that formula I is a potent, competitive, and selective triple reuptake inhibitor of DAT, SERT, and NET in humans. In addition, formula I has unique triple reuptake inhibition properties that will allow for the administration of efficacious doses within the approved therapeutic range of single and dual SERT, DAT and NET inhibitors. In particular, in PET studies conducted on healthy men, formula I can achieve near-efficacious levels of SERT occupancy within the SSRI over a safe dose range, while allowing for an increase in DAT occupancy to approximately 60%. This unique TRI characteristic of formula I allows flexibility in tailoring better tolerability and efficacy to individual patients in a gradual titration.

Given the approximately linear relationship between plasma concentration and DAT occupancy, using a concentration-controlled dosing approach, using the PK/PD relationship established in the PET study of formula I, the expected large variation in dose and plasma drug concentration can provide an accurate dose for an individual patient to obtain optimal results.

Example 1 above describes exemplary methods and compositions for treating prader-willi syndrome and related disorders, and example 2 above describes methods and compositions for treating hypothalamic injury-induced obesity (HO) and related disorders using formula I and deuterated analogs thereof as described herein, e.g., as described herein.

The patient is administered a sub-therapeutic dose of 1mg to 20mg per day for one day, one week, two weeks, three weeks, or four weeks. Periodically collecting blood samples to determine the drug concentration at steady state and to determine the latest target dose required to achieve a DAT occupancy between 15% and 75%, whether or not by means of a pharmaco-metric modeling method that also utilizes PK/PD data; optionally, determining an approximate target dose by reaching a plasma drug concentration value between 100ng/ml and 4000ng/ml at steady state; optionally, determining an approximate target dose by achieving a plasma drug concentration value between 200ng/ml and 2000ng/ml at steady state; optionally, the near target dose is determined by reaching a plasma drug concentration value between 400ng/ml and 2000ng/ml at steady state. Every 3 or 6 months, or when there are significant changes in patient medication, body weight and other physical changes that affect drug absorption and metabolism, the blood level will be re-monitored to adjust the administration as necessary; optionally, the patient will start a low dose of between 5mg and 20mg per day and gradually increase the dose at 5mg or 10mg or 20mg intervals until efficacy on hyperphagia and/or neuropsychiatric and behavioral symptoms is safely achieved. The clinician can accelerate the titration, slow the titration if necessary, and later re-accelerate the titration depending on the patient's tolerance.

Example 11:

in alternative embodiments, methods are provided that include administering a drug in an amount sufficient to achieve a therapeutic level range of steady state plasma concentrations (optionally human plasma concentrations), and this example describes exemplary analytical methods for determining the concentration of formula I in human plasma using LC-MS methods known to those skilled in the art, and exemplary bioanalytical methods for determining the concentration of formula I in human EDTA plasma.

An LC-MS/MS method was developed and validated for quantification of formula I in 0.250mL human EDTA plasma in a total of 7 runs, of which 1 run was rejected. The method uses a stably labelled formula I as internal standard. After addition of internal standard (equivalent to 285.4ng/mL in human EDTA plasma) and 0.250mL of each Quality Control (QC) sample and calibration standard, 0.525mL of methyl tert-butyl ether (MTBE) was added to the 96-well sample tubes. The organic layer was removed and evaporated to dryness using liquid-liquid extraction (LLE). The residue was reconstituted and injected into the LC-MS/MS system. By using a probe in the Acquity UPLC, BEH Shield RP18 ^TM The chromatographic separation was carried out by gradient elution on a 50X 2.1 mm, 1.7 μm particle size column. The mobile phase contains water, acetonitrile, ammonium formate and formic acid. Detection was done using a Sciex API 4000 tandem mass spectrometer in positive ion electrospray SRM mode. Standard curves of formula I ranging from 1.00 to 1000ng/mL were fitted to a 1/x2 weighted linear regression model. The intra-assay accuracy based on four assay QC levels (low, medium, GM and high) was within 4.2% CV and the inter-assay accuracy of the analytes was within 7.2% CV. The accuracy of the analysis, expressed as% DEV, is within 6.4% of the nominal concentration value of the analyte. At a lower limit of quantitation (LLOQ) of 1.00ng/mL for formula I, the predicted concentration of all LLOQ samples from six different matrix batches was within 14.1% of the nominal value. The LLOQ response ratio, when compared to QC0 response ratio, was ≧ 5 in all matrix batches. The analytes were stable in human EDTA plasma for at least 24 hours at room temperature, at-20 ℃ for at least 14 days, and then subjected to at least 3 freeze-thaw cycles. The treated sample was at room temperatureAnd (d) stabilizing for 72 hours (h).

According to the results of this validation, the acceptance criteria for sample analysis were as follows:

1) At least three-quarters of the predicted concentrations in all calibration standards should be within ± 15.0% of their nominal concentrations, except for LLOQ, which would be within ± 20.0%. Standards that do not meet these criteria will be excluded from regression. At least three quarters of all standards will meet the acceptance criteria and are included in the final regression;

2) At least one replica of the lowest concentration in the standard curve will meet the above criteria and be included in the final regression of the levels to meet LLOQ requirements. If this criterion is not met, the next criterion level will be tested the same and the LLOQ is increased accordingly;

3) At least two-thirds of the predicted concentrations of all analytical quality control samples will be within ± 15.0% of their nominal concentrations, with at least 50% of the QC samples meeting acceptance criteria at each level;

4) If a single dilution of diluted QC is used, the predicted concentration of at least 50% of the diluted QC sample at a particular dilution will be within ± 15.0% of its nominal concentration, so that the diluted sample results at the same or lower dilution are accepted.

If different dilutions of dilution QC are used, the predicted concentration of at least 50% of the diluted QC samples will be within ± 15.0% of their nominal concentration at each dilution, so that the diluted sample results at the same dilution are accepted. The results of diluting QC samples will not be used to determine run acceptability.

