RU2780002C2 - Organic compounds - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a method for the treatment or prevention of a disorder of the central nervous system, including the administration to a patient who needs it of a compound of the formula I:

Formula I,

in which: X is -NH-; L is O; Z is -CH(O-R₁)-, -O-, or -C(O)-; R₁ is H; in a free or pharmaceutically acceptable salt form. In this case, the disorder is a pain disorder selected from neuropathic pain, idiopathic pain, chronic pain, fibromyalgia, toothache, and traumatic pain; or the disorder is a pain disorder in a patient also suffering from a gastrointestinal and/or pulmonary disorder, or in a patient also suffering from a disorder related to opioid use; or the disease or disorder is opiate overdose or a disorder related to opioid use. The invention also relates to the use of the specified compound in the production of a drug for the treatment or prevention of disorders of the central nervous system, where the disorder is selected from the above-mentioned.

EFFECT: treatment method is developed, including the administration of a compound of the formula I for the treatment or prevention of the above-mentioned disorders.

16 cl, 2 dwg, 17 ex

Description

Cross-references to related applications

[0001] This application claims the priority of U.S. Provisional Applications Nos. 62/537287, filed July 26, 2017, and 62/639244, filed March 6, 2018; and 62/682546, filed June 8, 2018; the content of each of which is incorporated into the present invention by reference in its entirety.

TECHNICAL FIELD OF THE PRESENT INVENTION

[0002] The present invention relates to novel methods and uses relating to specific substituted heterocyclic fused gamma-carbolines, their prodrugs in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, and their pharmaceutical compositions. such as methods of use in the treatment of diseases involving the 5-HT _2A receptor pathways, the serotonin transporter (SERT) pathways involving dopamine D ₁ and D ₂ receptor signaling systems, and/or the μ-opioid receptor, for example, diseases and disorders such as anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache diseases, social phobias, gastrointestinal disorders such as gastrointestinal motility dysfunction and obesity; depression and behavioral disorders associated with psychosis or Parkinson's disease; psychosis such as schizophrenia associated with depression; bipolar disorder; behavioral disorders; drug addiction such as opiate dependence and alcohol dependence, drug withdrawal syndrome, and other psychiatric and neurological diseases, as well as combinations with other agents. In addition, these compounds and compositions are useful in methods of treating obsessive compulsive disorder (OCD), obsessive compulsive personality disorder (OCPD), and related disorders. In some embodiments, the disease or disorders may include treatment-resistant depression, cocaine and/or amphetamine addiction, opioid use disorder, and opioid withdrawal symptoms.

BACKGROUND OF THE INVENTION

[0003] Substituted heterocyclic fused gamma-carbolines are known as 5-HT ₂ receptor agonists or antagonists, in particular 5-HT _2A and 5-HT _2C receptors, in the treatment of disorders of the central nervous system. These compounds are described in US patent No. 6548493; 7238690; 6552017; 6713471; 7183282; US RE39680 and US RE39679 as novel compounds useful in the treatment of disorders associated with 5-HT _2A receptor modulation such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache-related disorders pain, social phobias, gastrointestinal disorders such as gastrointestinal motility dysfunction and obesity. PCT/US08/03340 (WO 2008/112280) and its US equivalent US 2010/113781 and US application serial no. 10/786935 (published as US 2004/209864) also describe methods for the preparation of substituted heterocyclic fused gamma-carbolines and the use of these gamma-carbolines as serotonin agonists and antagonists useful in combating and preventing disorders of the central nervous system such as addictive behaviors and disorders sleep.

[0004] In addition, WO/2009/145900 (and its equivalent US 2011/071080) describes the use of specific substituted heterocyclic fused gamma-carbolines for the treatment of a combination of psychosis and a depressive disorder, as well as sleep, depressive and/or behavioral disorders in patients with psychosis or Parkinson's disease. In addition to disorders associated with psychosis and/or depression, this patent application describes and claims the use of these compounds at low dose for selective antagonism of 5-HT _2A receptors with no or minimal effect on dopamine D ₂ receptors, thereby being suitable for treatment of sleep disorders without side effects associated with high loading of the dopamine D ₂ pathways or side effects of other pathways (eg, GABA _A receptors) associated with conventional sedative-hypnotic agents (eg, benzodiazepines), including, but not limited to, the development of drug dependence , muscle hypotension, weakness, headache, blurred vision, dizziness, nausea, vomiting, epigastric distress, diarrhea, joint pain and chest pain. WO 2009/114181 (and its equivalent US 2011/112105) also describes methods for preparing crystals of toluenesulfonic acid addition salts of these substituted heterocyclic fused gamma-carbolines.

[0005] In addition, recent data show that the above substituted heterocyclic fused gamma-carbolines can act, in part, through NMDA receptor antagonism via mTOR1 signaling, in a manner similar to that of ketamine. Ketamine is a selective NMDA receptor antagonist. Ketamine acts through a system that is not related to the usual psychogenic monoamines (serotonin, norepinephrine and dopamine) and this is the main reason for its much faster effects. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also indirectly leads to activation of AMPA-type glutamate receptors. Subsequent effects include the brain-derived neurotrophic factor (BDNF) and mTORC1 kinase pathways. As with ketamine, recent evidence suggests that the compounds of the present invention enhance both NMDA and AMPA-induced currents in pyramidal neurons in the rat medial prefrontal cortex via activation of D1 receptors, and that this is associated with increased mTORC1 signaling.

[0006] Metabolites of the compounds described in the above publications, as well as related compounds, are also described in WO 2017/132408 and US 2017/319580.

[0007] Obsessive-compulsive disorder (OCD) and related disorders have become widespread and difficult to treat. It is estimated that OCD affects about 2.3% of people at some point in their lives, and during that year, an estimated 1.2% of people worldwide suffer from the disorder. Half of the people suffering from OCD begin to show symptoms before the age of 20, which can seriously affect their ability to receive an adequate and effective education. However, without effective treatment, the disease can last for decades. Selective serotonin reuptake inhibitors (SSRIs) are the mainstay of pharmacological treatment for OCD. The second line of therapy is antipsychotic agents such as clomipramine, risperidone, quetiapine, and olanzapine. A significant number of patients either do not respond to these agents or cannot cope with the side effects caused by these agents. More recently, it has been reported that the opioid analgesic, tramadol, may be effective in the treatment of OCD. Opiates work very differently from traditional OCD drugs, so they offer a treatment option for people who cannot take traditional serotonergic drugs or for whom these agents are ineffective. However, strong opiate agents can be addictive and may be contraindicated in some patients. Thus, there remains a strong need for new treatments for pain, OCD and other disorders.

[0008] Drug dependence disorders such as opiate use disorder (OUD) are another group of disorders that are difficult to successfully treat. Opioid overdoses claim approximately 100 lives in the United States each day, and the opioid craze continues to grow in the United States. Methadone, buprenorphine, and naltrexone are the most commonly used treatments for OUD. Methadone is a mu-opioid receptor (MOP) agonist, buprenorphine is a partial MOP agonist, and naltrexone is an MOP antagonist. Each of these agents has had limited success, and long-term adherence to prescribed treatments for OUD remains low. In addition, these treatments often exacerbate common comorbidities associated with OUD, such as mood disorders and anxiety, further increasing the risk of remission. Abrupt cessation of opioid use (i.e., "going off") is also associated with serious side effects, including dysphoria, depression, and anxiety, and conventional medications do not address these problems and may exacerbate them. Thus, there is an urgent need for improved treatments for OUD.

SUMMARY OF THE INVENTION

[0009] Surprisingly, the compounds of the present invention have been found to have high activity at serotonin receptors (eg, 5-HT _2A ), serotonin transporters (SERTs), dopamine receptors (eg, D1 and/or D2), and the mu-opiate receptor, and they additionally exhibit a unique ligand-displaced mu-opiate receptor activity. It is also believed that the compounds of the present invention, through their D1 receptor activity, may also enhance NMDA and AMPA mediated signaling via the mTOR pathway.

[0010] The present invention relates to compounds of formula I which are useful in the treatment or prevention of disorders of the central nervous system. In a first aspect, the present invention relates to a compound (compound I) of formula I:

wherein:

X is -NH- or -N(CH ₃ )-;

L is selected from O, NH, NR ^a and S;

Z is -CH(OR ₁ )-, -O- or -C(=O)-;

R ₁ is H, -C(O)-C _1-21 alkyl (e.g. -C(O)-C _1-5 alkyl, -C(O)-C _6-15 alkyl or -C(O)- C _16-21 alkyl), preferably said alkyl is normal, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C _1-22 alkoxy (e.g. ethoxy) groups, e.g. R ₁ is C(O)-C ₃ alkyl, -C(O)C ₆ alkyl, -C(O)-C ₇ alkyl, -C(O)-C ₉ alkyl, -C(O)-C ₁₁ alkyl, -C(O)-C ₁₃ alkyl or -C(O)-C ₁₅ alkyl;

^Ra is:

halogen, C _1-4 alkyl, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, or C ₃ - ₆ cycloalkyl, each of which can be independently substituted with up to three independently selected R ^b groups, for example C- _1-3 haloalkyl or C _1-3 hydroxyalkyl; or

aryl optionally substituted with up to five independently selected R ^b ; and

each R ^b is independently selected from H, halo, NH ₂ , NO ₂ , OH, C(O)OH, CN, SO ₃ and C _1-4 alkyl;

in free or salt form, for example isolated or purified free or salt form.

[0011] The present invention relates to additional exemplary embodiments of a compound of Formula I, in free or salt form, such as isolated or purified free or salt form, comprising:

1.1 Compound I, in which L represents -O-;

1.2 Connection I or 1.1, in which Z represents -CH(OR ₁ )-;

1.3 Connection I or 1.1, in which Z represents -C(=O)-;

1.4 Compound I wherein L is NH.

1.5 Compound I, wherein L is NR ^a ;

1.6 Connection I, in which L represents S;

1.7 Compound I or any of 1.1-1.6 in solid form, eg solid salt form;

1.8 Connection I or any of 1.1-1.7, in which Z represents -CH(OR ₁ )-;

1.9 Compound I or any of 1.1-1.7 wherein Z is -C(=O)-;

1.10 Compound I or any of 1.1-1.7 wherein Z is -O-;

1.11 Compound I or any of 1.1-1.10 wherein X is -NH-;

1.12 Connection I or any of 1.1-1.10, in which X represents -N(CH ₃ )-;

1.13 Compound I or any of 1.1-1.12 wherein L is -O- and X is -N(CH ₃ )-;

1.14 Compound I or any of 1.1-1.12 wherein L is -O- and X is -NH-;

1.15 Compound 1.13 wherein Z is -C(=O)-;

1.16 Compound 1.14 wherein Z is -C(=O)-;

1.17 Compound I or any of 1.1-1.14 wherein Z is -CH(OR ₁ )- and R ₁ is H;

1.18 Compound I or any of 1.1-1.14 wherein Z is -CH(OR ₁ )- and R ₁ is -C(O)-C _1-5 alkyl, -C(O)-C _6-15 alkyl or -C(O)-C _16-21 alkyl;

1.19 Compound I or any of 1.1-1.14 wherein Z is -CH(OR ₁ )- and R ₁ is selected from the group consisting of C(O)-C ₃ alkyl, -C(O)C ₆ alkyl, -C(O)-C ₇ alkyl, -C(O)-C ₉ alkyl, -C(O)-C ₁₁ alkyl, -C(O)-C ₁₃ alkyl or -C(O)-C ₁₅ alkyl; for example, in which R ¹ represents acetyl, ethylcarbonyl or propylcarbonyl;

1.20 Compound I or any of 1.1-1.12 or 1.17-1.19 wherein L is NR ^a and wherein R ^a is:

halogen, C_1-4 alkyl, C₂-_four alkenyl, C_2-4 alkynyl or C₃-₆ cycloalkyl, each of which may optionally be substituted with up to three independently selected R^b groups; or in which R^a is aryl optionally substituted with up to five independently selected R^b; in which R^b independently selected from H, halogen, NH₂, NO₂, OH, C(O)OH, CN, SO₃and C_1-4alkyl;

1.21 Connection 1.20, in which R ^a represents C _1-4 alkyl or C ₃ - ₆ cycloalkyl, optionally substituted with up to three independently selected R ^b groups;

1.22 Compound 1.20 wherein R ^a is aryl optionally substituted with up to three independently selected R ^b groups;

1.23 Connection 1,20, in which R ^a is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or phenyl;

1.24 Compound I or any of 1.1-1.14 or 1.17-1.23, wherein Z is -CH(OR ₁ )-; and the specified carbon atom CH in the group-CH(OR ₁ )- has either the R configuration or the S configuration, or a mixture thereof;

1.25 Compound 1.24 wherein said carbon atom CH is substantially present in either the R or S configuration, e.g. 75% or more than 80% or more than 85% or more than 90% or more than 95% or more than 97% or more than 98% or more than 99% diastereomeric excess.

1.26 Compound I or any of 1.1-1.25, where the compound is selected from the group consisting of:

;

;

1.27 Compound I or any of 1.1-1.25, where the compound is selected from the group consisting of:

;

;

1.28 Compound I or any of 1.1-1.27 where the compound is

в свободной или солевой форме (например, фармацевтически приемлемой солевой форме);

in free or salt form (eg, pharmaceutically acceptable salt form);

1.29 Compound I or any of 1.1-1.27 where the compound is

в свободной или солевой форме (например, фармацевтически приемлемой солевой форме);1.30

in free or salt form (eg, pharmaceutically acceptable salt form);

1.31 Compound I or any of 1.1-1.27 where the compound is

в свободной или солевой форме (например, фармацевтически приемлемой солевой форме);1.32

in free or salt form (eg, pharmaceutically acceptable salt form);

1.33 Compound I or any of 1.1-1.32, in free form;

1.34 Compound I or any of 1.1-1.32 in salt form, eg a pharmaceutically acceptable salt form;

1.35 Compound I or any of 1.1-1.34 in solid form.

in free or salt form, for example isolated or purified free or salt form.

[0012] In a second aspect, the present invention relates to a compound (compound II) of formula II:

Formula II

wherein:

X is -NH- or -N(CH ₃ )-;

Y is -CH(OR ₁ )- or -C(=O)-;

R ₁ is H, -C(O)-C _1-21 alkyl (e.g. -C(O)-C _1-5 alkyl, -C(O)-C _6-15 alkyl or -C(O)- C _16-21 alkyl), preferably said alkyl is normal, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C _1-22 alkoxy (e.g. ethoxy) groups, e.g. R ₁ is C(O)-C ₃ alkyl, -C(O)C ₆ alkyl, -C(O)-C ₇ alkyl, -C(O)-C ₉ alkyl, -C(O)-C ₁₁ alkyl, -C(O)-C ₁₃ alkyl or -C(O)-C ₁₅ alkyl;

in free or salt form, for example isolated or purified free or salt form.

[0013] The present invention relates to additional exemplary embodiments of a compound of formula II, in free or salt form, for example, isolated or purified free or salt form, including:

2.1 Compound II, wherein X is -NH-;

2.2 Compound II, wherein X is -N(CH ₃ )-;

2.3 Compound II or 2.1-2.4, in which Y represents -C(=O)-;

2.4 Compound II, in which Y represents -CH(OR ₁ )-; i.e. having the formula II-A:

Formula II-A

2.5 Compound II or 2.1-2.4, in which Y represents -CH(OR ₁ )-;

2.6 Compound II wherein X is NH and Y is -C(=O)-; i.e. having the formula II-B:

Formula II-B

2.7 Compound II wherein X is -NH- and Y is -CH(OR ₁ )-;

2.8 Compound II, in which X is -NH-, and Y is -CH(OR ₁ )-, in which R ₁ is H; i.e. having the formula II-C:

Formula II-C

2.9 Compound II wherein X is -N(CH ₃ )- and Y is -C(=O)-; i.e. having the formula II-D:

Formula II-D

2.10 Compound II wherein X is -N(CH ₃ )- and Y is -CH(OR ₁ )-;

2.11 Compound II wherein X is -N(CH ₃ )- and Y is -CH(OR ₁ )- wherein R ₁ is H; i.e. having the formula II-E:

Formula II-E

2.12 Compound II or any of 2.1-2.11 in solid form, eg solid salt form.

[0014] In a third aspect, the present invention relates to a compound (compound III) of formula III:

Formula III

wherein:

X is -NH- or -N(CH ₃ )-;

R ₁ is H, -C(O)-C _1-21 alkyl (e.g. -C(O)-C _1-5 alkyl, -C(O)-C _6-15 alkyl or -C(O)- C _16-21 alkyl), preferably said alkyl is normal, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C _1-22 alkoxy (e.g. ethoxy) groups, e.g. R ₁ is C(O)-C ₃ alkyl, -C(O)C ₆ alkyl, -C(O)-C ₇ alkyl, -C(O)-C ₉ alkyl, -C(O)-C ₁₁ alkyl, -C(O)-C ₁₃ alkyl or -C(O)-C ₁₅ ;

in free or salt form, for example isolated or purified free or salt form.