The HPLC parameters used are shown in the table below:

mobile phase a-water and acetonitrile (90/10) containing 10mM ammonium formate and 0.1% formic acid. 0.63g of ammonium formate was dissolved in 900mL of water and 100mL of acetonitrile to which 1.0mL of formic acid was added.

Mobile phase D-water and acetonitrile (10/90) containing 10mM ammonium formate and 0.1% formic acid. 0.63 grams (g) of ammonium formate was dissolved in 100mL of water and 900mL of acetonitrile to which 1.0mL of formic acid was added.

The mass spectral parameters used are shown in the following table:

IS-formula I

Example 12：

Striatal receptor occupancy of dopamine transporter (DAT) and serotonin transporter (SERT) with formula I plasma concentrations following multiple doses of 3-60mg and 10-60 mg once daily for SERT and DAT healthy male cohorts at the midpoint time of PET (positron emission tomography) scan after dosing (T =4 and 24), respectively (table below, RO stands for receptor occupancy). Assuming steady state conditions, specific DAT and SERT tracers were used, respectively ¹¹ C-PE2I and ¹¹ C-MADAM, post-dose PET scans were performed on day 10 (4 hours after the last dose) and day 14 (24 hours after the last dose). For the 45mg and 60mg cohorts, titration was performed by administering 30mg for 3 days, and then the indicated dose was administered starting on day 4. A representative report on the use of these two tracers is Learned-Coughlin SM et al, biol Psychiatry.2003,54 (8): 800-5; jucaite A et al, eur J Nucl Med Mol imaging.2006,33 (6): 657-68; and Lundberg J et al, int J neuropsychopharmacol.2007,10 (6): 777-85.

Subject ID	Dosage (mg)	Sky and sky	Time (h)	Formula I plasma concentration (ng/ml)	SERT RO％
						1	3	10	4	68	51
2	3	10	4	64	28
						5	3	10	4	63	13
1	3	14	24	52	38
						2	3	14	24	45	29
5	3	14	24	42	6
						33	10	10	4	184	53
35	10	10	4	201	53
						37	10	10	4	212	52
33	10	14	24	127	47
						35	10	14	24	129	48
37	10	14	24	156	51
						47	30	10	4	691	71
48	30	10	4	847	72
						57	30	10	4	667	74
47	30	14	24	668	69
						48	30	14	24	434	66
57	30	14	24	567	67
						63	45	10	4	1163	73
65	45	10	4	1191	74
						69	45	10	4	1105	75
63	45	14	24	940	73
						65	45	14	24	904	75
69	45	14	24	895	78
						75	60	10	4	1039	70
84	60	10	4	837	61
						86	60	10	4	2035	76
75	60	14	24	698	76
						84	60	14	24	679	72
86	60	14	24	1557	77

Subject ID	Dosage (mg)	Sky and sky	Time (h)	Formula I plasma concentration (ng/ml)	DAT RO％
						36	10	10	4	204	12
38	10	10	4	214	21
						40	10	10	4	173	18
36	10	14	24	141	1
						38	10	14	24	149	19
40	10	14	24	147	13
						45	30	10	4	607	36
49	30	10	4	225	22
						53	30	10	4	896	43
45	30	14	24	430	26
						49	30	14	24	207	23
53	30	14	24	705	43
						62	45	10	4	809	42
64	45	10	4	924	44
						66	45	10	4	905	48
62	45	14	24	647	36
						64	45	14	24	668	41
66	45	14	24	673	43
						77	60	11	4	1340	60
80	60	10	4	1263	59
						77	60	14	24	920	48
80	60	14	24	991	49

Example 13

This embodiment describesMethods for measuring inhibitory potency on dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT or 5-HTT) and compounds of formulae I, 8A, 8B, 12A, 12B, 16A and 16B measured using these methods (Eurofin Discovery Taiwan Category # s 220320, 204410, 274030); and methods for measuring inhibitory potency on the transporter, dopamine (DAT) (Giros et al, trends Pharmacol Sci.14 (2): 43-49, 1993 Gu et al, J Biol chem.269 (10): 7124-7130, 1994):

scheme overview:

the source is as follows: human recombinant CHO-S cells;

vehicle: 1.0% DMSO;

incubation time/temperature: 3 hours at 4 ℃;

incubation buffer: 50mM Tris-HCl, pH 7.4, 100mM NaCl, 1. Mu.M leupeptin, 10. Mu.M PMSF;

kd:0.58nM (historical);

ligand: 0.15nM of protein 2 [ 2 ] ¹²⁵ I]RTI-55；

Non-specific ligand: 10.0 μ M nomifensine;

specific binding: 90% (historical value);

the quantitative method comprises the following steps: radioligand binding;

significance criteria: not less than 50% of maximum stimulation or inhibition;

bmax:0.047pmole/mg protein

Measurement of the inhibitory potency against the transporter Noradrenaline (NET) (Galli et al, J Exp biol.198 (Pt 10): 2197-2212, 1995)

Scheme overview:

the source is as follows: human recombinant MDCK cells;

vehicle: 1.0% DMSO;

incubation time/temperature: 3 hours at 4 ℃;

kd:0.024 μ M (historical value);

ligand: 0.2nM [ 2 ] ¹²⁵ I]RTI-55；

Non-specific ligand: 10.0 μ M desipramine;

specific binding: 75% (historical value);

the quantitative method comprises the following steps: radioligand binding;

the significance criteria are: not less than 50% of maximum stimulation or inhibition;

bmax:2.50pmole/mg protein

Measuring the inhibitory potency against Transportin serotonin (5-hydroxytryptamine) (SERT) (Shearman et al, am J physiol.275 (6Pt 1): C1621-1629,1998 wolf et al, J Biol chem.267 (29): 20820-20825, 1992)

Scheme overview:

the source is as follows: human recombinant HEK-293 cells;

vehicle: 1.0% dmso;

incubation time/temperature: 60 minutes at 25 ℃;

incubation buffer: 50mM Tris-HCl, pH 7.4, 120mM NaCl,5mM KCl;

kd:0.078nM (historical value);

ligand: 0.4nM, 3H, paroxetine;

non-specific ligand: 10.0 μ M imipramine;

specific binding: 95% (historical value);

the quantitative method comprises the following steps: radioligand binding;

significance criteria: greater than or equal to (≧) 50% of maximum stimulation or inhibition;

bmax:4.40pmole/mg protein (historical values)

Potency data are expressed as% inhibition at concentrations of 10nM and 100nM of the compounds in the following table.