[0015] The present invention relates to additional exemplary embodiments of a compound of formula III, in free or salt form, for example, isolated or purified free or salt form, including:

3.1 Compound III, in which R ₁ represents H; i.e. having the formula III-A:

Formula III-A

in free or salt form, for example isolated or purified free or salt form;

3.2 Compound III or 3.1 wherein X is -NH-;

3.3 Compound III or 3.1, in which X represents -N(CH ₃ )-;

3.4 Compound 3.1 wherein X is -NH-; i.e. having the formula III-B:

Formula III-B

3.5 Compound 3.1 wherein X is -N(CH ₃ )-; i.e. having the formula III-C:

Formula III-C

3.6 Compound III or any of 3.1-3.5, wherein the compound has a diastereomeric excess of greater than 70%;

3.7 Compound III or any of 3.1-3.6, wherein the compound has a diastereomeric excess of greater than 80%;

3.8 Compound III or any of 3.1-3.7, wherein the compound has a diastereomeric excess of greater than 90%;

3.9 Compound III or any of 3.1-3.8, wherein the compound has a diastereomeric excess of greater than 95%;

3.10 Compound III or any of 3.1-3.9, wherein the compound is in substantially pure diastereomeric form (i.e., substantially free of other diastereomers)

3.11 Compound III or any of 3.1-3.10 in solid form, eg solid salt form.

[0016] In a fourth aspect, the present invention relates to a compound (compound IV) of formula IV:

Formula IV

wherein:

X is -NH- or -N(CH ₃ )-;

R ₁ is H, -C(O)-C _1-21 alkyl (e.g. -C(O)-C _1-5 alkyl, -C(O)-C _6-15 alkyl or -C(O)- C _16-21 alkyl), preferably said alkyl is normal, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C _1-22 alkoxy (e.g. ethoxy) groups, e.g. R ₁ is C(O)-C ₃ alkyl, -C(O)C ₆ alkyl, -C(O)-C ₇ alkyl, -C(O)-C ₉ alkyl, -C(O)-C ₁₁ alkyl, -C(O)-C ₁₃ alkyl or -C(O)-C ₁₅ alkyl;

in free or salt form, for example isolated or purified free or salt form.

[0017] The present invention relates to further exemplary embodiments of a compound of formula IV, in free or salt form, such as isolated or purified free or salt form, comprising:

4.1 Compound IV, wherein R ₁ is H; i.e. having the formula IV-A:

Formula IV-A

in free or salt form, for example isolated or purified free or salt form.

4.2 Compound IV or 4.1 wherein X is -NH-;

4.3 Compound IV or 4.1 wherein X is -N(CH ₃ )-;

4.4 Compound 4.1 wherein X is -NH-; i.e. having the formula IV-B:

Formula IV-B

4.5 Compound 4.1 wherein X is -N(CH ₃ )-; i.e. having the formula IV-C:

Formula IV-C

4.6 Compound IV or any of 4.1-4.5, wherein the compound has a diastereomeric excess of greater than 70%

4.7 Compound IV or any of 4.1-4.6, wherein the compound has a diastereomeric excess of greater than 80%

4.8 Compound IV or any of 4.1-4.7, wherein the compound has a diastereomeric excess of greater than 90%

4.9 Compound IV or any of 4.1-4.8, wherein the compound has a diastereomeric excess of greater than 95%

4.10 Compound IV or any of 4.1-4.9, wherein the compound is in substantially pure diastereomeric form (i.e., substantially free of other diastereomers);

4.11 Compound IV or any of 4.1-4.10 in solid form, eg solid salt form.

[0018] In a fifth aspect, the present invention relates to each of the following compounds I or 1.1-1.35, compound II or 2.1-2.12, compound III or 3.1-3.11, or compound IV or 4.1-4.11 (hereinafter together "compounds formulas I-IV et seq. or “compounds of the present invention”) in free or pharmaceutically acceptable salt form. The present invention relates to additional exemplary embodiments of the compounds of formulas I-IV and beyond, including:

5.1 Compounds of formulas I-IV and the like, wherein the salt is an acid addition salt selected from hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic and the like;

5.2 Compounds of formulas I-IV et seq., wherein the salt is a fumaric acid addition salt;

5.3 Compounds of formulas I-IV et seq., wherein the salt is an addition salt of phosphoric acid;

5.4 Compounds of formulas I-IV et seq., in which the salt is the addition salt of toluenesuloacid;

5.5 Any of 5.1-5.4 wherein the salt is in solid form.

[0019] In an eighth aspect, the present invention relates to a pharmaceutical composition (pharmaceutical composition 6) containing a compound of any of Compound I or 1.1-1.35, Compound II or 2.1-2.12, Compound III or 3.1-3.11, or Compound IV or 4.1- 4.11 (together with a compound of formulas I-IV et seq. or a compound of the present invention), for example, in admixture with a pharmaceutically acceptable diluent or carrier. The present invention relates to additional exemplary embodiments of the pharmaceutical composition 6, including:

6.1 Pharmaceutical composition 6 containing compound I or any of 1.1-1.35;

6.2 Pharmaceutical composition 6 containing compound II or any of 2.1-2.12;

6.3 Pharmaceutical composition 6 containing compound III or any of 3.1-3.11;

6.4 Pharmaceutical composition 6 containing compound IV or any of 4.1-4.11;

6.5 Pharmaceutical composition 6 or any of 6.1-6.4, where the compound of formula I-IV and further is in solid form;

6.6 Pharmaceutical composition 6 or any of 6.1-6.5, where the compound of formulas I-IV and further is in a pharmaceutically acceptable salt form, as defined in compounds 5.1-5.5;

6.7 Pharmaceutical composition 6 or any of 6.1-6.6, wherein the compound of formulas I-IV and beyond is in admixture with a pharmaceutically acceptable diluent or carrier.

[0020] In a preferred embodiment, the pharmaceutical composition of the present invention comprises a compound of formula II-A, II-B or II-C, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another preferred embodiment, the pharmaceutical composition of the present invention comprises a compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another preferred embodiment, the pharmaceutical composition of the present invention comprises a compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

[0021] In a further embodiment, the pharmaceutical compositions of the present invention are for extended or delayed release, eg, depot formulation. In one embodiment, the depot formulation (depot formulation 6.8) is a pharmaceutical composition of any of 6.1-6.7, preferably in free or pharmaceutically acceptable salt form, and preferably in admixture with a pharmaceutically acceptable diluent or carrier, e.g. in the form of an injectable depot form.

[0022] In the following embodiment, the depot composition (depot composition 6.9) contains a pharmaceutical composition of any of 6.1-6.7, where R ₁ is -C(O)-C _6-15 alkyl, in free or pharmaceutically acceptable salt form, in mixtures with a pharmaceutically acceptable diluent or carrier.

[0023] In the following embodiment, the present invention relates to pharmaceutical composition 6,10, which is a pharmaceutical composition 6 or any of 6.1-6.9, where the compound of formula I-IV and further is in a polymer matrix. In one embodiment, the compound of the present invention is dispersed or dissolved in a polymeric matrix. In a further embodiment, the polymer matrix comprises standard polymers used in depot formulations such as polymers selected from polyester hydroxy fatty acid and its derivatives, or polymer alkyl alpha cyanoacrylate, polyalkylenexalate, polyorthoester, polycarbonate, polyortho-carbonate, polyamino acid, hyaluronic ester acids and their mixtures. In a further embodiment, the polymer is selected from the group consisting of polylactide, poly d, l-lactide, polyglycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, the copolymers listed above, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(orthocarbonates ), poly(acetals), poly(lactic acid-caprolactone), polyrthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes such as glycerol mono- and distearate, and the like. In a preferred embodiment, the polymeric matrix comprises poly(d,l-lactide-co-glycolide).

[0024] For example, in one embodiment of pharmaceutical composition 6.10, the compound is a compound of formula I, wherein X is -NH- or -N(CH ₃ )- and Y is -C(=O)- or - C(H)(OH)-, in free or pharmaceutically acceptable salt form. In another example of pharmaceutical composition 6.10, the compound is a compound of formula II-A, II-B or II-C, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another example of pharmaceutical composition 6.10, the compound is a compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another example of pharmaceutical composition 6.10, the compound is a compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. In another embodiment of each of the examples above of pharmaceutical composition 6.10, the polymeric matrix contains a poly(d,l-lactide-co-glycolide).

[0025] (Pharmaceutical) compositions 6 and 6.1-6.10 are particularly suitable for extended or delayed release, where the compound of the present invention is released upon degradation of the polymer matrix. These compositions may be formulated to provide controlled and/or sustained release of the compounds of the present invention (eg, as a depot composition) over a period of up to 180 days, eg, from about 14 to about 30 to about 180 days. For example, the polymeric matrix can break down and release the compounds of the present invention over a period of about 30, about 60, or about 90 days. In another example, the polymer matrix can break down and release the compounds of the present invention over a period of about 120 or about 180 days.

[0026] In yet another embodiment, the pharmaceutical compositions of the present invention, for example, the depot composition of the present invention, for example, pharmaceutical composition 6.6 or 6.10, are formulated for administration by injection.

[0027] In a seventh aspect, the present invention relates to compounds of formulas I-IV and further, as described in the present invention above, in an osmotically controlled release oral delivery system (OROS) as described in WO 2000/35419 (US 2001/ 0036472) and EP 1539115 (US Publication No. 2009/0202631), the contents of each of which are incorporated by reference in their entirety. Therefore, in one embodiment of the seventh aspect, the present invention relates to a pharmaceutical composition or device comprising (a) a gelatin capsule containing a compound of any of formulas I-IV and further in free or pharmaceutically acceptable salt form or a pharmaceutical composition of the present invention as described in the present invention above; (b) a multilayer shell, layered on a gelatin capsule, containing, in the direction outward from the capsule: (i) a barrier layer, (ii) a foam layer and (iii) a semi-permeable layer; and (c) and a hole formed or formed in the shell (pharmaceutical composition P.1).

[0028] In another embodiment, the present invention relates to a pharmaceutical composition containing a gelatin capsule containing a liquid, a compound of formulas I-V and further in free or pharmaceutically acceptable salt form, or a pharmaceutical composition of the present invention, for example, any of pharmaceutical compositions 6 or 6.1- 6.10, wherein the gelatin capsule is surrounded by a multilayer shell comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semi-permeable layer surrounding the foamable layer, and an outlet formed or formed in the shell (pharmaceutical composition P.2 ).

[0029] In yet another embodiment of the seventh aspect, the present invention relates to a composition comprising a gelatin capsule containing a liquid, a compound of formulas I-v and further in free or pharmaceutically acceptable salt form, or a pharmaceutical composition of the present invention, for example, any of pharmaceutical compositions 6 or 6.1-6.10, wherein the gelatin capsule is surrounded by a multilayer shell containing a barrier layer in contact with the outer surface of the gelatin capsule, a foam layer in contact with the barrier layer, a semi-permeable layer surrounding the foam layer, and an outlet formed or formed in the shell, where the barrier layer forms an insulating layer between the foamable layer and the environment at the outlet (pharmaceutical composition P.3).

[0030] In yet another embodiment of the seventh aspect, the present invention relates to a composition comprising a gelatin capsule containing a liquid, a compound of formulas I-V and further in free or pharmaceutically acceptable salt form, or a pharmaceutical composition of the present invention, for example, any of pharmaceutical compositions 6 or 6.1-6.10, wherein the gelatin capsule is surrounded by a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with a part of the barrier layer, a semi-permeable layer surrounding at least the expandable layer, and an outlet formed or formed in the dosage form, extending from the outer surface of the gelatin capsule to the environment of use (pharmaceutical composition P.4). The expandable layer can be formed in one or more discrete sections, such as, for example, two sections located on opposite sides or ends of the gelatin capsule.

[0031] In a specific embodiment of the seventh aspect, the compound of the present invention in an osmotically controlled release oral delivery system (i.e., pharmaceutical compositions P.1-P.4) is in a liquid formulation, where the formulation may be pure, be a liquid active agent, liquid active agent in solution, suspension, emulsion or self-emulsifying composition or the like.

[0032] For more information on the composition of an osmotically controlled release oral delivery system, including characteristics of the gelatin capsule, barrier layer, expandable layer, semi-permeable layer and aperture, can be found in WO 2000/35419 and US 2001/0036472, the contents of which are incorporated by reference in their entirety.

[0033] Another osmotically controlled release oral delivery system for a compound of formulas I-V and beyond or a pharmaceutical composition of the present invention can be found in EP 1539115 (U.S. Publication No. 2009/0202631), the contents of which are incorporated by reference in its entirety. Therefore, in another embodiment of the seventh aspect, the present invention relates to a composition or device comprising (a) two or more layers, said two or more layers comprising a first layer and a second layer, said first layer comprising a compound of formulas I-V and so on, in a free or pharmaceutically acceptable salt form, or a pharmaceutical composition as described in the present invention above, wherein said second layer contains a polymer; (b) an outer shell surrounding said two or more layers; and (c) a hole in said outer shell (pharmaceutical composition P.5).

[0034] Pharmaceutical composition P.5 preferably uses a semi-permeable membrane surrounding a three-layer core: in these embodiments, the first layer is called the first drug layer, and it contains low amounts of drug (for example, compounds of formulas I-V and beyond) and an osmotic agent , such as salt, the middle layer, called the second drug layer, contains large amounts of drug, excipients, and does not contain salt; and the third layer, called the osmotic substance layer, contains osmotic agents and does not contain a drug (pharmaceutical composition P.6). At least one hole is drilled through the membrane at the end of the first drug layer of the capsule-shaped tablet.

[0035] Composition P.5 or P.6 may comprise a membrane forming a section, a membrane surrounding an inner protective layer, at least one outlet formed or formed therein, and wherein at least a portion of the membrane is semi-permeable ; a foamable layer located in a section remote from the outlet and in fluid communication with the semi-permeable portion of the membrane; a first drug layer adjacent to the exit port; and a second drug layer located in a section between the first drug layer and the foamable layer, the drug layers containing the compound of the present invention in free or pharmaceutically acceptable salt form thereof (pharmaceutical composition P.7). Depending on the relative viscosity of the first drug layer and the second drug layer, different release profiles are obtained. It is mandatory to determine the optimum viscosity for each layer. In the present invention, the viscosity is modulated by the addition of a salt, sodium chloride. The delivery profile from the core depends on the weight, composition and thickness of each of the drug layers.

[0036] In a specific embodiment, the present invention relates to pharmaceutical composition P.7, in which the first drug layer contains a salt and the second drug layer does not contain salt. The pharmaceutical composition P.5-P.7 may optionally comprise a flow promoting layer between the membrane and the drug layers.

[0037] Pharmaceutical compositions P.1-P.7 will be generally referred to as an osmotically controlled release oral delivery system formulation.

[0038] In an eighth aspect, the present invention relates to a method (method 1) for treating or preventing a disorder of the central nervous system, comprising administering to a patient in need a compound of formulas I-IV et seq. or pharmaceutical composition 6 or 6.1-6.10 or P.1-P .7, for example, method 1, where the administered compound or composition is:

1.1 Compound I or any of 1.1-1.35, in free or pharmaceutically acceptable salt form;

1.2 Compound II or any of 2.1-2.12 in free or pharmaceutically acceptable salt form;

1.3 Compound III or any of 3.1-3.11 in free or pharmaceutically acceptable salt form;

1.4 Compound IV or any of 4.1-4.11 in free or pharmaceutically acceptable salt form;

1.5 Compounds of option 5 or any of 5.1-5.5;

1.6 A compound of formula II-A, II-B or II-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

1.7 Compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

1.8 A compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

1.9 Pharmaceutical composition as defined by any of compositions 6 and 6.1-6.10;

1.10 A pharmaceutical composition containing a compound of formula II-A, II-B or II-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

1.11 A pharmaceutical composition containing a compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

1.12 A pharmaceutical composition containing a compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

1.13 Depot composition as defined in depot composition 6.09 or 6.10;

1.14 Pharmaceutical composition P.1-P.7;

1.15 An osmotically controlled release oral delivery system composition as described above in the present invention;

[0039] In the following embodiment of the eighth aspect, the present invention relates to method 1 or any of the methods 1.1-1.15, where the method is further described below:

1.16 Method 1 or any of the methods 1.1-1.15, wherein the central nervous system disorder is a disorder selected from the group consisting of obesity, anxiety, depression (e.g., resistant depression and MDD), psychosis (including psychosis associated with dementia, such as hallucinations in advanced Parkinson's disease or paranoid ideas), schizophrenia, sleep disorders (in particular sleep disorders associated with schizophrenia and other psychiatric and neurological disorders), sexual disorders, migraine, headache-related disorders, social phobias, agitation in dementia (eg, agitation in Alzheimer's disease), agitation in autism and related autistic disorders, disorders of the gastrointestinal tract, such as gastrointestinal motility dysfunction, and dementia, eg, dementia in Alzheimer's disease or Parkinson's disease; behavioral disorders; and drug addiction, eg, opiate addiction and/or alcohol addiction, or withdrawal from drugs or alcohol addiction (eg, opiate addiction); or compulsive overeating; or opiate overdose; or opiate use disorder (OUD);

1.17 Method 1 or any of the methods 1.1-1.6 wherein the central nervous system disorder is a disorder involving the serotonin 5-HT ₂ A, dopamine D2 and/or D1 receptor system and/or serotonin reuptake transporter (SERT) pathways as similar to the description in WO/2009/145900 and US 2011/071080, the contents of which are incorporated into the present invention by reference in its entirety;

1.18 Method 1 or any of methods 1.1-1.17, wherein the central nervous system disorder is a μ-opioid receptor-involving disorder;

1.19 Method 1 or any of the methods 1.1-1.18, wherein the central nervous system disorder is a disorder selected from the following: (i) psychosis, eg, schizophrenia, in a patient suffering from depression; (2) depression in a patient suffering from psychosis, such as schizophrenia; (3) behavioral disorders associated with psychosis, such as schizophrenia or Parkinson's disease; (4) sleep disorders associated with psychosis, such as schizophrenia or Parkinson's disease; and (5) drug dependence, drug use disorders, and/or drug induced disorders, optionally wherein the patient suffers from residual symptoms of anxiety or an anxiety disorder ;

1.20 Method 1 or any of the methods 1.1-1.18, wherein the central nervous system disorder is a psychosis, such as schizophrenia, and said patient is a patient suffering from depression;

1.21 Method 1 or any of the methods 1.1-1.20, wherein said patient is unable to tolerate the side effects of conventional antipsychotic drugs e.g. , trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone;

1.22 Method 1 or any of the methods 1.1-1.20, wherein said patient is unable to tolerate the side effects of conventional antipsychotic drugs, eg, haloperidol, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone;

1.23 Method 1 or any of methods 1.1-1.22, wherein said disorder is depression and said patient is a patient suffering from psychosis, eg schizophrenia or Parkinson's disease;

1.24 Method 1 or any of methods 1.1-1.22, wherein said disorder is a sleep disorder and said patient suffers from depression;

1.25 Method 1 or any of methods 1.1-1.22, wherein said one or more disorders is a sleep disorder and said patient suffers from a psychosis, eg, schizophrenia;

1.26 Method 1 or any of methods 1.1-1.22, wherein said one or more disorders is a sleep disorder and said patient suffers from Parkinson's disease;

1.27 Method 1 or any of methods 1.1-1.22, wherein said one or more disorders is a sleep disorder and said patient suffers from depression and psychosis, eg schizophrenia or Parkinson's disease.