Example 14

Description of the embodimentsA method of measuring the inhibitory potency against MCHR1 and the inhibitory potency of compound formula II using this method (Eurofin Discovery Taiwan Category # 251010):

scheme overview:

the source is as follows: human recombinant CHO-K1 cells;

vehicle: 1.00% DMSO;

incubation time/temperature: 2 hours at 25 ℃;

incubation buffer: 25mM HEPES, pH 7.4, 10mM MgCl ₂ ，1mM EDTA， 0.2％BSA；

Kd:0.10nM (historical);

ligand: 0.050nM [ 2 ], [ 2 ] ¹²⁵ I]Tyr-S36057；

Non-specific ligand: 1.0 μ M MCH (human, mouse, rat);

specific binding: 85% (historical value);

the quantitative method comprises the following steps: radioligand binding;

bmax:26.0pmole/mg protein (historical values)

Potency data are expressed as IC50 and Ki in the following Table

Compound numbering	IC50	Ki
			Formula II	10.6nM	7.04nM
P	10.5nM	6.99nM

Example 16:

administration of a Compound of formula I alone to obese patients with PWS or hypothalamic injury Induction Using PK guided administration

An initial low dose of a compound of formula I of 10 mg/day is administered to the patient for 2 weeks, followed by an optional additional titration step that will increase the dose alone over 2 weeks to reach a target trough plasma concentration of approximately 375ng/mL (or corresponding to approximately 30% DAT occupancy in healthy humans). The patient will then be titrated to the dose required to reach a target plasma trough concentration of about 700ng/mL (corresponding to about 45% dat occupancy in healthy humans), or about 1295ng/mL (corresponding to about 60% dat occupancy in healthy humans) for a low dose. Figure 32 illustrates PK/PD model notification simulations of plasma levels required to achieve target receptor occupancy. The target plasma concentrations were calculated using the PK-PD model described for formula I in the examples.

PK-directed administration is based on drug plasma concentration, not the actual dose (in mg) given to an individual. In other words, depending on the age, size, ability to metabolize drugs, and other factors of the patient, two patients may receive completely different doses even though they may be randomly assigned to the same "dose" group as described below.

The drug is formulated as tablets or capsules in amounts of 5 to 240mg, in appropriate increments, which should bring all participants as close as possible to their target plasma levels. All patients received one or two tablets/capsules daily and were taken in the morning.

The required C trough for each target DAT occupancy level has been selected so that they are at or slightly above the target DAT receptor occupancy within 12 hours of the day, as shown in the simulations below, corresponding to daily fluctuations in plasma levels after dosing in the morning. Pk-directed administration provides each patient with the best opportunity to achieve the desired efficacy without unnecessary drug exposure. FIG. 25 shows plasma levels over 24 hours, with the dose optimized to provide the required 30% DAT receptor occupancy coverage over a 12 hour day period. See fig. 33 for an illustration.

Example 17:

this example describes simulated personalized dosing based on day 7C trough to estimate day 14 dose variation to achieve 30% dat receptor occupancy. See the inset illustration in fig. 34.

Example 18:

this example describes simulating individualized dosing to achieve 60% dat receptor occupancy in a 160kg patient. See the inset illustration in fig. 35.

Example 19：

This example describes the administration of a compound of formula I alone to PWS or hypothalamic injury-induced obese patients using an initial PK assessment, followed by PK-directed administration.

The patient will receive an initial PK assessment to determine the individual PK parameters of the subject to adjust the initial starting dose of formula I. In an initial PK assessment, subjects will receive a single low dose, e.g., a 10mg dose, of a compound of formula I. PK mapping will be performed before and after dosing hours, 2 hours, 4 hours, 24 hours, 3 days and 7 days.

Next, the patients will be dosed individually using the PK simulation method described in the embodiments, to enable them to achieve target trough plasma concentrations of about 375ng/mL (or about 30% DAT occupancy corresponding to healthy persons), about 700ng/mL (about 45% DAT occupancy corresponding to healthy persons), or about 1300ng/mL (about 60% DAT occupancy corresponding to healthy persons). Optional steady state repeat PK will be performed 3 to 12 months after treatment, if necessary.

The drug was formulated as tablets or capsules in amounts of 5 to 240mg, with appropriate increments, which should bring all participants as close as possible to their target plasma levels. All patients received one or two tablets/capsules daily and were taken in the morning.

The desired C trough for each target DAT occupancy level has been selected so that they are at or slightly above the target DAT receptor occupancy within 12 hours of the day, as shown in the simulation below, corresponding to daily fluctuations in plasma levels after the morning dose. PK-directed administration provides each patient the best opportunity to achieve the desired efficacy without unnecessary drug exposure.

Example 20

The 14 th day PK data (Cmax, C trough and AUC) for the list of healthy people in a 14 day, once daily oral dose, multiple ascending dose study of the compound of formula I.

Several embodiments of the present invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

1. A therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture comprising a melanin concentrating hormone receptor 1 (MCHR 1) antagonist, or a pharmaceutically acceptable salt thereof, and optionally

Any one or more of the following active agents:

(1) Non-acylated ghrelin (UAG) analogs and/or livolitides,

(2) Carbetocin, or DURATOCIN ^TM 、PABAL ^TM Or lonantene ^TM ，

(3) Oxytocin and/or preproendon-neurotensin,

(4) Liraglutide, or Victoza ^TM Or SAXENDA ^TM ，

(5) Exenatide, byetta ^TM 、BYDUREON ^TM 、BYDUREON ^TM Or BCISE ^TM ，

(6) The peptide of the Samerala is used as a peptide,

(7) The amount of the active agent is that of rimonabant,

(8) A beta adrenergic blocker, wherein optionally the beta adrenergic blocker is metoprolol (or LOPRESSOR) ^TM 、METOLAR XR ^TM 、TOPROL X ^TM ) Atenolol (or TENORMIN) ^TM ) Propranolol (or INDERAL) ^TM ) And/or nadolol (or CORGARD) ^TM ) Or any combination thereof,

(9) A melatonin receptor agonist, wherein optionally, the melatonin receptor isThe agonist is melatonin or N-acetyl-5-methoxytryptamine, rameitazone (or ROZEREM) ^TM ) And/or tixemerion (or HETLIOZ) ^TM ) Or any combination thereof,

(10) A histamine receptor 1 antagonist, wherein said histamine receptor 1 antagonist is doxepin (or SINEQUAN) ^TM 、QUITAXON ^TM Or APONAL ^TM ) Or a low dose of doxepin (wherein optionally the low dose is 3mg or 6mg, trazodone (or DESYREL) per dose ^TM 、DESYREL DIVIDOSE ^TM Or OLEPTRO ^TM ) Amitriptyline (or ELAVIL) ^TM 、PROTANOL ^TM 、QUALITRIPTINE ^TM 、REDOMEX ^TM Or SAROTEN ^TM ) Or amitriptyline with chlorine nitrogen

(MORELIN ^TM 、RISTRYL ^TM Or SEDANS ^TM ) And/or mirtazapine (or REMERON) ^TM ) Or any combination thereof,

(11) A histamine H3 receptor antagonist or inverse agonist, wherein optionally said H3 receptor antagonist or inverse agonist is: pitocidal (or Tioprostol, sipronin or WAKIX) ^TM ) Thioperamide, clorproc, siprepopule, conradine (or nimesulide, coniferine, dibastin) and/or betahistine (or SERC) ^TM ) SUVN-G3031 (Suven Life Sciences Ltd), or any combination thereof,

(12) Modafinil (or PROVIGIL) ^TM 、ALERTEC ^TM Or MODAVIGIL ^TM ) And/or armodafinil (or NUVIGIL) ^TM ) (13) human growth hormone (hGH) (or growth hormone) or recombinant form thereof (or OMNITROPE) ^TM 、JINTROPIN ^TM 、NUTROPIN ^TM Or NUTROPIN DEPOT ^TM 、HUMATROPE ^TM 、GENOTROPIN ^TM 、NORDITROPIN ^TM Or SAIZEN ^TM ) Or any combination thereof,

(14) Testosterone and/or 17 beta-hydroxyandrost-4-en-3-one,

(15) Progesterone and/or pregn-4-ene-3, 20-dione,

(16) Estrogen, estrone, estradiol or estriol, or any combination thereof,

(17) A thyroid hormone or derivative thereof, wherein optionally the thyroid hormone or derivative thereof is: triiodothyroxine (T3), thyroxine (T4), levothyroxine or L-thyroxine, or any combination thereof,

(19) Metformin (or GLUCOPHAGE) ^TM ) And/or repaglinide (or PRANDIN) ^TM ，

(20) Insulin or human insulin or recombinant or analogous forms thereof (or ACTRAPID) ^TM 、HUMALOG ^TM 、NOVORAPID ^TM 、APIDRA ^TM 、LANTUS ^TM Or LEVEMIR ^TM ) Or any combination thereof,

(21) Glucocorticoid receptor antagonists or anti-corticosteroids, or mifepristone (or RU-486, or MIFEGYNE) ^TM Or MIFEPREX ^TM ) Metirane (or METOPIRONE) ^TM ) Ketoconazole (or nizzaral) ^TM ) Or aminoglutethimide (or ELIPEN) ^TM 、CYTADREN ^TM Or ORIMETEN ^TM )，

(22) A histamine receptor 2 antagonist, wherein optionally, said histamine receptor 2 antagonist is: cimetidine (or TAGAME) ^TM ) Ranitidine (or ZANTAC) ^TM ) And/or famotidine (or PEPCID) ^TM ) Or any combination thereof,

(23) A mood stabilizer, wherein optionally the mood stabilizer is: gabapentin (or NEURONTIN) ^TM ) (ii) a Clonazepam (or KLONOPIN) ^TM Or RIVOTRILF ^TM ) (ii) a Valproate, valproic acid, sodium valproate or semi-sodium valproate (or CONVULEX) ^TM 、DEPAKOTE ^TM 、EPILIM ^TM Or STAVZOR ^TM ) (ii) a Oxcarbazepine (or TRILEPTAL) ^TM Or OXTELAR XR ^TM ) (ii) a Lithium or lithium carbonate (or LITHOBID) ^TM Or LITHOMAX ^TM ) (ii) a Topiramate (or TOPAMAX) ^TM 、TROKENDI XR ^TM Or QUDEXY XR ^TM ) And/or lamotrigine (or lamita) ^TM ) Or any combination thereof，

(24) A neuroleptic agent, wherein optionally, the neuroleptic agent comprises: risperidone (or Risperdal), aripiprazole (or ABILIFY) ^TM ) Quetiapine (or SEROQUEL) ^TM ) Olanzapine (or ZYPREXA) ^TM ) Ziprasidone (or GEODON) ^TM ) And/or haloperidol (or halopdol) ^TM Or SERENACE ^TM ) Or any combination thereof,

(25) Quetiapine, or SEROQUEL ^TM Or TEMPROLIDE ^TM ，

(26) Naltrexone (or FEBIA) ^TM Or VIVITROL ^TM )，

(27) Gamma-aminobutyric acid (GABA) B (GABAB) receptor modulators, such as sodium oxybate (XYremTM), or controlled release sodium oxybate (or FT 218), or sodium suboxybate, optionally JZP-258, or baclofen,