1.28 Method 1 or any of 1.1-1.27, wherein said patient suffers from a drug disorder, optionally in combination with any pre-existing medical condition, for example, wherein said patient suffers from opiate addiction and/or alcohol addiction, or from drug or alcohol addiction withdrawal , optionally where the patient is suffering from residual symptoms of anxiety or an anxiety disorder; optionally where the patient is suffering from an opiate overdose;

1.29 Any of the above methods, where the effective amount is 1 mg-1000 mg, preferably 2.5 mg-50 mg;

1.30 Any of the above methods, where the effective amount is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day;

1.31 Any of the above methods in which the disease to be treated is dyskinesia, for example, in a patient receiving dopaminergic drugs, for example, drugs selected from levodopa and excipients for levodopa (carbidopa, COMT inhibitors, MAO- B inhibitors), dopamine agonists and anticholinergic drugs such as levodopa;

1.32 Any of the above methods where the patient suffers from Parkinson's disease.

[0040] Drug use disorders and drug induced disorders are two categories of drug related disorders defined by the fifth edition of the DSM (the Diagnostic and Statistical Manual of Mental Disorders or DSM-V). A substance use disorder is a set of symptoms resulting from the use of a drug that an individual continues to take despite the resulting problems. A drug-induced disorder is a disorder caused by the use of the drug itself. Drug-induced disorders include intoxication, withdrawal, drug-induced mental disorders including drug-induced psychosis, drug-induced bipolar and related disorders, drug-induced depressive disorders, drug-induced anxiety disorders, obsessive drug-induced compulsive and related disorders, drug-induced sleep disorders, drug-induced sexual dysfunctions, substance-induced delusions, and drug-induced neurocognitive disorders.

[0041] The DSM-V includes criteria for classifying a substance use disorder as mild, moderate, or severe. In some embodiments of the methods described herein, the drug use disorder is selected from mild drug use disorder, moderate drug use disorder, or severe drug use disorder. In some embodiments, the drug use disorder is a mild drug use disorder. In some embodiments, the drug use disorder is a mild drug use disorder. In some embodiments, the drug use disorder is a severe drug use disorder.

[0042] Anxiety is a common comorbid disorder in patients undergoing treatment for drug use or substance abuse. The standard treatment for substance abuse disorder is the combination of the partial opioid agonist buprenorphine with the opioid antagonist naloxone, but neither drug has any significant effect on anxiety, thus leading to the single outcome of needing administer a third drug, such as a benzodiazepine class anxiolytic. This complicates treatment regimens and patient compliance. In contrast, the compounds of the present invention provide opiate antagonism along with serotonin antagonism and dopamine modulation. This can lead to a significant improvement in the treatment of patients who use or abuse drugs accompanied by anxiety. Depression is also a common disorder in patients undergoing treatment for drug use or drug abuse. Thus, antidepressants such as SSIR are also often used concomitantly in patients undergoing drug abuse treatment. The compounds of the present invention may also improve treatment in these patients by providing treatment for drug use or substance abuse, as well as anxiety and depression.

[0043] The compounds of the present invention may have anxiolytic properties that reduce the need to treat a patient with an anxiolytic agent when said patients suffer from comorbid anxiety. Thus, in some embodiments, the present invention relates to the method of Method 1 or any of Methods 1.1-1.32, wherein the central nervous system disorder is drug dependence, drug use disorders, and/or drug induced disorders. substance abuse disorder, for example, in a patient suffering from anxiety symptoms or diagnosed with anxiety as a comorbid disorder, or as a residual disorder, wherein the method does not include the additional administration of an anxiolytic agent such as a benzodiazepine. Benzodiazepines are GABA modulating compounds, including those discussed with reference to Method 3.1 and 3.2 below.

[0044] In another embodiment of the eighth aspect, the present invention relates to method 1 or any of the methods 1.1-1.15, where the method is further described below:

1.33 Method 1 or any of the methods 1.1-1.32, wherein the central nervous system disorder is a disorder selected from obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), generalized anxiety disorder, social anxiety disorder, panic disorder , agoraphobia, gambling addiction, impulsive eating disorder, body dysmorphic disorder, hypochondria, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorder, and related disorders, and their combinations.

1.34 Method 1 or any of the methods 1.1-1.33 wherein the central nervous system disorder is selected from Obsessive-Compulsive Disorder (OCD), Obsessive-Compulsive Personality Disorder (OCPD), Social Anxiety Disorder, Panic Disorder, Agoraphobia, Gambling Addiction, Impulsive Disorder eating disorder, body dysmorphic disorder, and impulse control disorder.

1.35 Method 1 or any of the methods 1.1-1.33, wherein the central nervous system disorder is obsessive-compulsive disorder (OCD) or obsessive-compulsive personality disorder (OCPD).

1.36 Any of the above in which said patient does not respond to or cannot tolerate side effects from treatment with selective serotonin reuptake inhibitors (SSRIs) such as citalopram, escitalopram, fluoroxetine, fluvoxamine, paroxetine and sertraline.

1.37 Any of the above in which said patient does not respond to or cannot tolerate the side effects of treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran and levomilnacipran.

1.38. Any of the above methods in which said patient does not respond to or cannot tolerate side effects from treatment with antipsychotic agents such as clomipramine, risperidone, quetiapine, and olanzapine.

1.39 Method 1, or any of Method 1.1-1.33, wherein the central nervous system disorder is a pain disorder, e.g., a pain-related condition such as headache, idiopathic pain, neuropathic pain, chronic pain (e.g., chronic pain from moderate to moderately severe, such as in patients requiring 24-hour extended treatment for other conditions), fibromyalgia, toothache, traumatic pain, or chronic fatigue.

1.40 Any of the above methods in which the patient does not respond to or cannot tolerate the side effects of non-opioid analgesics and/or opiate and opioid drugs, or in which the use of opiate drugs is contraindicated in said patient, for example, due to prior drug abuse or high risk of substance abuse, such as opiate and opioid drugs, including, for example, morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl , alfentanil, trefantinil, bryfentanil, remifentanil, octfentanil, sufentanil, carfentanil, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, desocin, pentazocine, phenazocine, butorphanol, nalbuphine, leforphanol, lefomethorphan, tramadol, tapentadol, and any combination of them;

1.41 Method I or any of the methods 1.1-1.40, where the central nervous system disorder or disease is drug addiction (e.g., opiate addiction (i.e., opioid use disorder), cocaine addiction, amphetamine addiction, and/or alcohol addiction ), or withdrawal from drug or alcohol addiction (such as opiate, cocaine or amphetamine addiction), and where the patient also suffers from a comorbid condition such as anxiety, depression or psychosis; where the patient is optionally also suffering from an opiate overdose;

1.42 Any of the above methods, where the effective amount is 1 mg-1000 mg, preferably 2.5 mg-50 mg;

1.43 Any of the above methods, where the effective amount is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day.

[0045] In another embodiment, the present invention relates to method 1 or any of the methods 1.1-1.32, or any of the methods 1.33-1.43, where the compounds of formulas I-IV and further or pharmaceutical composition 6 or 6.1-6.10 or P.1 -P.7 includes:

1.44 A compound of formula II-A, II-B, II-C or II-D in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

1.45 A compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier; or

1.46 A compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier

[0046] In another embodiment of the eighth aspect, the present invention relates to method 1 or any of methods 1.1-1.46, for example, any method of treating pain, where the patient suffers from a disorder of the gastrointestinal tract and/or a pulmonary disorder. Traditional opioid analgesics suffer from two major side effects: gastrointestinal distress (including nausea, vomiting, and constipation) and respiratory depression. 90-95% of patients taking opioids for long-term analgesia develop severe constipation, requiring prolonged use of laxatives and/or enemas. Stronger opioids such as morphine, oxycodone, and hydromorphone cause more severe constipation than other opioids. Respiratory depression is the most serious side effect of opioid treatment because it poses a risk of death, especially when patients combine (intentionally or unintentionally) prescribed opioid analgesics with other legal or illegal respiratory depressants (including alcohol). Patients in need of pain management, especially chronic pain management, are at particular risk of side effects if they suffer from pre-existing gastrointestinal or pulmonary disorders. Unlike traditional opioid analgesics, the compounds of the present invention (eg, a compound of formula I, eg formula 1.31) provide analgesic effect without significant gastrointestinal side effects and without significant respiratory depression. Therefore, these compounds will provide improved safety and efficacy for patients in need of pain management with these pre-existing gastrointestinal and pulmonary disorders. In further embodiments, a compound of the present invention can be combined with a traditional opiate agent to provide improved pain control with a dose reduction effect compared to the traditional opiate agent (and concurrently reduced risk of side effects).

[0047] Thus, in specific embodiments, the present invention further provides:

1.37 Method 1 or any of 1.1-1.46, wherein the patient is suffering from a prior or concomitant gastrointestinal and/or pulmonary disorder;

1.38 Method 1.47 wherein the antecedent or comorbid disorder is selected from the group consisting of irritable bowel syndrome, pelvic diaphragm dysfunction, diverticulitis, inflammatory bowel disease, colon or colorectal cancer, celiac disease, non-celiac gluten sensitivity, asthma, chronic obstructive pulmonary disease (COPD), dyspnea, pneumonia, congestive heart failure, interstitial lung disease, pneumothorax, bronchitis, pulmonary embolism, and traumatic brain injury (eg, fracture of the sternum or ribs, contusion of the intercostal muscles);

1.39 Method 1.47 or 1.48 wherein the central nervous system disorder is a pain disorder, e.g., a pain-related condition such as headache, idiopathic pain, neuropathic pain, chronic pain (e.g., moderate to moderately severe chronic pain, e.g., patients requiring 24-hour long-term treatment for other diseases), fibromyalgia, toothache, traumatic pain or chronic fatigue;

1.40 Any of method 1 or 1.1-1.49, where the central nervous system disorder is an opiate use disorder, opiate withdrawal, or opiate dependence, and where the method provides relief from withdrawal symptoms (e.g., gastrointestinal symptoms such as diarrhea, anxiety, depression, pain, sleep disturbance, or any combination thereof);

1.41 Any of method 1 or 1.1-1.50, where the method further comprises the co-administration of another opiate or opioid agent, for example, administered simultaneously, separately or sequentially;

1.42 Method 1.51 wherein the additional opiate or opioid agent is selected from the group consisting of morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanil, trefantinil, bryfentanil, remifentanil, octfentanil, sufentanil, carfentanil, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, desocin, pentazocine, phenazocine, butorphanol, nalbuphine, leforphanol, lefomethorphan, or any of tramadol, tapeleridine their combinations;

1.43 Any of method 1 or 1.1-1.52, wherein the method further comprises co-administering an NMDA receptor antagonist, eg, administered simultaneously, separately or sequentially;

1.44 Method 1.53, wherein the NMDA receptor antagonist is selected from the group consisting of ketamine (eg, S -ketamine and/or R -ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine and agmatine, or any combination thereof;

1.45 Any of the methods 1.47-1.54 wherein the compound is a compound of formula I wherein X is -NH-, L is O, and Z is -O-.

[0048] In yet another embodiment, the present invention relates to any of methods 1 or 1.1-1.55 as described in the present invention above, where the disorder is schizophrenia or a sleep disorder. In some embodiments, said schizophrenia is associated with depression.

[0049] In yet another embodiment, the present invention relates to any of the methods 1.1-1.55, in which the depot composition of the present invention (for example, the depot composition of any of formulas 6.8-6.10), or (pharmaceutical) composition 6 or 6.1-6.7, or pharmaceutical composition P.1-P.7 is administered for controlled and/or sustained release of the compounds of the present invention over a period of about 14 days, from about 30 to about 180 days, preferably over a period of about 30, about 60 or about 90 days. Controlled and/or sustained release is particularly suitable for circumventing early termination of therapy, in particular for antipsychotic drug therapy.

[0050] In yet another embodiment, the present invention relates to any method 1 or 1.1-1.55, as described in the present invention above, in which the depot composition of the present invention is administered to controlled and/or sustained release of the compounds of the present invention over a period of time .

[0051] In a ninth aspect, the present invention relates to a method (method 2) for preventing or treating one or more sleep disorders, comprising administering to a patient in need a compound of formulas I-IV et seq. or pharmaceutical composition 6 or 6.1-6.10 or P.1-P .7 (method 2), for example, method 2, where the compound or composition administered is:

2.1 Compound I or 1.1-1.35 in free or pharmaceutically acceptable salt form;

2.2 Compound II or 2.1-2.12 in free or pharmaceutically acceptable salt form;

2.3 Compound III or 3.1-3.11 in free or pharmaceutically acceptable salt form;

2.4 Compound IV or 4.1-4.11 in free or pharmaceutically acceptable salt form;

2.5 Compound 5 or 5.1-5.5;

2.6 A compound of formula II-A, II-B, II-C or II-D in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

2.7 A compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

2.8 A compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

2.9 Pharmaceutical composition as defined by any of compositions 6 and 6.1-6.10;

2.10 A pharmaceutical composition containing a compound of formula II-A, II-B or II-, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier;

2.11 A pharmaceutical composition containing a compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

2.12 A pharmaceutical composition containing a compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;

2.13 Depot composition as defined in depot composition 6.09 or 6.10;

2.14 Pharmaceutical composition P1-P.7;

2.15 Composition of an osmotically controlled release oral delivery system as described above in the present invention;

[0052] In a further embodiment of the ninth aspect, the present invention relates to method 2 or 2.1-2.15, wherein the sleep disorder includes insomnia while maintaining sleep, frequent awakening, and feeling unrested upon awakening; for example:

2.8 Any of the above, where the sleep disorder is sleep maintenance insomnia;

2.9 Any of the above methods, where the effective amount is 1 mg-5 mg, preferably 2.5-5 mg per day;

2.10 Any of the above methods, where the effective amount is 2.5 mg or 5 mg per day;

2.11 Any of the above methods where a sleep disorder is present in a patient suffering from or at risk of dyskinesia, e.g. a patient receiving dopaminergic drugs, e.g. selected from levodopa and levodopa excipients (carbidopa, COMT inhibitors, MAO-B inhibitors ), dopamine agonists and anticholinergic drugs, for example, receiving levodopa;

2.12 Any of the above methods where the patient suffers from Parkinson's disease.

[0053] In a further embodiment of the ninth aspect, the present invention relates to method 2 or any of 2.1-2.20, wherein the sleep disorder includes insomnia while maintaining sleep, frequent awakening, and feeling unrested upon awakening.

[0054] Compounds of the present invention, pharmaceutical compositions of the present invention, or depot compositions of the present invention can be used in combination with a second therapeutic agent, especially at lower doses than when the individual agents are used as monotherapy, in order to enhance the therapeutic activity of the combined agents without causing undesirable side effects commonly associated with conventional monotherapy. Therefore, the compounds of the present invention can be administered simultaneously, sequentially or continuously with other antidepressant, antipsychotic, other hypotensive agents, and/or agents used to treat Parkinson's disease or behavioral disorders. In another example, side effects can be reduced or minimized by administering a compound of the present invention in combination with one or more second therapeutic agents in free or salt form, wherein the doses of (i) the second therapeutic agent(s) or (ii) or the compound of the present invention and the second therapeutic agents are less than if the agents/compounds were administered as monotherapy. In a specific embodiment, the compounds of the present invention are useful in the treatment of dyskinesia in a patient receiving dopaminergic drugs, e.g., selected from levodopa and levodopa excipients (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergic drugs, for example, such as those used in the treatment of Parkinson's disease.

[0055] In some further embodiments of the present invention, the pharmaceutical compositions of the present invention or depot compositions of the present invention can be used in combination with a second therapeutic agent, especially at lower doses than when the individual agents are used as monotherapy in order to increase therapeutic activities combination agents without causing unwanted side effects, where the second therapeutic agent is an opiate antagonist or (eg, naloxone). The compounds of the present invention can be administered simultaneously, sequentially or continuously with these opiate antagonists.

[0056] Therefore, in a tenth aspect, the present invention relates to method 1 or any of methods 1.1-1.55, or method 2 or any of 2.1-2.20, further comprising administering one or more therapeutic agents to a patient, where one or more therapeutic agents are selected of compounds that modulate GABA activity (eg, increase activity and promote GABA transmission), a GABA-B agonist, a 5-HT receptor modulator (eg, 5-HT _1A agonist, 5-HT _2A antagonist, 5-HT _2A inverse agonist, and etc.), melatonin receptor agonist, ion channel modulator (e.g. blocker), serotonin-2 antagonist/reuptake inhibitor (SARI), orexin receptor antagonist, H3 agonist or antagonist, noradrenergic agonist or antagonist, galanin agonist, CRH antagonist , human growth hormone, growth hormone agonist, estrogen, estrogen agonist, neurokinin-1 drug, antidepressant, opiate agonist and/or and a partial opiate agonist, an opiate antagonist, and/or an opiate inverse agonist, and an antipsychotic agent, such as a custom antipsychotic agent, in free or pharmaceutically acceptable salt form (method 1-A and 2-A, respectively; together “method 3”).

[0057] In further embodiments of the tenth aspect, the present invention relates to method 1 or any of methods 1.1-1.55, or method 2 or any of 2.1-2.20, further comprising administering to the patient one or more therapeutic agents selected from the above and additionally selected from agonists or partial agonists, or inverse agonists or antagonists of mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors. In further embodiments of the tenth aspect, the present invention also provides method 1 or any of methods 1.1-55, or method 2 or any of 2.1-2.20, further comprising administering to the patient one or more therapeutic agents selected from a serotonin HT6 receptor antagonist and mGluR- 2, -3 or -5 receptor agonist or antagonist (including both positive and negative modulators and partial agonists).

[0058] In a further embodiment of the tenth aspect, the present invention relates to method 3 (i.e., method 1-A or 2-A), wherein the method further comprises administering to the patient one or more therapeutic agents, as follows:

3.1 Method 1-A or 2-A, wherein the therapeutic agent(s) are compounds that modulate GABA activity (eg, increase activity and promote GABA transmission);

3.2 Method 1-A or 2-A or 3.1 wherein the GABA compound is selected from the group consisting of one or more of doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplone, zopiclone, esopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;

3.3 Method 1-A or 2-A, wherein the therapeutic agent is an additional 5HT2a antagonist;

3.4 Method 1-A or 2-A or 3.3 wherein said additional 5HT2a antagonist is selected from one or more of ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis, France) , HY 10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego, CA) and AVE8488 (Sanofi-Aventis, France);

3.5 Method 1-A or 2-A, wherein the therapeutic agent is a melatonin receptor agonist;

3.6 Method 1-A or 2-A or 3.5 wherein the melatonin receptor agonist is selected from the group consisting of one or more of melatonin, ramelteon ( ^ROZEREM® , Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD ), PD-6735 (Phase II) and agomelatine;

3.7 Method 1-A or 2-A, wherein the therapeutic agent is an ion channel blocker;

3.8 Method 1-A or 2-A or 3.7 wherein the ion channel blocker is one or more of lamotrigine, gabapentin and pregabalin;

3.9 Method 1-A or 2-A, wherein the therapeutic agent is an orexin receptor antagonist;

3.10 Method 1-A or 2-A or 3.9, wherein the orexin receptor antagonist is selected from the group consisting of orexin, 1,3-biaryl urea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline) and a benzamide derivative;

3.11 Method 1-A or 2-A, wherein the therapeutic agent is a serotonin-2 antagonist/reuptake inhibitor (SARI);

3.12 Method 1-A or 2-A or 3.11 wherein the serotonin-2 antagonist/reuptake inhibitor (SARI) is selected from the group consisting of one or more of Org 50081 (Organon-Netherlands), ritanserin, nefazodone, serzone and trazodone ;

3.13 Method 1-A or 2-A, wherein the therapeutic agent is a 5HTIa agonist;

3.14 Method 1-A or 2-A or 3.13 wherein the 5HTIa agonist is selected from the group consisting of one or more of repinotane, sarizotan, eptapirone, buspirone, and MN-305 (MediciNova, San Diego, CA);

3.15 Method 1-A or 2-A, wherein the therapeutic agent is a neurokinin-1 drug;

3.16 Method 1-A or 2-A or 3.15 wherein the neurokinin-1 drug is casopitant (GlaxoSmithKline);

3.17 Method 1-A or 2-A, wherein the therapeutic agent is an antipsychotic agent;

3.18 Method 1-A or 2-A or 3.17 wherein the antipsychotic agent is selected from the group consisting of chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

3.19 Method 1-A or 2-A, wherein the therapeutic agent is an antidepressant;

3.20 Method 1-A or 2-A or 3.19 wherein the antidepressant is selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluorxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline , paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine and venlafaxine;

3.21 Method 1-A or 2-A, 3.17 or 3.18, wherein the antipsychotic agent is a non-standard antipsychotic agent;

3.22 Method 1-A or 2-A, or any of 3.17-3.21, wherein the non-standard antipsychotic agent is selected from the group consisting of clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

3.23 Method 1-A or 2-A wherein the therapeutic agent is selected from any of the methods 3.1-3.22, e.g. selected from the group consisting of modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam , flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplone, zopiclone, esopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin, volin- plianserin, risperidone Aventis, France), pruvanserine, MDL 100907 (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego, CA), AVE8488 (Sanofi-Aventis, France), repinotane, sarizotane, eptapirone , buspirone, MN-305 (MediciNova, San Diego, CA), melatonin, ramelteon (ROZEREM ^® , Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (phase II studies), agomelatine , lamotrigine, gabapentin, preg abalin, orexin, 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), benzamide derivative, Org 50081 (Organon-Netherlands), ritanserin, nefazodone, serzone, trazodone, casopitant (GlaxoSmithKline), amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoroxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, trazoproxyproline, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

3.24 Method 1-A or 2-A, wherein the therapeutic agent is an H3 agonist;

3.25 Method 1-A or 2-A, wherein the therapeutic agent is an H3 antagonist;

3.26 Method 1-A or 2-A, wherein the therapeutic agent is a noradrenergic agonist or antagonist;

3.27 Method 1-A or 2-A, wherein the therapeutic agent is a galanin agonist;

3.28 Method 1-A or 2-A, wherein the therapeutic agent is a CRH antagonist;

3.29 Method 1-A or 2-A, wherein the therapeutic agent is human growth hormone;

3.30 Method 1-A or 2-A, wherein the therapeutic agent is a growth hormone agonist;

3.31 Method 1-A or 2-A, wherein the therapeutic agent is an estrogen;

3.32 Method 1-A or 2-A, wherein the therapeutic agent is an estrogen agonist;

3.33 Method 1-A or 2-A, wherein the therapeutic agent is a neurokinin-1 drug;

3.34 Method 1-A or 2-A wherein the therapeutic agent is combined with compounds of formula (I) and the therapeutic agent is an anti-Parkinson's agent such as L-dopa, co-careldopa, duodopa, stavelo, symmetrel, benztropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone;

3.35 Method 1-A or 2-A wherein the therapeutic agent is an opiate agonist or partial opiate agonist, e.g. partial mu agonistic activity and kappa antagonistic activity);

3.36 Method 3.35 wherein the therapeutic agent is buprenorphine, optionally wherein said method does not include co-treatment with an anxiolytic agent, eg a GABA compound or a benzodiazepine;

3.37 Method 1-A or 2-A, in which the compounds of formula (I) can be used to treat sleep disorders, depression, psychosis, or any combination thereof, in patients suffering from these diseases and/or Parkinson's disease;

3.38 Method 1-A or 2-A, wherein the disorder is selected from at least one or more of psychosis, e.g., schizophrenia, depression, behavioral disorders, sleep disorder (e.g., sleep maintenance and/or falling asleep), or any combination these disorders;

3.39 Method 1-A or 2-A wherein the therapeutic agent(s) is an opiate receptor antagonist or inverse agonist, e.g., a full opiate antagonist, e.g., selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan nalodeine, cyprodim or norbinaltorfimin.

3.40 Any of the above in which the disorder is a sleep disorder;

3.41 Any of the above, wherein the disorder is a sleep disorder associated with psychosis, such as schizophrenia or Parkinson's disease; in free or pharmaceutically acceptable salt form.

[0059] In an eleventh aspect of the present invention, the combination of a compound of the present invention and one or more second therapeutic agents as defined in Methods 1-A, 2-A or any of Methods 3 or 3.1-3.41 may be administered to a patient as a pharmaceutical composition, or depot compositions as described in the present invention above. Combination compositions may include mixtures of combination drugs, as well as two or more separate drug compositions, where the individual compositions may, for example, be administered together to a patient.

[0060] In a specific embodiment, methods 1-A, 2-A, 3, or 3.1-3.41 comprise administering to a patient in need a compound of the present invention in combination with a non-standard antipsychotic agent, e.g., a compound selected from clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, or paliperidone, in free or pharmaceutically acceptable salt form, for example, where the dose of the non-standard antipsychotic agent is reduced and/or side effects are reduced.

[0061] In another embodiment, methods 1-A, 2-A, 3, or 3.1-3.41 comprise administering to a patient in need a compound of the present invention in combination with an antidepressant, e.g., amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoroxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, or venlafaxine, in free or pharmaceutically acceptable salt form. Alternatively, an antidepressant may be used as an adjunct drug in addition to the compound of the present invention.

[0062] In yet another embodiment, methods 1-A, 2-A, 3, or 3.1-3.,41 comprise administering to a patient in need a compound of the present invention in combination with a compound that modulates GABA activity, e.g., a compound selected from doxepin , алпразолама, бромазепама, клобазама, клоназепама, клоразепата, диазепама, флунитразепама, флуразепама, лоразепама, мидазолама, нитразепама, оксазепама, темазепама, триазолама, индиплона, зопиклона, эзопиклона, залеплона, золпидема, габоксадола, вигабатрина, тиагабина, EVT 201 (Evotec Pharmaceuticals ), estazolam, or any combination thereof, in free or pharmaceutically acceptable salt form. In other embodiments, the methods described herein do not further include administering a GABA compound, a benzodiazepine, or any other anxiolytic agent.

[0063] In another preferred embodiment, methods 1-A, 2-A, 3, or 3.1-3.41 comprise administering to a patient in need a compound of the present invention in combination with doxepin in free or pharmaceutically acceptable salt form. The doses of doxepin may vary within any range known to those skilled in the art. In one example, a 10 mg dose of doxepin can be combined with a dose of a compound of the present invention.

[0064] In another embodiment, methods 1-A, 2-A, 3, or 3.1-3.41 comprise administering to a patient in need a compound of the present invention in combination (including as part of a daily dosing regimen) with a non-standard stimulant, e.g., modafinil, adrafinil, or armodafinil. A regimen administering a compound of the present invention with these drugs promotes more regular sleep and avoids side effects such as psychosis or mania associated with high levels of these drugs, for example in the treatment of bipolar depression, cognitive impairment associated with schizophrenia, drowsiness and fatigue in conditions such as Parkinson's disease and cancer.

[0065] In another embodiment, methods 1-A, 2-A, 3, or 3.1-3.41 comprise administering to a patient in need a compound of the present invention in combination (including as part of a daily dosing regimen) with an opiate receptor antagonist or inverse agonist, for example, a full opiate antagonist, for example, selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodim or norbinaltorfimin.

[0066] In some of the above embodiments, each of the compounds of formulas I-IV and beyond; pharmaceutical compositions 6 and 6.1-6.8; depot compositions 6.9 and 6.10; pharmaceutical compositions P.1-P.7; methods 1 and 1.1-1.55; and methods 2 and 2.1-2.20; the compound of the present invention is substantially free of a compound of formula A and/or substantially free of a compound of formula B.

[0067] In a twelfth aspect, the present invention relates to the use of a compound as defined below:

11.1 Compound I or 1.1-1.35 in free or pharmaceutically acceptable salt form;

11.2 Compound II or 2.1-2.12 in free or pharmaceutically acceptable salt form;

11.3 Compound III or 3.1-3.11 in free or pharmaceutically acceptable salt form;

11.4 Compound IV or 4.1-4.11 in free or pharmaceutically acceptable salt form;

11.5 Compound 5 or 5.1-5.5;

11.6 A compound of formula II-A, II-B, II-C, II-D or II-E in free or pharmaceutically acceptable salt form;

11.7 Compound of formula III-A, III-B or III-C in free or pharmaceutically acceptable salt form;

11.8 Compound of formula IV-A, IV-B or IV-C in free or pharmaceutically acceptable salt form;

11.9 Pharmaceutical composition 6 and 6.1-6.10;

11.10 Pharmaceutical composition P.1-P.7;

11.11 Composition of an osmotically controlled release oral delivery system as described in the present invention above;

(in preparing a medicament) for the treatment or prevention of one or more disorders as described in the present invention above, for example in any of Method 1 or 1.1-1.55, any of Method 2 and 2.1-2.20, and Method 3 or 3.3-3.41 , or any of the methods described in the eleventh aspect of the present invention.

[0068] In the thirteenth aspect, the present invention relates to a pharmaceutical composition as described in the present invention above, for example:

12.1 Pharmaceutical compositions 6 and 6.1-6.10;

12.2 Pharmaceutical compositions P.1-P.7;

12.3 The formulation of an osmotically controlled release oral delivery system as described in the present invention above,

for use in the treatment or prevention of one or more disorders as described herein above, for example in any of Methods 1 and 1.1-1.55, Methods 2 and 2.1-2.20, Methods 1-A, 2-A, 3 or 3, 1-3,41 or any of the methods described in the eleventh or twelfth aspects of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 shows the mu-receptor antagonistic activity of the compound of example 3 compared to naloxone as determined in example 10.

[0070] Figure 2 shows the mu receptor agonist activity of the compounds of examples 1 and 3 compared to DAMGO and buprenorphine as defined in example 10.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0071] Unless otherwise indicated or clear from the context, the following terms used in the present invention have the following meanings:

[0072] “Alkyl”, as used herein, is a saturated or unsaturated hydrocarbon moiety, e.g., one to twenty carbon atoms in length, which may be linear or branched (e.g., n-butyl or t-butyl), preferably linear unless otherwise noted. For example, "C ₁ - ₂₁ alkyl" means alkyl containing 1-21 carbon atoms. In one embodiment, alkyl is optionally substituted with one or more hydroxy or C _1-22 alkoxy (eg, ethoxy) groups. In another embodiment, the alkyl contains 1-21 carbon atoms, preferably a normal chain, and is optionally saturated or unsaturated, for example, in some embodiments, when R ₁ is an alkyl chain containing 1-21 carbon atoms, preferably 6-15 atoms carbon, 16-21 carbon atoms, for example, so that together with -C(O)-, with which it is connected, for example, when cleaved from a compound of formula I, forms a natural or unnatural, saturated or unsaturated fatty acid residue.

[0073] The term “pharmaceutically acceptable diluent or carrier” is intended to refer to diluents and carriers that are useful in pharmaceutical preparations and that do not contain allergenic, pyrogenic or pathogenic substances, and substances known to potentially cause or contribute to disease. Pharmaceutically acceptable diluents or carriers thus exclude bodily fluids such as, for example, blood, urine, cerebrospinal fluid, saliva and the like, as well as their constituents such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in any of several well-known scientific sources for pharmaceutical formulations, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated herein by reference in their entirety.

[0074] The terms "purified," "in purified form," or "in isolated and purified form" for a compound refer to the physical state of said compound after isolation from a preparation process (e.g., from a reaction mixture), or a natural source, or a combination of both. Thus, the term "purified," "in a purified form" or "in an isolated and purified form" for a compound refers to the physical state of said compound after it has been obtained by the purification method or methods described herein or well known to those skilled in the art. field (e.g., chromatography, recrystallization, LC-MS and LC-MS/MS methods, and the like), with a sufficient degree of purity to be characterized by standard analytical methods described in the present invention or well known to a person skilled in the art.

[0075] Compounds of formula I wherein Z is -(C=O)- or -(CH(OH))-, including, for example, compounds of formulas II-B and II-C, can be obtained as metabolites of a compound of formula A , and/or as metabolites of a compound of formula B:

Formula A

Formula B

It is known that the compound of formula A provides an effective treatment of disorders associated with 5-HT _2A , SERT and/or D ₂ receptors, without significant extrapyramidal side effects, as similarly described and stated in WO 2009/145900 and US 2011/0071080, the content of which incorporated by reference in its entirety. However, the plasma concentrations of the compounds of formulas II-B and II-C resulting from the metabolism of the compound of formula A are quite low and are not likely to contribute significantly to the therapeutic activity of the compound of formula A. The compounds of formulas II-D and II-E can also present as metabolites, although they have not yet been discovered. Surprisingly, the compounds of formula I have been found to have activity as μ-opioid receptor antagonists. This is unexpected because the compound of formula A was not known or does not have any activity or binding at the μ-opioid receptors. Compounds of formula I in which X is -NH- and in which L is -O- have been shown to have particularly good μ-opioid receptor antagonism. These compounds of formula I may therefore be useful in the treatment of addiction, such as opiate dependence and/or alcohol dependence, inhibition of the endogenous opiate response to the administration of a illicit drug, as well as inhibition of the direct effects of the administration of illicit opiate drugs.