(28) The process of solirunning or SUNOSTM,

(29) A hypothalamic secretin/orexin 2 receptor selective agonist, optionally TAK-925, TAK-988 or TAK-994,

(30) A selective Norepinephrine Reuptake Inhibitor (NRI), or a Selective Serotonin Reuptake Inhibitor (SSRI), or a selective serotonin norepinephrine inhibitor (SNRI), wherein optionally the SSRI or SNRI inhibitor is reboxetine (or AXS-12, or EdonaxTM), atomoxetine (or StratteTM), venlafaxine (Effexor or Effexor XRTM), fluoxetine (ProzacTM), citalopram (Celexa TM), escitalopram (Lexapro), paroxetine (Paxil TM), sertraline (Zoloft TM), or duloxetine (Cymbalta TM),

(31) Amphetamine, dextroamphetamine (or Adderall TM), dextroamphetamine-amphetamine (MydayisTM) or lisdexamphetamine (or Vyvanse TM),

(33) Tricyclic antidepressant (TCA), wherein optionally the TCA is imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil) or another TCA,

(34) Monoamine oxidase inhibitors (MAOI), wherein optionally the MAOI is selegiline (EmsamTM), isocarboxazid (Marplan TM), phenelzine (Nardil TM) and tranylcypromine (ParnateTM) or another MAOI,

(35) THN102, or a combination of modafinil and flecainide,

(36) An inhibitor of an astrocyte connexin inhibitor, wherein optionally the inhibitor of an astrocyte connexin inhibitor is flecainide,

(37) A prostaglandin DP1 receptor antagonist, wherein optionally the prostaglandin DP1 receptor antagonist is ONO-4127Na,

(38) Opioids, wherein optionally, the opioids include morphine,

(39) An anti-obesity drug, wherein optionally the anti-obesity drug comprises lorcaserin (BelviqTM), orlistat (AllitTM), phentermine and topiramate (QsymiaTM), or naltrexone hydrochloride or bupropion hydrochloride (Contrave TM),

(40) Farnesoid X Receptor (FXR) agonist, wherein optionally the FXR agonist comprises obeticholic acid (OCA), EYP001 (ENYO Pharma), TQA3526, px-102, px-104 or toffee,

(41) A PPAR agonist, optionally a PPAR α/δ agonist or a PPAR- α/γ agonist, wherein optionally the PPAR- α/γ agonist comprises pioglitazone, elafoscarnet or laniforno (or IVA337, inventiva),

(42) A CC chemokine receptor CCR2/CCR5 inhibitor, wherein optionally said CC chemokine receptor comprises toffee, a combination of toffee and cenavirone, or cenavirone,

(43) A Mitochondrial Pyruvate Carrier (MPC) inhibitor, wherein optionally, the MPC inhibitor comprises MSDC-0602K (Cirius Therapeutics),

(44) A fibroblast growth factor 19 (FGF 19) analog, wherein optionally, the FGF19 analog comprises odavumin (or NGM282, NGM biopharmaceutics)

(45) A fibroblast growth factor 21 (FGF 21) analog, wherein optionally the FGF21 analog comprises a pegylated fibroblast growth factor 21 analog, optionally pebeverine,

(46) A thyroid hormone receptor beta (THR-beta) agonist, wherein optionally the THR-beta agonist comprises remomectinuron (MGL-3196, magrigal Pharmaceuticals) or VK-2890,

(47) Inhibitors of stearoyl-CoA desaturase-1 (SCD 1), wherein optionally said SCD1 inhibitor comprises Almcoul (Galmed Pharmaceuticals),

(48) An inhibitor of apoptosis signal-regulating kinase 1 (ASK 1), wherein optionally the ASK1 inhibitor comprises Selenib (Gilead Sciences),

(49) An acetyl-CoA carboxylase (ACC) inhibitor, wherein optionally the ACC inhibitor comprises Ficolata (GS-0976) or MK-4074,

(50) Diazoxide (or progycem) ^TM ) Or diazoxide choline controlled release agents (DCCR formulations); or

(51) Any combination of (1) to (50).

2. The therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture of claim 1, wherein the MCHR1 antagonist is selected from the group consisting of:

(a) GW8564649, AZD-1979, AMG-076, BMS-830216, ATC-0065, ATC-0175, GW-803430, GW-3430, NGD-4715, SNAP-7941, T-226 or T-296, or any combination thereof;

(b) A compound of formula II:

or a pharmaceutically acceptable salt thereof;

(c) (1-azinone) substituted pyridoindoles as described in USPN 8,716,308;

(d) A compound having the formula

Or a pharmaceutically acceptable salt thereof, wherein

R ¹ Is H or optionally substituted alkyl;

R ² 、R ³ and R ⁴ Each independently selected from H, -O-alkyl, -S-alkyl, halo, -CF ₃ and-CN;

g is-CR ¹² R ¹³ -NR ⁵ -or-NR ⁵ -CR ¹² R ¹³ ；

R ⁵ Is H, optionally substituted alkyl, optionally substituted heterocycle, -C (= O) -R ⁶ 、–C(＝O)-O-R ⁷ or-C (= O) -NR ¹⁹ R ²⁰ ；

R ⁶ And R ⁷ Each is optionally substituted alkyl or optionally substituted heterocycle;

R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁹ and R ²⁰ Each independently selected from H or optionally substituted alkyl;

R ¹⁴ and R ¹⁵ Each independently is H or halogen;

y is CH;

l is-CH ₂ -O–、–CH ₂ CH ₂ -, -CH = CH-, or a bond; and is

B is aryl, heteroaryl or cycloalkyl; provided that when L is a direct bond, B cannot be unsubstituted heteroaryl or heteroaryl monosubstituted with fluoro;

(e) A deuterated form of the compound of (a), (b), (c), or (d); or

(f) A compound of the structure:

or a pharmaceutically acceptable salt thereof.