[0076] Surprisingly, the metabolites of a compound of formula A have somewhat different relative receptor binding affinity than compounds of formula A. For example, the receptor binding profile of a compound of formula II-B is very unique, with a combination of 5-HT _2A , D1 and Mu opiate receptors, making this compound very interesting for the treatment of behavioral disorders. The compound of formula A is not active, for example, on the mu opiate receptor.

[0077] It has also surprisingly been found that the compounds of formula I, in particular, in which X represents -NH, L represents O, and Z represents -O-, show strong 5-HT _2A , D1 and Mu opiate antagonism, along with moderate D1, D2 and SERT antagonism. Moreover, it has surprisingly been found that these compounds can act as "displaced" opiate ligands. This means that when the compounds bind to mu-opiate receptors, they can act as partial mu agonists through G protein-coupled signaling, but as mu antagonists through the beta-arrestin signaling system. This is different from the traditional opiate agonists, morphine and fentanyl, which tend to strongly activate both G-protein-coupled signaling and the beta-arrestin signaling system. Activation of the beta-arrestin signaling system by these drugs is believed to mediate the gastrointestinal dysfunction and respiratory depression commonly mediated by opiate drugs. Therefore, it is expected that the compounds of the present invention, in particular the compounds of formula I, should lead to pain relief with less pronounced gastrointestinal and respiratory side effects than existing opiate analgesics. This effect has been demonstrated in preclinical, phase II and phase III clinical studies for the displaced mu agonist, olikeridine. Oleriridine has been shown to result in mu-displaced agonism via G protein-coupled signaling with reduced beta-arrestin signaling compared to morphine, and this has been associated with its ability to induce analgesia with reduced respiratory side effects compared to morphine. Moreover, since the compounds of the present invention exhibit beta-arrestin pathway antagonism, they are expected to be useful in the treatment of opiate overdose as they will inhibit the most severe side effects of opiates while providing pain relief. Moreover, the compounds of the present invention also have a sleep promoting effect due to their serotonergic activity. Since many people suffering from chronic pain experience difficulty sleeping due to pain, these compounds may help these patients sleep through the night due to the synergistic effect of serotonergic and opiate receptor activity.

[0078] Thus, in certain embodiments, the compounds of the present invention can be used in a method of treating opiate use disorder (OUD), opiate overdose, or opiate withdrawal, either alone or in combination with an opiate antagonist or inverse agonist (e.g., naloxone or naltrexone). It is particularly noteworthy that the compounds of the present invention (e.g., a compound of formula I wherein X is -NH, L is O, and Z is -O-) show a strong ability to alleviate dysphoria and psychiatric comorbidities associated with drug withdrawal. substances (eg mood and anxiety disorders, sleep disturbance) and they also provide strong analgesia but without the side effects (eg gastrointestinal effects and respiratory depression) and the addictive potential seen with other opioid drugs (eg , oxycodone, methadone or buprenorphine). Evidence suggests that the unique pharmacological profile of these compounds will also reduce the risks of adverse drug-drug interactions (eg, alcohol). These compounds are therefore particularly useful in the treatment of opiate related disorders and symptoms associated with opiate withdrawal. In addition to the direct effect of the compounds on mu receptor activity, the effect of the compounds on serotonergic pathways results in an antidepressant effect, sleep maintenance and an anxiolytic effect. Since depression and anxiety are key factors that primarily contribute to susceptible patients to opioid use, the compounds of the present invention will reduce the symptoms of opiate withdrawal and at the same time reduce psychiatric comorbidities contributing to opioid use - a two-pronged strategy to reduce the risk of remission. The sleep support provided by these compounds will further improve the quality of life of patients undergoing OUD treatment.

[0079] Unless otherwise indicated, compounds of the present invention, for example, compound I or 1.1-1.35, compound II or 2.1-2.18, compound III or 3.1-3.13 or compound IV or 4.1-4.13 (together, compounds of formulas I-IV and further) may be present in free form or in salt form, for example as acid addition salts. An acid addition salt of a compound of the present invention which is sufficiently basic, such as an acid addition salt, such as an inorganic or organic acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, maleic, toluenesulfonic, propionic, succinic, glycolic , stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic acid and the like. In addition, the salt of the compound of the present invention, which is sufficiently acidic, is an alkali metal salt, such as sodium or potassium salt, an alkaline earth metal salt, such as calcium or magnesium salt, ammonium salt, or salt with an organic base, which gives a physiologically acceptable cation eg a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine. In a particular embodiment, the salt of a compound of the present invention is a toluenesulfonic acid addition salt. In another specific embodiment, the salt of a compound of the present invention is a fumaric acid addition salt. In a particular embodiment, the salt of the compound of the present invention is a phosphoric acid addition salt.

[0080] The compounds of the present invention may contain one or more chiral carbon atoms. Thus, the compounds exist as a single isomeric, eg, enantiomeric or diastereomeric form, or as a mixture of individual forms, eg, racemic/diastereomeric mixtures. Any isomer may be present in which the asymmetric center is in the ( R )-, ( S )-, or ( R,S )-configuration. The present invention is to be understood as including the individual optically active isomers as well as mixtures thereof (eg racemic/diastereomeric mixtures). Accordingly, the compounds of the present invention may be a racemic mixture or may be advantageously, for example, in pure, or substantially pure, isomeric form, for example, greater than 70% enantiomeric/diastereomeric excess (“ee”), preferably greater than 80% ee , more preferably more than 90% ee, most preferably more than 95% ee. Purification of said isomers and separation of said isomeric mixtures can be carried out by standard methods known in the art (eg, column chromatography, preparative TLC, preparative HPLC, fluid moving bed, and the like).

[0081] Geometric isomers in the nature of substituents around the double bond or ring may be present in cis (Z) or trans (E) form, and both isomeric forms are included within the scope of the present invention.

[0080] It is also contemplated that the compounds of the present invention include their stable and unstable isotopes. Stable isotopes are non-radioactive isotopes that contain one extra neutron compared to common nuclides of the same kind (i.e. element). It is expected that the activity of compounds containing these isotopes will be preserved, and this compound will also be suitable for measuring the pharmacokinetic parameters of non-isotopic analogs. For example, a hydrogen atom at a certain position in the compounds of the present invention can be replaced by deuterium (a stable isotope that is not radioactive). Examples of known stable isotopes include, but are not limited to, deuterium, ¹³ C, ¹⁵ N, ¹⁸ O. Alternatively, unstable isotopes, which are radioactive isotopes that contain extra neutrons compared to common nuclides of the same kind (i.e. element) , for example, ¹²³ I, ¹³¹ I, ¹²⁵ I, ¹¹ C, ¹⁸ F, can replace the corresponding common options I, C and F. Another example of a suitable isotope of the compounds of the present invention is the ¹¹ C isotope. These radioisotopes are useful for radioactive imaging and/or pharmacokinetic studies of the compounds of the present invention. In addition, the replacement of naturally occurring isotope atoms with heavier isotopes can result in desirable changes in pharmacokinetic rates when these substitutions are made in metabolically labile positions. For example, the incorporation of deuterium (2H) in place of hydrogen can slow down metabolic degradation when the position of the hydrogen is the site of enzymatic or metabolic activity.

[0081] In addition to the unique characteristics of the compounds of the present invention, compounds of formula I in which Y is -C(H)(OH)- can also be esterified to give physiologically hydrolysable and acceptable ester prodrugs. As used in the present invention, "physiologically hydrolysable and acceptable esters" means esters of the compounds of the present invention which hydrolyze under physiological conditions to form a hydroxy on the one hand and an acid, e.g. a carboxylic acid on the other hand, which are themselves physiologically tolerable. at the doses administered. For example, a compound of formula I or formula II wherein Y is -C(H)(OH) may be esterified to form a prodrug, i.e. a compound of formula I or formula II, in which R ₁ represents -C(O)-C _1-21 alkyl. In some preferred embodiments, R ₁ is -C(O)-C _1-21 , for example, esters of carboxylic acids, for example, esters of heptanoic, octanoic, decanoic, dodecanoic, tetradecanoic or hexadecanoic acids.

[0082] Similarly, when the compounds of the present invention contain an amino group, a prodrug of that amine, such as a methylamine prodrug, may also occur when the prodrug is cleaved, releasing the amine metabolite in vivo after administration.

[0083] Prodrugs of the compounds of the present invention wherein R ₁ is -C(O)-C _1-21 alkyl, preferably -C _6-21 alkyl, more preferably C _6-15 alkyl, more preferably linear, saturated or unsaturated, and optionally substituted with one or more hydroxy or alkoxy groups are particularly useful in sustained and/or delayed release so as to have a long acting effect, for example, where the compounds of the present invention are released over a period of from about 14 to about 30 to about 180 days, preferably in for about 30 or about 60 or about 90 days, for example, as defined in any of the depot compositions as described herein. Preferably, the sustained and/or delayed release formulation is an injectable formulation.

[0084] Alternatively and/or additionally, the compounds of the present invention may be included in a depot formulation, for example, by dispersing, dissolving, or encapsulating the compounds of the present invention in a polymeric matrix, as defined in any of compositions 6 and 6.1-6.10, such that the compound will be continuously released as the polymer breaks down over time. Release of the compounds of the present invention from the polymeric matrix provides controlled and/or delayed release of the compounds, eg, from the pharmaceutical depot of the composition, to the subject, eg, a warm-blooded animal, such as a human, who has been administered the pharmaceutical depot. Thus, the pharmaceutical depot delivers the compounds of the present invention to the subject at concentrations effective to treat a particular disease or condition over an extended period of time, such as 14-180 days, preferably about 30, about 60, or about 90 days.

[0085] Polymers suitable for the polymer matrix of the present invention (e.g., the depot composition of the present invention) may include polyester hydroxy fatty acid and its derivatives or other agents such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly- beta-hydroxybutyric acid, epsilon-caprolactone ring-opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, or polyglycolic acid-polyethylene glycol copolymer) alkyl-alpha-cyanoacrylate polymer (e.g., poly(butyl-2-cyanoacrylate)), polyalkylene oxalate (for example, polytrimethylene oxalate or polytetramethylene oxalate), polyorthoether, polycarbonate (for example, polyethylene carbonate or polyethylene propylene carbonate), polyorthocarbonate, polyamino acid (for example, poly-gamma-L-alanine, poly-gamma-benzyl- L-glutamic acid or poly-y-m ethyl-L-glutamic acid), hyaluronic acid ester and the like, and one or more of these polymers can be used.

[0086] If the polymers are copolymers, they can be any of random, block and/or graft copolymer. When the above alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any of the D-isomers, L-isomers and/or DL-isomers can be used. Among others, a polymer of alpha-hydroxycarboxylic acids (a polymer of lactic acid and glycolic acid), esters thereof, esters of poly-alpha-cyanoacrylic acid, etc., and a copolymer of lactic acid and glycolic acid (also called poly(lactide -alpha-glycolide) or poly(lactic-co-glycolic acid), hereinafter referred to as PLGA) are preferred. Thus, in one aspect, the polymer used for polymer matrices is PLGA. The term PLGA includes polymers of lactic acid (also called polylactide, poly(lactic acid) or PLA). Most preferably, the polymer is a biodegradable poly(d, l-lactide-co-glycolide) polymer.

[0087] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not cause significant inflammation in body tissues. The matrix material must be biodegradable, wherein the polymeric material must be degraded by body processes to products easily utilized by the body and must not accumulate in the body. The biodegradable products must also be biocompatible with the body, as the polymer matrix is biocompatible with the body. Specific suitable examples of polymer matrix materials include poly(glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, copolymers of the above, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho- carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes such as glycerol mono- and distearate, and the like. . The preferred polymer for use in the practice of the present invention is dl(polylactide-co-glycolide). Preferably, the molar ratio of lactide to glycolide in this copolymer is in the range of about 75:25-50:50.

[0088] Suitable PLGA polymers may have a weight average molecular weight of from about 5,000 to 500,000 daltons, preferably about 150,000 daltons. Depending on the degradation rate that is achieved, different polymer molecular weights can be used. For a diffusion mechanism of drug release, the polymer must remain intact until all of the drug is released from the polymer matrix and then decomposed. The drug may also be released from the polymeric matrix as the polymeric excipient is biodegraded.

[0089] PLGA can be obtained by any conventional method, or it may be commercially available. For example, PLGA can be prepared by ring-opening polymerization with a suitable cyclic lactide, glycolide, etc. catalyst. (see EP-0058481B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0090] PLGA is believed to be biodegradable due to the degradation of the entire solid polymer composition due to the destruction of hydrolysable and enzymatically cleavable ester bonds in biological conditions (for example, in the presence of water and biological enzymes found in the tissues of warm-blooded animals, such as humans), forming milk acid and glycolic acid. Lactic and glycolic acid are water-soluble, non-toxic products of normal metabolism that can be further degraded to form carbon dioxide and water. In other words, PLGA is believed to be degraded by hydrolysis of its ester groups in the presence of water, for example, in a warm-blooded animal such as a human to form lactic acid and glycolic acid and create an acidic microclimate. Lactic and glycolic acids are by-products of various metabolic pathways in a warm-blooded animal such as humans under normal physiological conditions and are therefore well tolerated and cause minimal systemic toxicity.

[0091] In another embodiment, the polymer matrix suitable for the present invention may include a star polymer, where the structure of the polyester has a star shape. These polyesters contain one polyol residue as a central fragment, surrounded by chains of acid residues. The polyol moiety can be, for example, glucose or, for example, mannitol. These esters are known and are described in GB 2145422 and US Pat. 5538739, the content of which is incorporated by reference.

[0092] Star-shaped polymers can be obtained using polyhydroxy compounds, for example, a polyol, for example, glucose or mannitol as an initiator. The polyol contains at least 3 hydroxy groups and has a molecular weight of up to about 20,000 Daltons, with at least 1, preferably at least 2, for example, as the middle 3 hydroxy groups of the polyol present as ester groups which contain polylactide or co-polylactide chains. Branched polyesters such as poly(d, l-lactide-co-glycolide) contain a central glucose moiety containing arms of linear polylactide chains.

[0093] Depot compositions of the present invention (for example, compositions 6 and 6.1-6.10 in a polymer matrix), as described in the present invention above, may contain polymer in the form of microparticles or nanoparticles, or in liquid form, and the compounds of the present invention are dispersed or encapsulated in German “Microparticles” means solid particles that contain compounds, either in solution or in solid form, where the compound is dispersed or dissolved in a polymer that serves as a particle matrix. By appropriate selection of polymeric materials, a microparticle composition can be obtained in which the resulting microparticles exhibit both diffusion release properties and biodegradable properties.

[0094] When the polymer is in the form of microparticles, the microparticles can be obtained using a suitable method such as solvent evaporation or a solvent extraction method. For example, in a solvent extraction method, the compounds of the present invention and the polymer can be dissolved in a volatile organic solvent (for example, a ketone such as acetone, a halogenated hydrocarbon such as chloroform or methylene chloride, a halogenated aromatic hydrocarbon, a cyclic ether such as dioxane, an ester , such as ethyl acetate, nitrile, such as acetonitrile, or alcohol, such as ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabilizer (eg, polyvinyl alcohol, PVA). Then, the organic solvent is evaporated, obtaining microparticles encapsulated in them with the compounds of the present invention. In a solvent extraction method, the compounds of the present invention and the polymer can be dissolved in a polar solvent (such as acetonitrile, dichloromethane, methanol, ethyl acetate or methyl formate), and then dispersed in an aqueous phase (such as water/PVA solution). The emulsion is prepared to provide microparticles with the compounds of the present invention encapsulated therein. Spray drying is an alternative way to obtain microparticles.

[0095] Another method for preparing microparticles of the present invention is also described in US Pat. No. 4,389,330 and US Pat. No. 4,530,840.

[0096] The microparticles of the present invention can be obtained by any method capable of producing microparticles in the size range acceptable for use in an injectable composition. One preferred preparation method is that described in US Pat. No. 4,389,330. In this method, the liquid active agent is dissolved or dispersed in an appropriate solvent. The polymeric matrix material is added to the agent-containing medium in an amount relative to the active ingredient that provides a product having the desired loading of liquid active agent. Optionally, all ingredients of the microparticulate product may be mixed together in a solvent medium.

[0097] Solvents for the compounds of the present invention and the polymer matrix material that can be used in the practice of the present invention include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, methylene chloride and the like; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate; and the like. In one embodiment, the solvent for practicing the present invention may be a mixture of benzyl alcohol and ethyl acetate. Additional information on the preparation of microparticles useful in the present invention can be found in US Patent Publication No. 2008/0069885, the contents of which are incorporated into this study by reference in its entirety.

[0098] The amount of compounds of the present invention included in the microparticles is usually in the range from about 1% by weight to about 90% by weight, preferably 30-50% by weight, more preferably 35-40% by weight. % by weight refers to the parts of the compounds of the present invention on the total weight of the microparticles.

[0099] Pharmaceutical depot compositions may contain a pharmaceutically acceptable diluent or carrier, such as a water-miscible diluent or carrier.

[0100] Detailed information on the composition of the oral delivery system with osmotically controlled release, can be found in EP 1539115 (US Publication No. 2009/0202631) and WO 2000/35419, the contents of each of which are incorporated by reference in their entirety.

[0101] A "therapeutically effective amount" is any amount of a compound of the present invention (e.g., as contained in a pharmaceutical depot) that, when administered to a subject suffering from a disease or disorder, is effective to cause a reduction, remission, or regression of the disease or disorder over a period of time as intended for treatment.

[0102] Dosages employed in the practice of the present invention will, of course, vary depending on, for example, the particular disease or condition being treated, the particular compound of the present invention employed, the route of administration, and the therapy desired. Unless otherwise indicated, the amount of a compound of the present invention to be administered (regardless of whether it is administered as free base or in salt form) refers to the amount of the compound of the present invention in free base form (i.e., the calculation of the amount is based on the amount of free base ).

[0103] The compounds of the present invention can be administered by any satisfactory route, including orally, parenterally (intravenously, intramuscularly, or subcutaneously), or transdermally. In certain embodiments, the compounds of the present invention, eg, as a depot formulation, are preferably administered parenterally, eg, by injection.

[0104] In general, satisfactory results for method 1 and 1.1-1.55, method 2 and 2.1-2.20 and method 3 and 3.1-3.40 or the use of the compounds of the present invention as described in the present invention above, for example, for the treatment of a combination of diseases such as a combination of at least depression, psychosis, eg (1) psychosis, eg schizophrenia, in a patient suffering from depression; (2) depression in a patient suffering from psychosis, such as schizophrenia; (3) behavioral disorders associated with psychosis, such as schizophrenia or Parkinson's disease; (4) sleep disorders associated with psychosis, such as schizophrenia or Parkinson's disease; and (5) drug dependence, drug use disorders, and/or drug induced disorders, as above, indicated to be obtained by oral administration at dosages on the order of approximately 1 mg-100 mg once daily, 2, 5 mg-50 mg, such as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once a day, by oral administration.

[0105] Satisfactory results for method 2 or 2.1-2.20 or the use of the compounds of the present invention as described in the present invention above, for example, for the treatment of a sleep disorder alone, are indicated to be obtained when administered orally at dosages of the order of approximately 2.5 mg-5 mg, for example, 2.5 mg, 3 mg, 4 mg or 5 mg of a compound of the present invention in free or pharmaceutically acceptable salt form, once a day, preferably by oral administration.

[0106] Satisfactory results for Method I-A or Method II-A, or any of 3.1-3.40 are indicated to be obtained at less than 100 mg, preferably at less than 50 mg, for example, at less than 40 mg, at less than 30 mg, at less than 20 mg, at less than l0 mg, at less than 5 mg, at less than 2.5 mg, once a day. Satisfactory results for method II-A or any of 3.1-3.41 are given for less than 5 mg, preferably less than 2.5 mg.

[0107] For the treatment of the disorders described in the present invention, where the depot composition is used to achieve a longer duration of action, doses will be higher compared to a composition with a shorter action, for example, more than 1-100 mg, for example, 25 mg, 50 mg , 100 mg, 500 mg, 1000 mg or more than 1000 mg. The duration of action of the compounds of the present invention can be controlled by manipulating the polymer formulation, i.e. polymer:drug ratio, and microparticle size. When the composition of the present invention is a depot composition, administration by injection is preferred.

[0108] Pharmaceutically acceptable salts of the compounds of the present invention can be obtained from the parent compound, which contains a basic or acid group by conventional chemical methods. Typically, these salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the corresponding acid in water or in an organic solvent, or in a mixture of these two solvents; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Further details on the preparation of these salts, for example the toluenesulfone salt in amorphous or crystalline form, can be found in PCT/US0/03340 and/or US provisional application No. 61/036069 (each equivalent to US 2011/112105).

[0109] Pharmaceutical compositions containing the compounds of the present invention can be obtained using conventional diluents or excipients (one example includes, but is not limited to, sesame oil) and methods known in the medical field of technology. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

[0110] The term "together" when referring to therapeutic use means the administration of two or more active ingredients to a patient as part of a regimen for treating a disease or disorder, whether the two or more liquid active agents are administered at the same time or at different times, or by the same or different routes of administration. The simultaneous administration of two or more active ingredients may occur at different times on the same day, or on different dates, or at different frequencies.

[0111] The term "simultaneously" when referring to therapeutic use means the administration of two or more active ingredients at the same time by the same route of administration.

[0112] the Term "separately" when referring to therapeutic use means the introduction of two or more active ingredients at the same time by different routes of administration.

Methods for preparing the compounds of the present invention:

[0113] Compounds of the present invention in which X is -NH- or -N(CH ₃ )- and Y is -C(=O) can be prepared by the reaction (6bR, 10aS)-2-oxo-2, 3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline or its 1-methyl analogue with 4-chloro- 4'-fluorobutyrophenone according to Scheme 1 below:

X=-NH- or -N(CH ₃ )-

Scheme 1

[0114] Compounds of the present invention in which X is -NH- or -N(CH ₃ )- and Y is -CH(OH)- can be prepared by the reaction of 4-((6bR,10aS)-2-oxo -2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1- (4-fluoro-phenyl)-butan-1-one obtained in Scheme 1 (or its 1-methyl analogue) with a reducing agent according to Scheme 2 below:

X=-NH- or -N(CH ₃ )-

Scheme 2

[0115] The reducing agent may be a metal hydride, such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, preferably sodium borohydride. Additional ketone reducing agents can be found in Jerry March, Advanced Organic Chemistry, Reactions Mechanisms and Structures, pp. 910-911, (1992, John Wiley & Sons, Inc.), Fourth Edition, the contents of which are incorporated by reference.

[0116] Isolation and purification of the diastereomers of the compounds of the present invention can be carried out by conventional methods known in the art, for example, column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, pseudo-moving bed, and the like.

[0117] Compounds of formula I, in which Y is -CH(OR ₁ )-, and R ₁ is other than H, can be obtained by several well-known esterification methods, such as alcohol hydrolysis of acyl halides, aldehydes or active esters. For example, a compound of formula I, in which R ₁ represents -C(O)-alkyl, can be obtained by the reaction:

LC(O)-C _1-21 alkyl in which L is a leaving group such as a halogen group (eg chlorine or bromine), trifluoromethylsulfonyloxy (-OSO ₂ CF ₃ ), tosyloxy (-OS(O) ₂ -C ₆ H ₄ -CH ₃ ), methylsulfonyloxy (-OS(O) ₂ -CH ₃ ), 1H-benzo[d][1,2,3]triazol-1-yloxy or succinimidyloxy group,

with a compound of formula I in which Y is -C(H)(OH),

preferably in the presence of a base (eg diisopropylamine, triethylamine or pyridine). For example, LC(O)-C _1-21 alkyl is an acetyl halide, decanoyl halide, or heptanoyl halide that can be prepared by reacting HO-C(O)-C _1-21 alkyl with, for example, thionyl chloride, P(X') ₃ or P (X') ₅ where X' represents Cl or Br. Where L is tosyloxy-C(O)-C _1-21 alkyl or methylsulfonyloxy-C(O)-C _1-21 alkyl, these compounds can be prepared by reacting HO-C(O)-C _1-21 alkyl with tosyl chloride or mesyl chloride, preferably in the presence of a base such as pyridine. The preparation of a compound of formula II-A in which R ₁ is other than H can be summarized in Scheme 3 below:

Scheme 3

[0118] Alternatively, the preparation of a compound of formula II-A in which R ₁ is other than H can be carried out by reacting HO-C(O)-C _1-21 alkyl with (i) a compound of formula I in which Y is - C(H)(OH), in the presence of a base such as DIEPA and NEt ₃ , and (ii) a dehydrating or condensing agent such as 2-fluoro-1-ethylpyridinium tetrafluoroborate (FEP), tetramethylfluoroamidinium hexafluorophosphate (TFFH), or hexafluorophosphate 1 ,1,3,3-bis(tetramethylene)chloruronium (PyClU).

[0119] Salts of the compounds of the present invention can be obtained similarly to the methods described in US patent No. 6548493; 7238690; 6552017; 6713471; 7183282; U.S. RE39680; U.S. RE39679; and WO 2009/114181 (US 2011/112105), the contents of each of which are incorporated by reference in their entirety.

[0120] The diastereomers of the resulting compounds can be separated, for example, by HPLC using CHIRALPAK® AY-H, 5 μm, 30×250 mm at room temperature and eluted with 10% ethanol/90% hexane/0.1% dimethylethylamine. Peaks can be detected at 230 nm, yielding 98-99.9% of its diastereomer.

Example 1 Preparation of 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1 ,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one

[0121] (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2] ethyl ester ,3-de]quinoxaline-8-carboxylic acid (6.4 g, 21.2 mmol) was suspended in HBr acetic acid solution (64 ml, 33% w/w) at room temperature. The mixture was heated at 50° C. for 16 hours. After cooling and treatment with ethyl acetate (300 ml), the mixture was filtered. The filter cake was washed with ethyl acetate (300 ml) and then dried in vacuo. Then, the resulting HBr salt was suspended in methanol (200 ml) and cooled with dry ice in isopropanol. With vigorous stirring, a solution of ammonia (10 ml, 7N in methanol) was slowly added to the suspension, adjusting the pH of the mixture to 10. The resulting mixture was dried in vacuo without further purification to give crude (6bR, 10aS)-2-oxo-2.3, 6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (8.0 g) which was used directly in the next step . MS (ESI) m/z 230.2 [M+H] ⁺ .

[0122] Crude (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2, 3-de]quinoxaline (1.4 g) was dissolved in DMF (14 ml), and then KI (2.15 g) and 4-chloro-4'-fluorobutyrophenone (2 ml) were added sequentially. The mixture was degassed with argon, followed by the additionN, N-diisopropylethylamine (DIPEA, 2 ml). The mixture was heated at 78°C for 2 hours After cooling, the solvents were removed under reduced pressure. The dark brown residue was suspended in dichloromethane (100 ml) and then extracted with water (30 ml). The organic layer was separated and dried over K₂CO₃. After filtration, the solvents were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography eluting with 0-10% methanol in ethyl acetate containing 0.1% 7N ammonia in methanol to give 4-((6bR,10aS)-2-oxo-2,3,6b,9, 10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)butan- 1-one as a light yellow solid residue (767 mg).^oneH NMR (500 MHz, DMSO-d ₆) δ 10.3 (s, 1H), 8.1-8.0 (m, 2H), 7.3 (dd,J= 8.86 Hz, 2H), 6.8 (d,J\u003d 7.25 Hz, 1H), 6.6 (dd,J=7.55 Hz, 1H), 6.6 (d,J= 7.74 Hz, 1H), 3.8 (d,J=14.49 Hz, 1H), 3.3-3.3 (m, 1H), 3.2-3.2 (m, 1H), 3.1-3.0 (m, 1H), 3, 0 (t,J=6.88 Hz, 2H), 2.8-2.8 (m, 1H), 2.6-2.5 (m, 1H), 2.3-2.2 (m, 2H), 2, 1-2.0 (m, 1H), 1.9-1.8 (m, 1H), 1.8 (t,J\u003d 6.99 Hz, 2H), 1.6 (t,J=11.25 Hz, 2H). MS (ESI) m/z 394.2 [M+H]⁺.

Example 2 Preparation of 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1 ,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-ol

[0109] 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1, 2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one (50 mg, 0.127 mmol) was dissolved in methanol (5 ml). NaBH ₄ (31 mg, 0.82 mmol) was added portionwise with stirring. After completion of the addition, the mixture was stirred at room temperature for 30 minutes. The methanol was evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 ml) and then extracted with water (2×0.5 ml). The combined organic phase was dried over K ₂ CO ₃ . After filtration, the filtrate was concentrated under reduced pressure, and then further dried in vacuo to give 4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[ 3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-ol as a pale yellow foamy residue ( 45 mg, 90% yield. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.3 (s, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 2H), 6, 7 (d, J = 7.29 Hz, 1H), 6.7-6.6 (m, 1H), 6.6 (d, J = 7.74 Hz, 1H), 5.4 (s, 1H ), 4.7-4.4 (m, 1H), 3.8 (d, J = 14.49 Hz, 1H), 3.3-3.3 (m, 1H), 3.3-3, 2 (m, 1H), 3.2-3.1 (m, 1H), 2.8-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.3- 2.1 (m, 2H), 2.1-2.0 (m, 1H), 2.0-1.9 (m, 1H), 1.8-1.7 (m, 1H), 1, 7-1.5 (m, 3H), 1.5-1.4 (m, 1H), 1.4-1.3 (m, 1H). MS (ESI) m/z 396.2 [M+H] ⁺ .

Example 3 Preparation of (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5 ]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0110] A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline- 2(3H)-one (100 mg, 0.436 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (100 μl, 0.65 mmol) and KI (144 mg, 0.87 mmol) in DMF (2 ml ) was degassed with argon for 3 minutes and DIPEA (150 μl, 0.87 mmol) was added. The resulting mixture was heated to 78° C. and stirred at this temperature for 2 hours. The mixture was cooled to room temperature and then filtered. The filter residue was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in methanol/7N NH ₃ in methanol (1:0.1 v/v) as eluent to give a partially purified product which was further purified by a semi-preparative HPLC system. using a gradient of 0-60% acetonitrile in water containing 0.1% formic acid over 16 minutes to give the title compound as a solid residue (50 mg, 30% yield). MS (ESI) m/z 406.2 [M+1] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.3 (s, 1H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6, 8 (dd, J =1.03, 7.25 Hz, 1H), 6.6 (t, J =7.55 Hz, 1H), 6.6 (dd, J =1.07, 7.79 Hz , 1H), 4.0 (t, J =6.35 Hz, 2H), 3.8 (d, J =14.74 Hz, 1H), 3.3-3.2 (m, 3H), 2 .9 (dd, J = 6.35, 11.13 Hz, 1H), 2.7-2.6 (m, 1H), 2.5-2.3 (m, 2H), 2.1 (t , J = 11.66 Hz, 1H), 2.0 (d, J = 14.50 Hz, 1H), 1.9-1.8 (m, 3H), 1.7 (t, J = 11, 04Hz, 1H).

Example 4 Determination of Functional Properties of Cellular and Nuclear Receptors

[0111] The determination of the functional properties of cellular and nuclear receptors was performed on compounds of formula II-B and II-C (examples 1 and 2, respectively) according to the method of Wang, JB et al. (1994), FEBS Lett., 338:217-222. Compounds were tested at several concentrations, determining their IC ₅₀ or EC ₅₀ . Cellular agonist effects were calculated as a percentage control response to a known reference agonist for each target, and cellular antagonistic effects were calculated as a percentage inhibition response to a control reference agonist for each target.

[0112] The following test was performed to determine the effect of a compound of formula II-B on the μ (MOP) (h) receptor:

test
(Receptor) ball stimulus aging Measured Component Detection method μ (MOP) (h)
(agonistic effect) human recombinant
MOP receptor
(CHO cells) No
(0.3 µM DAMGO
For control) 10 min at 37°C cAMP HTRF μ(MOP) (h)
(antagonistic effect) human recombinant
MOP receptor
(CHO cells) DAMGO
(20 nM) 10 min at 37°C cAMP HTRF

[0109] For antagonists, observed dissociation constants (K _B ) were calculated using the modified Cheng-Prusoff equation:

where A=the concentration of the reference agonist in the test, and EC _50A =EC _{50 the} value of the reference agonist.

[0110] It was found that the compound of formula II-B has μ (MOP) (h) (antagonistic effect) with an IC ₅₀ 1.3×10 ^-6 M; and K _B 1.4×10 ^-7 M; and the compound of formula II-C was found to have an IC ₅₀ greater than 1×10 ^-5 , which was the highest concentration tested.

[0111] Agonist activity results were expressed as a percentage of control agonist response:

and antagonistic activity in the form of inhibition as a percentage of the maximum response of the control agonist:

Obtained in the presence of compounds of formula II-B or II-C.

[0113] The EC ₅₀ value (concentration causing half-maximal response) and the IC ₅₀ value (concentration causing half-maximal inhibition of the control agonist response) were determined by non-linear regression analysis of response-concentration curves obtained with mean repetition values using curve fitting with the Hill equation:

where Y=response, A=left curve asymptote, D=right curve asymptote, C=compound concentration, and C ₅₀ =EC ₅₀ or IC ₅₀ , and nH=slope factor. The analysis was performed using self-developed software and verified by comparison with data generated by commercial software SigmaPlot® 4.0 for Windows® (© 1997 SPSS Inc.).

Example 5 Receptor Binding Profile of the Compound of Formulas II-B, II-C and Example 3

[0114] Receptor binding was determined for compounds of formulas II-B and II-C using the tosylate salt of a compound of formula A as a control. The following literature methods were used, each of which is incorporated herein by reference in its entirety: 5-HT _2A : Bryant, HU et al. (1996), Life Sci., 15:1259-1268; D2: Hall, D.A. and Strange, P.G. (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, QY et al. (1990), Nature, 347:76-80; SERT: Park, YM et al. (1999), Anal. Biochem ., 269:94-104; Mu opiate receptor: Wang, JB et al. (1994), FEBS Lett., 338:217-222.

[0115] In general, the results are expressed as a percentage of control specific binding:

And as percent inhibition of control specific binding:

Obtained in the presence of the test compounds.