3. A therapeutic combination, pharmaceutical agent, as claimed in any one of claims 1 or 2A form, drug delivery device, or article of manufacture further comprising an N-acetyltransferase 2 (NAT 2) inhibitor, an arylamine N-acetyltransferase inhibitor, acetaminophen, N-acetyl-p-aminophenol (APAP), or paracetamol (or TYLENOL) ^TM Or PANADOL ^TM )。

4. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of claims 1 to 3, wherein two or three or more of said drugs or active agents are formulated as separate compositions or two or three or more of said drugs or active agents are formulated as one composition or pharmaceutical formulation.

5. The therapeutic combination, pharmaceutical dosage form, pharmaceutical delivery device or article of manufacture of any one of claims 1 to 4, wherein one or two or more of said drugs or active agents are packaged individually, or together, or in any combination in a single package, multiple packages or packets, or blister packs, lidded blisters or blister cards or packets, or shrink wrap.

6. The therapeutic combination, pharmaceutical dosage form, pharmaceutical delivery device, or article of manufacture of any one of claims 1 to 5, wherein one or two or more or all of the drugs or active agents are formulated or manufactured as a parenteral formulation, aqueous solution, liposome, injectable solution, tablet, pill, lozenge, capsule, caplet, spray, sachet, inhalant, powder, lyophilized powder, inhalant, patch, gel, geltab, nanosuspension, nanoparticle, nanoliposome, microgel, pellet, suppository, or any combination thereof, wherein the pharmaceutical delivery device or article of manufacture comprises an implant.

7. The therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture of claim 6, wherein one or two or more or all of the drug or active agent is formulated or manufactured together in a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a lyophilized powder, a feed, a food product, a food supplement, a pellet, a lozenge, a liquid, an elixir, an aerosol, an inhalant, an adhesive, a spray, a powder, a lyophilized powder, a patch, a tablet, a pill, a capsule, a gel, a geltab, a lozenge, a caplet, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, or a suppository.

8. The therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture of any one of claims 1 to 7, wherein one or two or more or all of the drugs or active agents are packaged in a dosage that matches a timed dosing regimen to match an optimal dosage throughout the day.

9. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of claims 1 to 8, wherein the MCHR1 antagonist has the formula:

or a pharmaceutically acceptable salt thereof,

wherein R is ¹ To R ¹⁸ At least one of which is-D (deuterium), or R ¹ To R ¹⁸ All are-D and R ¹ -R ¹⁸ The remainder of (a) is hydrogen.

10. The therapeutic combination, pharmaceutical dosage form, drug delivery device or article of manufacture of any one of claims 1 to 9, wherein the MCHR1 antagonist is:

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the pharmaceutical combination or compound of any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. A method for treating, ameliorating, slowing the progression of, alleviating a symptom of, reducing an adverse event associated with, or preventing a disease or condition comprising or associated with:

hyperphagia (optionally assessed by HQ-CT),

moderate to severe Binge Eating Disorder (BED),

the nervous bulimia nervosa is induced,

the early-onset of the morbid obesity,

non-alcoholic steatohepatitis (NASH),

non-alcoholic fatty liver disease (NAFLD),

primary Sclerosing Cholangitis (PSC),

primary biliary hepatocholangitis (PBC),

inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS),

in the case of type II diabetes mellitus,

obesity induced by hypothalamic injury,

the state of the art for Obsessive Compulsive Disorder (OCD),

destructive mood disorder (DMDD),

in opposition to contra-sexual disorder (ODD),

the skin scratching disease is caused by the skin scratching,

the trichotillomania removal method is adopted,

intermittent rage disorder (IED),

excessive Daytime Sleepiness (EDS),

excessive daytime sleepiness associated with hypersomnia and sleep apnea,

excessive daytime sleepiness associated with hypersomnia,

in the case of hypersomnia, the symptoms of hypersomnia,

hypersomnia is accompanied by cataplexy,

hypersomnia type 2 (NT 2) according to ICSD-3,

hypersomnia, no cataplexy,

the material is subject to a catapulting action,

in the case of an idiopathic hypersomnia,

rapid Eye Movement (REM) sleep behavior disorder,

the occurrence of an epileptic seizure is detected,

in Major Depressive Disorder (MDD),

treatment-resistant depression (TRD),

the negative symptoms of schizophrenia are those of the general type,

MDD associated with Parkinson's disease,

the treatment of Parkinson's disease is carried out,

the general anxiety of the patient is caused by the general anxiety,

social anxiety disorder (social phobia),

the pain of the Fibromyalgia (FM),

in the case of diabetic nephropathy, the disease is,

the pain of the lower back is caused by the back pain,

the chronic fatigue syndrome of the human body is shown,

attention Deficit Hyperactivity Disorder (ADHD),

the self-curing disease of the patient is caused by autism,

the plant of the asperger lineage is,

a gene-confirmed disease or syndrome, wherein optionally, the gene-confirmed disease or syndrome is or includes prader-willi syndrome, babybi syndrome, smith-magenis syndrome, 1p36 deletion syndrome, 1ip11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) -deficient obesity, leptin receptor (LEPR) -deficient obesity, melanocortin 4 receptor (MC 4R) pathway heterozygous obesity, trisomy 21, rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disease, angler-mans syndrome, shaff-poplar syndrome, olbratt genetic osteodystrophy, schilder-lasel syndrome, maternal 14 maternal disomy, alsetter-rem syndrome, wilms' tumor, aniridia, genitourinary system abnormality, tardive or WAGR or wargo syndrome; delavar syndrome, lorenox-Kastokes syndrome, gilles-Pile syndrome or cerebellar ataxia or Duzier syndrome or myoclonic dystonia epilepsy (MAE), or Niemann-pick disease type C, or Norrin, or Korea-Laudo,

the method comprising administering the therapeutic combination, pharmaceutical dosage form, drug delivery device, article of manufacture, compound, or pharmaceutical composition of any one of claims 1 to 11.

13. The method of claim 12, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device, article of manufacture, compound or pharmaceutical composition is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intracerebrally, epidurally, intracranially, rectally, intrathecally, intracerebral epidurally, subcutaneously, intravenously, intramuscularly, and/or intraarterially.