[0116] IC ₅₀ values (concentration causing half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of competitive curves obtained with mean repetition values using curve fitting with the Hill equation:

where Y=specific binding, A=left curve asymptote, D=right curve asymptote, C=compound concentration, C ₅₀ =IC ₅₀ , and nH=slope factor. This analysis was performed using self-developed software and verified by comparison with data generated by commercial software SigmaPlot® 4.0 for Windows® (© 1997 SPSS Inc.). Inhibition constants (Ki) were calculated using the Cheng-Prusoff equation:

where L=radioligand concentration in this assay, and K _D =radioligand receptor affinity. The Scatchard plot was used to determine K _D .

[0112] The following receptor affinity results were obtained using the tosylate salt of a compound of formula A as a control:

Receptor Formula II-B
(Example 1) Formula II-C
(Example 2) Example 3 Formula A
(tosylate salt) Ki (nM) or maximal inhibition 5-HT _2A eleven 31% inhibition at 240 nM 8.3 ten D2 47% inhibition at 240 nM 11% inhibition at 240 nM 160 49 D1 22 13% inhibition at 100 nM fifty 41 SERT 44% inhibition at 240 nM No inhibition observed 590 16 Mu opiate receptor 22 85 eleven >10000 delta opioid No inhibition Kappa opioid 16% at 100nM NOP (nociceptin receptor) No inhibition

Example 5: DOI-induced head jerk model in mice

[0113] R-(-)-2,5-dimethoxy-4-iodomamphetamine (DOI) is a serotonin 5-HT ₂ receptor family agonist. When administered to mice, it induces a behavioral profile associated with frequent head jerks. The frequency of these head jerks over a given period of time can be taken as an estimate of 5-HT ₂ receptor agonism in the brain. Conversely, this behavioral assay can be used to detect 5-HT ₂ receptor antagonism in the brain by administering DOI with or without an antagonist and recording a reduction in DOI-induced head jerks following antagonist administration.

[0114] The method of Darmani et al., Pharmacol Biochem Behav. (1990) 36:901-906 (the contents of which are incorporated by reference in its entirety) apply with some modifications. (±)-DOI HCl was injected subcutaneously and the mice were immediately placed in a conventional plastic cage. The number of convulsive movements of the head was counted for 6 minutes, starting from 1 minute after the administration of DOI. The test compound was administered orally 0.5 hours before the administration of the DOI. Results were calculated as EC50 for reduction of DOI-induced head jerks. The results are shown in the following table:

[0115]

Compound EC ₅₀ (mg/kg, po) example 1 (formula II-B) 0.23 example 2 (formula II-C) 2.03 example 3 0.44 formula A 0.09 formula B 0.31

The results show that the compounds of example 1 and 3 effectively block DOI head jerk, comparable to the reference compounds of formula A and C, and comparable to the in-vitro 5-HT _2A results shown in example 5. In contrast, the compound of example 2 was relatively inactive in this functional assay, confirming that this compound is relatively weaker in its serotonin receptor antagonism than structurally similar compounds.

Example 7: Mouse Tail Flick Tests

[0116] The mouse tail flick test is a measure of analgesia as indicated by the pain reflex threshold in delayed mice. Male CD-1 mice placed their tails under a focused beam of a high-intensity infrared heat source, which resulted in heating of the tail. The animal could turn its tail away from the heat source at any time when it became uncomfortable. Recorded the length of time (delay) between turning on the heating device and pulling the mouse's tail out of the way of the heat source. Morphine administration resulted in anelgesia and this caused a delay in the mouse's response to heat (extended latency). Pre-administration of a morphine antagonist (MOR), ie, naloxone (NAL), reverses the effect and results in a normal waiting time. This test is used as a functional assay to determine mu-opiate receptor antagonism.

Example 7a Antagonism of Morphine Induced Analgesia by the Compounds of Examples 1 and 3

[0117] Ten male CD-1 mice (approximately 8 weeks old) were assigned to each of 5 treatment groups. Groups were treated in the following manner: group (1) [negative control]: administered 0.25% methylcellulose medium orally 60 minutes before the tail-twitch test, and saline-based medium 30 minutes before the tail-twitch test; group (2) [positive control]: administered 0.25% methylcellulose medium orally 60 minutes before the test and 5 mg/kg morphine in saline solution 30 minutes before the test; group (3) [positive control]: administered 3 mg/kg naloxone in saline solution 50 minutes before the test and 5 mg/kg morphine in saline solution 30 minutes before the test; groups (4)-(6): administered 0.1 mg/kg, 0.3 mg/kg or 1 mg/kg of the test compound in 0.25% methylcellulose medium orally 60 minutes before the test and 5 mg/kg of morphinase 30 minutes before the test. The experiment was repeated for the compounds of example 1 and example 3. The results are shown in the following table as the average delay in seconds:

Group 1 Wednesday/Wednesday Group 2 Medium/Morph Group 3 Cash/morph Group 4 Comm/morph (0.1 mg/kg) Group 5 Comm/morph (0.3 mg/kg) Group 6 Comm/morph (1 mg/kg) Example 1 1.028 9.361 2.496 8,870 6.907 6.240 Example 3 0.887 8.261 3.013 6.947 5,853 6.537

[0118] The results show that the compounds of Example 1 and Example 3 exhibit dose-dependent blockade of morphine-induced mu-opiate receptor activity.

Example 7b Naloxone Inhibited Analgesia with Compound of Example 3

[0119] In a second study, using the mouse tail flick test as defined above, the compound of Example 3 was further compared at doses of 1.0 mg/kg, 3.0 mg/kg, and 10 mg/kg relative to morphine at 5 mg/kg. kg with and without prior dosing of naloxone at 3 mg/kg (ip). In the pretreatment groups, naloxone was administered 20 minutes prior to the tail twitch test. In the non-pretreatment groups, saline was administered 20 minutes prior to the tail twitch test. In each group, medium, morphine or the compound of example 3 was administered 30 minutes prior to the tail twitch test. The results are shown in the table below as average latency in seconds:

Wednesday Morphine Example 3 at 1 mg/kg Example 3 at 3 mg/kg Example 3 at 10 mg/kg Pre-treatment with brine 0.9 9.8 4.1 7.4 9.8 Pretreatment with naloxone 0.8 1.5 1.3 1.7 2.1

[0120] Found that the introduction of the compound of example 3 at all doses significantly increased the delay in tail twitching, and that this effect was attenuated by pre-treatment with naloxone. This result demonstrates the dose-dependent analgesic effect induced by the compound of Example 3 and further suggests that this effect is mediated by mu-opioid receptor agonism.

Example 7c: time course for analgesia, compound of example 3

[0121] The tail twitch test as defined above was repeated to determine the temporal dynamics of analgesia resulting from administration of the compound of Example 3. Mice were administered subcutaneously or (1) medium 30 minutes prior to the test, (2) 5 mg/kg morphine 30 minutes prior to the test. minutes before the test, or (3)-(7) 1 mg/kg of the compound of Example 3 30 minutes, 2 hours, 4 hours, 8 hours or 24 hours before the test. The results are shown in the table below as average latency in seconds:

Treatment TF Delay (s) Wednesday, 30 minutes before 1.30 Morphine, 30 minutes before 7.90 Compound of Example 3, 30 min to 5.77 Compound of Example 3, 2 h to 2.42 Compound of example 3, 4 h to 1.48 Compound of Example 3, 6 h to 1.36 Compound of Example 3, 24 hours to 1.29

[0122] The results show that the compound of example 3 causes effective analgesia when administered 30 minutes or 2 hours before the tail twitch test (ANOVA, P<0.001 vs. medium). When administered 4 hours, 8 hours, or 24 hours prior to the tail twitch test, the compound of Example 3 at 1 mg/kg did not produce an analgesic effect significantly different from the medium control. Thus, the compound of example 3 did not produce prolonged analgesia, which means that it will have a lower abuse potential and a lower risk of drug interactions compared to other opiate analgesics.

Example 7d: Analgesia after long-term administration of the compound of example 3

[0123] The tail twitch test described above was repeated using a testing model in which the animals were subjected to a 14 day long treatment regimen followed by a short treatment 30 minutes prior to the tail twitch test. Mice were divided into three broad groups with six subgroups of 10 mice each. Three groups received long-term treatment with (A) medium, (B) compound of example 3 at 0.3 mg/kg, or (C) compound of example 3 at 3.0 mg/kg. Each subgroup additionally received as a short-term treatment (1) medium or (2)-(6) the compound of example 3 at 0.01, 0.03, 0.1, 0.3 or 1.0 mg/kg. All injections were performed subcutaneously. The results are shown in the table below as the average delay to tail twitch in seconds:

Group Long processing short term processing Delay (s) (A) Wednesday Wednesday 1.09 Wednesday Example 3, 0.01 mg/kg 1.87 Wednesday Example 3, 0.03 mg/kg 2.50 Wednesday Example 3, 0.1 mg/kg 5.26 Wednesday Example 3, 0.3 mg/kg 8.26 Wednesday Example 3, 1.0 mg/kg 9.74 (B) Example 3, 0.3 mg/kg Wednesday 0.893 Example 3, 0.3 mg/kg Example 3, 0.01 mg/kg 1.66 Example 3, 0.3 mg/kg Example 3, 0.03 mg/kg 1.30 Example 3, 0.3 mg/kg Example 3, 0.1 mg/kg 2.60 Example 3, 0.3 mg/kg Example 3, 0.3 mg/kg 3.93 Example 3, 0.3 mg/kg Example 3, 1.0 mg/kg 5.64 (C) Example 3, 3.0 mg/kg Wednesday 1.04 Example 3, 3.0 mg/kg Example 3, 0.01 mg/kg 1.64 Example 3, 3.0 mg/kg Example 3, 0.03 mg/kg 1.80 Example 3, 3.0 mg/kg Example 3, 0.1 mg/kg 3.94 Example 3, 3.0 mg/kg Example 3, 0.3 mg/kg 4.84 Example 3, 3.0 mg/kg Example 3, 1.0 mg/kg 7.94

[0124] Found that 0.1, 0.3 and 1.0 mg/kg short-term treatment with the compound of example 3 caused a statistically significant dose-dependent analgesic effect compared with the group with short-term treatment environment. This is true for each of the long group (A), (B) and (C). Compared to medium pre-treatment, pre-treatment with Example 3 at 0.3 mg/kg or 3.0 mg/kg generally showed a statistically significant reduction in tail-flick latency when compared to the same short-term treatment subgroups. These results show that while some tolerance to the analgesic effect of the compound of example 3 occurs after 14 days of long-term treatment, the resulting analgesia remains effective despite long-term pre-treatment.

Example 8 CNS Phosphoprotein Profile

[0125] An integrated molecular phosphorylation study was also performed to study the central nervous system (CNS) profile of the compounds of Example 1 and Example 3. The degree of protein phosphorylation for selected key central nervous system proteins was measured in the nucleus accumbens of mice. The proteins tested included ERK1, ERK2, Glu1, NR2B and TH (tyrosine hydroxylase), and the compounds of Example 1 and 3 were compared with the antipsychotic agents risperidone and haloperidol.

[0126] Mice were treated with Example 1 or 3 at 3 mg/kg or haloperidol at 2 mg/kg. Mice were sacrificed 30 minutes to 2 hours after injection by focused microwave irradiation of the skull, which preserved the brain phosphoprotein as it existed at the time of death. Then, nuclei accumbens were dissected from each brain, cut into layers and frozen in liquid nitrogen. Samples were additionally prepared for phosphoprotein analysis by SDS-PAGE electrophoresis, followed by phosphoprotein-specific immunoblotting as defined in Zhu H, et al., Brain Res. 2010 Jun 25; 1342:11-23. Phosphorylation at each site was quantified, normalized to total protein (non-phosphorylated) and expressed as a percentage of the level of phosphorylation in vehicle-treated control mice.

[0127] The results show that neither Example 1 nor Example 3 had a significant effect on Ser40 tyrosine hydroxylase phosphorylation at 30 minutes or 60 minutes, in contrast to haloperidol, which caused a greater than 400% increase, and risperidone, which caused over 500% increase in TH phosphorylation. This demonstrates that the compounds of the present invention do not impair dopamine metabolism.

[0128] The results further demonstrate that neither the compound of example 1 nor the compound of example 3 had a significant effect on NR2B phosphorylation at Tyr1472 after 30-60 minutes. The compounds caused a slight increase in GluR1 phosphorylation at Ser845, and a slight decrease in ERK2 phosphorylation at Thr183 and Tyr185. Phosphorylation of proteins at various sites in particular proteins is known to be associated with various cellular activities such as protein transport, ion channel activity, strength of synaptic signaling, and changes in gene expression. Phosphorylation of Tyr1472 at the NMDA glutamate receptor has been shown to be important in the maintenance of neuropathic pain. Ser845 GluR1 phosphorylation of the AMPA-type glutamate receptor is associated with several aspects of enhancing synaptic transmission and enhancing synaptic localization of the receptor to support long-term cognitive-related potentiation. Phosphorylation of this residue has also been reported to increase the likelihood of channel opening. Phosphorylation of the ERK2 kinase, a member of the MAP kinase cascade, at residues T183 and Y185 is required for the full activation of this kinase, and ERK2 is involved in many aspects of cell physiology, including cell growth, survival, and transcriptional regulation. This kinase has been reported to be important for synaptogenesis and cognitive function.

Example 9: Ball Burrow Study in Mice (OCD Model)

[0129] The ball burying test was used to measure repetitive and anxiety-related behavior in rodents. It is based on the observation that rats and mice will bury harmful or harmless objects in their beds and has been used as an animal model to measure the effect of pharmacological interventions in the treatment of recurrent behavioral disorders such as OCD.

[0130] Initially, mice were divided into four treatment groups: (1) medium negative control, (2) 0.3 mg/kg compound of example 3, (3) 1.5 mg/kg compound of example 3, and (4) 20 mg/kg MPEP (2-methyl-6-(phenylethynyl)pyridine), positive control. MPEP is a selective mGluR5 glutamate receptor antagonist. Mice in groups (2) and (3) were orally administered the compound of Example 3 at the indicated dose in 0.5% methylcellulose aqueous medium 30 minutes prior to the test. The mice in groups (1) were given the medium orally and the mice in the group (4) were given an intraperitoneal injection of MPEP just before the start of the test.

[0131] The test was performed in rectangular cages with 4-5 cm wood chip flooring in a room with the curtains down and the door closed to minimize distractions. Fifteen transparent marbles were evenly distributed over the deck in three rows of five marbles. One mouse was placed in each cage. The mouse and cage were left alone for 30 minutes. At the end of the test, the mouse is taken out and the number of marbles buried at least 2/3 of their depth is counted. The results are shown in the following table:

Group Buried marble balls (1) Wednesday 13.2 (2) 0.3 mg/kg Example 3 9.3 (3) 1.5 mg/kg of Example 3 4.7 (4) MPEP 0.2

[0132] The results show that compared to control, there is a statistically significant reduction in "ballooning" for mice treated with 0.3 mg/kg of Example 3 (p<0.01) and 1.5 mg/kg of Example 3 (p<0.001). In addition, there is evidence of a clear dose-response relationship. The results confirm the usefulness of the compound of example 3 in indications for the treatment of OCD.

Example 10: Mu Opiate Receptor Activity Assays

[0133] The compounds of Example 1 and 3 were tested in CHO-K1 cells expressing hOP3 (human μ1 mu-opiate receptor subtype) using an HTRF-based cAMP assay kit (cAMP Dynamic2 assay kit from Cisbio, #62AM4PEB). Frozen cells were thawed in a 37°C water bath and suspended in 10 ml F-12 Ham's medium containing 10% FBS. Cells were recovered by centrifugation and suspended in assay buffer (5 nM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g /L BSA without protease supplemented with 1 mM IBMX). Buprenorphine, a mu-opiate receptor partial agonist, and naloxone, a mu-opiate receptor antagonist, and DAMGO, a synthetic opioid peptide full agonist, were used as controls.

[0134] For the agonism assay, 12 µl of the cell suspension (2500 cells/well) was mixed with 6 µl of forksolin (10 µm final assay concentration), and 6 µl of the test compound at increasing concentrations were mixed in the wells of a 384-well white plate, and the plates were kept for 30 minutes at room temperature. After addition of lysis buffer and one hour additional incubation, cAMP concentrations were measured according to the kit instructions. All data analysis was determined in triplicate. Curve fitting was performed using XLfit software (IDBS) and EC ₅₀ values were determined using 4-parameter exponential fitting. The agonism test measures the ability of a test compound to inhibit forscalin-stimulated cAMP accumulation.

[0135] For antagonism assay, 12 µl of cell suspension (2500 cells/well) was mixed with 6 µl of test compound at increasing concentrations, and mixed in the wells of a 384-well white plate, and the plate was incubated for 10 minutes at room temperature. 6 μl of a mixture of DAMGO (D-Ala ² -N -MePhe ⁴ -Gly-olenkephalin, 10 nM final assay concentration) and forxoline (10 μm final assay concentration) was added and the plates were incubated for 30 minutes at room temperature. After addition of lysis buffer and one hour of additional inhibition, cAMP concentrations were measured according to the kit instructions. All data analysis was determined in triplicate. Curve fitting was performed using XLfit software (IDBS) and EC ₅₀ values were determined using 4-parameter exponential fitting. The observed dissociation constant (K _B ) was calculated using the modified Cheng-Prusoff equation. The antagonism test measures the ability of a test compound to reverse the inhibition of forscalin-stimulated cAMP accumulation induced by DAMGO.