14. The method of claim 12 or claim 13, wherein the active agent is administered to achieve a therapeutic level range of steady state plasma concentrations, and wherein: a therapeutic level of plasma concentration of the (1-azinone) substituted pyridoindole or the compound of formula II ranges from about: 5 to 4000ng/ml, 10 to 1000ng/ml, 10 to 500ng/ml, 25 to 250ng/ml, 50 to 500ng/ml, 50 to 1000ng/ml, 50 to 500ng/ml, 100 to 1000ng/ml, 100 to 500ng/ml, 200 to 1000ng/ml, 500 to 1000ng/ml, 1000 to 2000ng/ml, 2000 to 3000ng/ml or 3000 to 4000ng/ml.

15. The method of claim 14, wherein the steady state is reached after:

(a) Elimination half-life (T1) of said active agent in humans _/2 ) About 3 to 5 times of, or

(b) About 7 to 14 days after regular or regular administration to optionally once daily dosing of the medicament or therapeutic combination, pharmaceutical dosage form.

16. The method of claim 14 or claim 15, wherein the plasma concentration of the active agent is:

(b) Blood sample measurements taken from about 2 hours to 24 hours, or 4 to 12 hours, or 1,2,3,4, 5,6, 7, 8,9, or 10 hours or more after the last dose or administration of the drug or therapeutic combination, pharmaceutical dosage form.

17. The method of any one of claims 12-15, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture comprises formula II or a deuterated derivative of formula II.

18. A method for administering the therapeutic combination, pharmaceutical dosage form, drug delivery device, article of manufacture, compound or pharmaceutical composition of any one of claims 1 to 11, wherein the dose is determined by:

(i) Daily administration of a test dose (e.g., a dose at which no adverse event is observed or a dose at which minimal adverse event is observed or a safe dose) until the patient reaches a steady state plasma drug concentration,

(ii) Prior to the next predetermined dose, a blood sample is drawn and the test plasma drug concentration is evaluated,

(iii) Initial treatment dose/day was calculated as follows:

B. for drugs whose dose is non-linear with plasma concentration, the initial target therapeutic plasma drug concentration is divided by the test plasma drug concentration, then the dividend is multiplied by the test dose, and then the product is multiplied by a non-linear exponential factor, optionally the initial target therapeutic plasma drug concentration is a concentration corresponding to:

(1) Levels of certain pharmacodynamic efficacy markers determined by imaging methods such as Positron Emission Tomography (PET); or

(2) The lowest effective therapeutic dose as determined by clinical studies,

(iv) Optionally comprising:

(1) The initial therapeutic dose is administered daily until the patient reaches a steady state plasma drug concentration,

(2) Prior to the next scheduled dose, a blood sample is drawn and the current therapeutic plasma drug concentration is evaluated,

(3) The next treatment target dose/day was calculated as follows:

(4) Continuing the procedure until a minimum therapeutic dose or an optimally effective dose is reached; or

(b) A model-based method for safe and predictable titration and determination of the initial therapeutic dose and determination of the lowest therapeutic dose or determination of an optimal effective dose, and the method comprises:

(i) Administering the test dose daily for about 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 1 to 3 days, or about 1 day,

(ii) Withdrawing a first blood sample from about 1 hour to 3 days, 6 hours to 2 days, or about 1 day after administration of the first test dose,

(iii) Withdrawing a second or subsequent blood sample about 1 hour to 28 days, 6 hours to 14 days, 1 day to 7 days, or about 2 days after withdrawing the first or subsequent blood sample,

(iv) Initial treatment start dose/day was calculated as follows:

A. using the initial target treatment plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample and the time at which the blood sample was drawn and a pharmaco-metric model,

B. and optionally, using the initial target therapeutic plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample, the time at which the blood sample was drawn, the human PK data and the Bayesian pharmacogenomics model,

C. and optionally, using the initial target therapeutic plasma drug concentration, the test dose, the time of administration of the test dose, the plasma concentration of the blood sample, the time at which the blood sample was drawn, the human PK data, the patient's genetic information, the patient's non-genetic host factors, the patient's other drugs, and a Bayesian pharmaco-metric model,

(v) And optionally including:

(1) An initial treatment-initiating dose is administered daily until the patient reaches a steady state plasma drug concentration,

(2) Before the next scheduled dose, a blood sample is drawn and the current therapeutic plasma drug concentration is evaluated,

(3) Calculate the next treatment target dose/day:

(4) The procedure is continued until a minimum therapeutic dose or an optimally effective dose is reached.

19. The method of claim 18, wherein the therapeutic combination, pharmaceutical dosage form, drug delivery device, or article of manufacture, compound, or pharmaceutical composition comprises formula II or a deuterated derivative of formula II.

20. The method of any one of claims 12-19, wherein the disorder is type 1 lethargy.

21. The method of claim 20, wherein the human is also suffering from cataplexy.

22. The method of claim 20, wherein the human does not have cataplexy.

23. The method of any one of claims 12 to 19, wherein the disorder is prader-willi syndrome.

24. Use of a therapeutic combination, pharmaceutical dosage form, drug delivery device, article of manufacture, compound or pharmaceutical composition or hormone receptor 1 (MCHR 1) antagonist of any one of claims 1 to 11 in the manufacture of a medicament for the treatment of a condition selected from:

hyperphagia (optionally assessed by HQ-CT),

moderate to severe Binge Eating Disorder (BED),

the symptoms of bulimia nervosa are shown,

the early-onset of the morbid obesity,

non-alcoholic steatohepatitis (NASH),

non-alcoholic fatty liver disease (NAFLD),

primary Sclerosing Cholangitis (PSC),

primary Biliary Cholangitis (PBC),

inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS),

in the case of type II diabetes mellitus, the disease,

obesity induced by hypothalamic injury,

the state of the art for Obsessive Compulsive Disorder (OCD),

destructive mood disorder (DMDD),

oppositional defiance barrier (ODD),

the skin scratching disease is caused by the skin scratching,

the trichotillomania removal method is adopted,

intermittent rage disorder (IED),

excessive Daytime Sleepiness (EDS),

excessive daytime sleepiness associated with hypersomnia and sleep apnea,

excessive daytime sleepiness associated with hypersomnia,

in the case of hypersomnia, the sleep disorder,

hypersomnia is accompanied by cataplexy,

hypersomnia type 2 (NT 2) according to ICSD-3,

hypersomnia, no cataplexy,

the material is subject to a catapulting action,

in the case of an idiopathic hypersomnia,

rapid Eye Movement (REM) sleep behavior disorder,

the occurrence of an epileptic seizure is detected,

epilepsy, an addiction or addiction disorder or behavior, wherein optionally the addiction, addiction disorder or addictive behavior is or comprises an Internet Gaming Disorder (IGD) or a drug addiction, and optionally the drug addiction is or comprises cocaine dependence or alcohol dependence,

in Major Depressive Disorder (MDD),

treatment-resistant depression (TRD),

the negative symptoms of schizophrenia are those of the general type,

the MDD associated with Parkinson's disease,

the treatment of Parkinson's disease is carried out,

the general anxiety of the patient is caused by the general anxiety,

social anxiety disorder (social phobia),

the onset of Fibromyalgia (FM),

in the treatment of diabetic nephropathy, the disease is,

the pain of the lower back is caused by the back pain,

the chronic fatigue syndrome of the human body is shown,

attention Deficit Hyperactivity Disorder (ADHD),

the self-curing disease of the patient is caused by autism,

the plant of the asperger lineage is,

a gene-confirmed disease or syndrome, wherein optionally said gene-confirmed disease or syndrome is or includes prader-willi syndrome, babybi syndrome, smith-magenis syndrome, 1p36 deletion syndrome, 1ip11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) deficient obesity, leptin receptor (LEPR) deficient obesity, melanocortin 4 receptor (MC 4R) pathway hybrid obesity, trisomy 21, rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disease, angler syndrome, shaff-poplar syndrome, olblatt genetic osteodystrophy, schirfer-lasel syndrome, maternal 14 disomy, alsetter-rahm syndrome, wilms' tumor, aniridia, genitourinary system abnormalities, mental retardation or WAGR or WAGRO syndrome; delavir syndrome, renox-gares syndrome, gilles-piss syndrome or cerebellar ataxia or dorzee syndrome or myoclonic dystonia epilepsy (MAE), or niemann-pick disease type C, or norrie disease, or cro-lodi disease.

25. A therapeutic combination, pharmaceutical dosage form, drug delivery device, article of manufacture, compound or pharmaceutical composition or hormone receptor 1 (MCHR 1) antagonist according to any one of claims 1 to 11 for use in the treatment of a condition selected from:

hyperphagia (optionally assessed by HQ-CT),

moderate to severe Binge Eating Disorder (BED),

the nervous bulimia nervosa is induced,

the early-onset of the morbid obesity,

non-alcoholic steatohepatitis (NASH),

non-alcoholic fatty liver disease (NAFLD),

primary Sclerosing Cholangitis (PSC),

primary Biliary Cholangitis (PBC),

inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS),

in the case of type II diabetes mellitus, the disease,

obesity induced by hypothalamic injury,

the state of the art for Obsessive Compulsive Disorder (OCD),

destructive mood disorder (DMDD),

in opposition to contra-sexual disorder (ODD),

the disease of scratching the skin of a patient,

the trichotillomania removal method is adopted,

intermittent rage disorder (IED),

excessive Daytime Sleepiness (EDS),

excessive daytime sleepiness associated with hypersomnia and sleep apnea,

excessive daytime sleepiness associated with hypersomnia,

in the case of hypersomnia, the sleep disorder,

hypersomnia is accompanied by cataplexy,

according to ICSD-3 hypersomnia type 2 (NT 2),

hypersomnia, no cataplexy,

the process of the cataplexy is carried out,

in the case of an idiopathic hypersomnia,

rapid Eye Movement (REM) sleep behavior disorder,

the occurrence of an epileptic seizure is,

in Major Depressive Disorder (MDD),

treatment-resistant depression (TRD),

the negative symptoms of schizophrenia are those of the general type,

MDD associated with Parkinson's disease,

the treatment of Parkinson's disease is carried out,

the general anxiety of the patient is caused by the general anxiety,

social anxiety disorder (social phobia),

the onset of Fibromyalgia (FM),

in the treatment of diabetic nephropathy, the disease is,

the pain of the lower back is caused by the back pain,

the chronic fatigue syndrome of the human body is shown,

attention Deficit Hyperactivity Disorder (ADHD),

the self-curing disease of the patient is caused by autism,

the plant of the asperger lineage is,

a gene-confirmed disease or syndrome, wherein optionally, the gene-confirmed disease or syndrome is or includes prader-willi syndrome, babybi syndrome, smith-magenis syndrome, 1p36 deletion syndrome, 1ip11.2 deletion syndrome, fragile X syndrome, proopiomelanocortin (POMC) -deficient obesity, leptin receptor (LEPR) -deficient obesity, melanocortin 4 receptor (MC 4R) pathway heterozygous obesity, trisomy 21, rett syndrome, cyclin-dependent kinase-like 5 (CDKL-5) X-linked genetic disease, angler-mans syndrome, shaff-poplar syndrome, olbratt genetic osteodystrophy, schilder-lasel syndrome, maternal 14 maternal disomy, alsetter-rem syndrome, wilms' tumor, aniridia, genitourinary system abnormality, tardive or WAGR or wargo syndrome; delavir syndrome, renox-gares syndrome, gilles-piss syndrome or cerebellar ataxia or dorzee syndrome or myoclonic dystonia epilepsy (MAE), or niemann-pick disease type C, or norrie disease, or cro-lodi disease.