[0136] The results are shown in figures 1 and 2 and in the table below. The results show that the compound of Example 3 is a weak Mu receptor antagonist, showing a much larger IC ₅₀ compared to naloxone, and it shows a moderately high affinity but partial agonist, showing only about 22% DAMGO agonist activity (versus up to about 79% potency for buprenorphine relative to DAMGO). The compound of Example 1 was also shown to have a moderately strong partial agonist activity.

Compound Antagonist IC ₅₀ (nM) Agonist EC ₅₀ (nM) K _B (nM) Naloxone 5.80 - 0.65 DAMGO - 1.56 - Buprenorphine - 0.95 - Compound Example 3 641 64.5 71.4 Compound Example 1 - 140 -

[0137] Buprenorphine is a drug used to treat chronic pain and opiate withdrawal, but suffers from the problem that users can become addicted due to its high partial agonist activity. To compensate for this, a commercial combination of buprenorphine and naloxone (sold as suboxone) is used. Without being bound by theory, it is believed that the compounds of the present invention, which are weaker partial mu agonists than buprenorphine with some moderate antagonistic activity, will allow the patient to be more effectively treated for pain and/or opiate withdrawal with a lower risk of dependence.

[0138] In a further related study, using a recombinant human MOP-beta blocking signaling pathway, it was found that the compound of Example 3 does not stimulate the beta-arrestin signaling system via the MOP receptor at concentrations up to 10 μM, but that it is an IC antagonist ₅₀ 0.189 µM. In contrast, the full opioid agonist Met-enkephalin stimulates the beta-arrestin signaling system with an EC ^{50 of} 0.08 µm.

Example 11 Rat Addiction/Tolerance Study

[0139] The compound of Example 3 was evaluated on repeated (28 days) daily subcutaneous administration to male Sprague-Dawley rats, monitoring the effect of the drug on dosing and determining whether there was pharmacological tolerance. In addition, behavioral, physical and physiological signs in rats were monitored after abrupt cessation of repeated dosing to determine if the compound caused physical dependence upon withdrawal. In addition, a pharmacokinetic study is conducted in parallel with the tolerance and dependence study to determine the plasma levels of the drug at the specific doses used in the tolerance and dependence study. Morphine was used as a positive control to ensure model validity and as a reference agent for comparison from a similar pharmacological class.

[0140] The compound of example 3 was evaluated at two doses, 0.3 and 3 mg/kg, administered subcutaneously four times a day. Repeated administration has been found to produce peak plasma concentrations of 15-38 ng/ml (mean, n=3) for the 0.3 mg/kg dose, and 70-90 ng/ml (mean, n=3) for the 3 mg /kg dose. Peak concentration was reached 30 minutes to 1.5 hours after administration with comparable results obtained on the first, 14 and 28 days of administration.

[0141] At both doses of Example 3, no significant effect was observed on the animal's body weight, food and water intake, or body temperature during the intake or withdrawal phase. The predominant behavioral and physical effects caused by repeated administration at 0.3 mg/kg are hunched posture, Straub's tail and piloerection during the dosing phase. At a higher dose, the main observed behavioral and physical signs are a hunched posture, depressed behavior, Straub's tail, tail-beating, and piloerection.

[0142] A similar profile of behavioral and physical signs was observed after the abrupt cessation of compound administration on day 28 of the study. While rearing and toning was not observed during the dosing phase at 0.3 mg/kg, these parameters were found to increase significantly during the withdrawal phase. At the higher dose, moderate rearing was observed during the dosing phase, but during the withdrawal phase, rearing is more pronounced and increased body tone is observed.

[0143] As a positive control, morphine was dosed at 30 mg/kg orally twice a day. This dosing regimen is, as expected, associated with changes in body weight, food and water intake, rectal temperature, and clinical signs consistent with withdrawal-induced development of tolerance and withdrawal. Body weight increased significantly compared to the medium control group on days 2 and 3, while it decreased significantly from day 5. Morphine significantly reduced food intake on days 1-9. Thereafter, there was usually a decrease in food intake compared to the control group, but it did not differ significantly from the control on days 9, 13, 14, 16, 18, 21, 22, and 25. These effects on body weight and food intake demonstrate tolerance to the effect morphine.

[0144] The water consumption of the morphine treated group was also found to be significantly lower than that of the control group on 25 of the 28 days during the dosing phase. The body temperature is also usually lower than that of the control group during the dosing phase, especially on days 20, 21 and 27. The predominant behavioral effects induced by morphine during the dosing phase were observed to be Straub's tail, jumping, digging, increased body tone, increased locomotor activity, explosive movements and exophthalmos.

[0145] Furthermore, abstinence from morphine administration on day 28 was observed to result in an initial additional decrease in food intake, followed by recurrent bulimia, with significantly increased food intake on day 33 relative to the control group. By day 35, food intake returned to control levels. Similarly, rats previously treated with morphine also experienced an initial decrease in water intake at day 29, followed by recurrent excessive thirst (water intake returned to control levels by day 31). In addition, a statistically significant decrease in rectal body temperature was observed during dosing, but body temperature returned to control levels during the withdrawal phase.

[0146] Moreover, new behavioral and physical signs were observed during the phase of morphine withdrawal, and this indicates the presence of dependence. These signs include piloerection, ataxia/waddle gait, wet dog shaking, and abdominal cramping. Other abnormal behaviors observed during the intake phase gradually disappeared during the withdrawal phase. By day 35, rearing was the only behavioral or physical sign observed at high frequency in rats previously treated with morphine.

[0147] Thus, repeated administration of morphine is shown to produce clear signs of tolerance and dependence in this study, with changes in body weight, food and water intake, rectal temperature, and clinical signs consistent with the development of tolerance and dependence caused by withdrawal. This demonstrates the validity of the test method in detecting physiological changes upon dosing and dosing.

[0148] In contrast, repeated administration of the compound of Example 2 at 0.3 and 3 mg/kg four times a day did not produce tolerance when subcutaneously dosed for 28 days. Moreover, upon withdrawal, a similar but decreasing profile of behavioral and physical signs was observed at the highest dose, which was not considered clinically relevant. Thus, it was found that the compound of example 3 did not in general cause a physical dependence syndrome upon discontinuation of dosing.

Example 12 Oxycodone-Dependent Withdrawal Study in Mice

[0149] Oxycodone was administered to male C57BL/6J mice for 8 days on a escalation schedule of 9, 17.8, 23.7, and 33 mg/kg twice daily (7 hours between injections) at 1-2, 3- 4, 5-6 and 7-8 days, respectively. On the morning of the ninth day, the mice were injected subcutaneously with the compound of example 3 at 0.3, 1 or 3 mg/kg. This was followed 30 minutes later by injection of medium or injection of 3 mg/kg naloxone. Another group of mice served as negative controls, and instead of oxycodone, these mice were injected with saline on days 1-8. On day 9, these mice were injected with either medium (followed by naloxone, as above) or the compound of Example 3 at 3 mg/kg, subcutaneously (followed by naloxone, as above).

[0150] On day 9, immediately after injection of naloxone (or medium), mice were individually placed in transparent plastic cages and observed continuously for thirty minutes. Mice were monitored for general somatic signs of opiate withdrawal, including jumping, shaking off a wet dog, paw tremors, reversing, ptosis, and diarrhea. All of these behaviors were recorded as new occurrences when they were separated by at least one second or when they were interrupted by normal behavior. The body weight of the animal was also recorded immediately before and 30 minutes after administration of naloxone (or medium). Data were analyzed by ANOVA followed by Tukey's test for multiple comparisons, if necessary. The significance level was set at p <0.05.

[0151] The results are shown in the table below:

dosing: (1) on days 1-8,
(2) on day 9, followed by
(3) after 30 minutes Total number of features Paw tremor jumping Body weight loss (1) Salt solution; (2) medium, (3) naloxone 2.2 0.87 0 0.5% (1) brine; (2) compound 3.0 mg/kg, (3) naloxone 5.3 0.12 0 0.4% (1) oxycodone; (2) compound 3.0 mg/kg, (3) medium 155.1 73.6 63.2 7.8% (1) oxycodone; (2) compound 0.3 mg/kg, (3) naloxone 3 mg/kg 77.5 19.6 40.6 7.5% (1) oxycodone; (2) compound 1.0 mg/kg, (3) naloxone 3 mg/kg 62.5 14.8 34.8 6.0% (1) oxycodone; (2) compound 3.0 mg/kg, (3) naloxone 3 mg/kg 39.5 0.5 26.6 4.0%

[0152] The total number of signs includes paw tremors, jumping, and shaking off a wet dog. In oxycodone-treated mice, naloxone was found to cause a significant number of general signs, paw tremors, jumping, and weight changes (p ≤ 0.0001 for each). At all tested doses, the compound of example 3 resulted in a significant reduction in the total number of signs and paw tremors. In addition, at 3.0 mg/kg, the compound also caused a significant reduction in jumping and reduced body weight loss.

[0153] These results show that the compound of Example 3 dose-dependently attenuates the signs and symptoms of opiate withdrawal after abrupt withdrawal of opiate administration in opiate-dependent rats.

Example 13 Formalin Paw Test (Inflammatory Pain Model)

[0154] The introduction under the plantar aponeurosis of chemical stimuli, such as formalin, causes immediate pain and discomfort in mice, followed by inflammation. Subcutaneous injection of a 2.5% formalin solution (37% by weight aqueous formaldehyde diluted with saline) into the hindpaw results in a biphasic response: an acute pain response and a delayed inflammatory response. Thus, this animal model provides information on both acute pain and subacute/tonic pain in the same animal.

[0155] C57 mice were first habituated in the observation chamber. 30 minutes prior to formalin administration, mice were injected subcutaneously with either 5 mg/kg morphine (in saline) administered subcutaneously or the compound of Example 3 (in 45% w/v aqueous cycodextrin) administered subcutaneously at 0.3, 1, 0 or 3.0 mg/kg. In addition, another set of mice were treated with control medium or the compound of Example 3 at 3.0 mg/kg, oral rather than subcutaneous.

[0156] Mice were then injected subcutaneously into the plantar surface of the left hind paw with 20 µl of a 2.5% formalin solution. Over the next 40 minutes, the total time spent licking or biting the treated hind paw was recorded. The first 10 minutes represent an acute nociceptive response, while the next 30 minutes represent a delayed inflammatory response. At one minute intervals, each animal's behavior was assessed using a "behavioral mean score", which scores on a scale of 0 to 4:

0: no reaction, animal is sleeping

1: the animal walks easily on a treated paw, such as tiptoe

2: the animal lifts the treated paw

3: the animal shakes the treated paw

4: the animal licks and bites the treated paw

[0157] Data were analyzed by ANOVA followed by post hoc comparisons with Fisher's tests where appropriate. Significance was set at p<0.05.

[0158] The results are shown in the table below.

Average behavioral score (0-4) Average lick duration (min) 0-10
min 11-40
min 0-6
min 16-40
min 0-10
min 11-40
min 0-6
min 16-40 min Wednesday
(subcutaneously) 1.4 1.4 2.1 1.5 34 75 32 76 Wednesday
(orally) 1.2 0.9 1.9 1.0 29 fifty 33 40 Morphine 1.1 0.2 1.7 0.2 eleven 0 eleven 0 compound, subcutaneously 0.3 mg/kg 1.5 1.0 2.3 1.2 31 68 34 70 compound, subcutaneously 1.0 mg/kg 1.3 1.0 1.9 1.1 26 60 26 65 compound, subcutaneously 3.0 mg/kg 0.8 0.1 1.3 0.1 fourteen 36 eleven 36 compound, orally 3.0 mg/kg 0.9 0.8 1.5 0.9 eleven 3 9 3

[0159] The results show a significant treatment effect during both the early phase (0-10 min) and late phase (11-40 min) reaction time. Post-hoc comparison shows that, compared with medium treatment, subcutaneous injection of morphine or the compound of example 3 (at 3 mg/kg) significantly reduces the formalin injection-induced pain behavior score and also significantly reduces the duration of licking. Post hoc comparison also shows that subcutaneous injection of morphine or the compound of example 3 (at 3 mg/kg), as well as the compound of example 3 orally (at 3 mg/kg), significantly reduces the length of time spent licking. Although the mean pain behavior score was also reduced by 1.0 mg/kg compound subcutaneously and 3.0 mg/kg po, these effects were not statistically significant in this study. The duration of the lick was similarly reduced by using 1.0 mg/kg of the compound of example 3 subcutaneously, but the result was not statistically significant in this study. It was also found that none of the mice in the study experienced significant changes in body weight in any of the study groups.

Example 14: Self-administration in heroin addicted rats

[0160] A study was conducted to determine whether heroin addicted rats self administered the compound of Example 3 and found that they did not, further emphasizing the non-addictive nature of the compounds of the present invention.

[0161] The study was conducted in three stages. In the first stage, the rats were first trained to press a lever to obtain food, and then they were provided with an intravenous jugular catheter and taught to self-administer heroin. In response to a signal (light on in the cage), three lever presses by the animals resulted in a single injection of heroin through the catheter. Heroin was provided at an initial dose of 0.05 mg/kg/injection and later increased to 0.015 mg/kg/injection. This trained reaction was then suppressed by replacing the heroin with a saline solution. In the second step, the saline solution was replaced with a solution of the compound of Example 3 at one of four doses: 0.0003 mg/kg/injection, 0.001 mg/kg/injection, 0.003 mg/kg/injection, and 0.010 mg/kg/injection. Each individual rat was administered one or two different doses of the compound in an ascending fashion. This reaction was then suppressed by saline injection, followed by a third phase that repeated heroin use at 0.015 mg/kg/injection. The purpose of the third stage was to demonstrate that the rats still exhibit heroin addictive behavior at the end of the study. The results of the study are shown in the table below:

Treatment animals (n) Medium lever pressure Reaction suppression with brine 1 21 4.08 heroin injection (0.015 mg/kg/injection) 21 19.38* Compound of Example 2 at 0.0003 mg/kg/injection eight 3.17** Compound of Example 2 at 0.0003 mg/kg/injection eight 3.29** Compound of Example 2 at 0.0003 mg/kg/injection eight 3.99** Compound of Example 2 at 0.0003 mg/kg/injection eight 4.87** Reaction suppression with brine 2 19 3.60** Recovery of heroin administration (0.015 mg/kg/injection) 19 17.08** * P<0.001 for heroin injection versus saline response suppression 1 (multiple t test); ** P<0.001 for the compound of example 3 for heroin administration (Dunnett's test); P > 0.7 for all comparisons between compound of example 2 and inhibition of reaction with brine 1 (William's test)

[0162] The results show that there is a statistically significant increase in lever depression by rats when taking heroin, but there was no significant difference when administering saline or the compound of Example 3. Thus, the results suggest that rats do not become dependent on the compound of Example 3.

Example 15 Animal Pharmacokinetic Data

[0163] Using standard methods, the pharmacokinetic profile of the compound of example 3 was investigated in several animals.

Example 15a: PK study in rats

[0164] In the first study, rats were given the compound of Example 2 as an intravenous bolus (IV) at 1 mg/kg in 45% Trapposol medium or orally (orally) at 10 mg/kg in 0.5% CMC medium (N=3 for each groups). In the second study, rats were administered the compound of example 2 at 10 mg/kg orally or 3 mg/kg subcutaneously (SC), each in 45% Trapposol medium (N=6 for each group). Plasma drug concentrations were measured at time points from 0 to 48 hours post dosing. Representative results are shown below (* indicates plasma concentrations below quantifiable values):

First study second study intravenously (1 mg/kg) orally (10 mg/kg) orally (10 mg/kg) subcutaneously (3 mg/kg) 30 min (ng/ml) 99.0 30.7 54.9 134.4 1 h (ng/ml) 47.3 37.2 60.6 140.9 6 hours (ng/ml) 1.1 9.4 21.0 18.2 24 hours (ng/ml) * 0.1 0.4 1.9 48 hours (ng/ml) * * ND ND Cmax (ng/ml) 314.8 37.2 60.6 140.9 AUC (ng-h/ml) 182 215 409 676 Bioavailability 100% 12% 22% 123% t-1/2 (h) 3.1 9.5

Example 15b: PK studies in mice

[0165] A similar study in mice was performed using 10 mg/kg oral administration of the compound of formula 3, and received the following results: Tmax=0.25 hours; Cmax=279 ng/ml; AUC (0-4h)=759 ng-h/ml; the ratio in blood and plasma (0.25-4 hours) ranges from 3.7 to 6.6. The study was also performed at a dose of 0.1 mg/kg subcutaneously. Representative results are shown in the table below:

study: orally, 10 mg/kg (0.5% CMC medium) subcutaneously, 0.1 mg/kg (45% Trapposol medium) duration (h) plasma (ng/ml) brain (ng/g) plasma (ng/ml) brain (ng/g) 0.25 279 1288 27.5 57.1 0.5 179 1180 31.1 71.9 one 258 989 29.2 78.5 2 153 699 14.6 38.7 four 199 734 4.7 32.6 Tmax (h) 0.25 0.25 0.5 1.0 Cmax
(ng/ml) 279 1288 31.1 78.5 AUC0-4h
(ng-h/ml) 759 2491 67 191 B/P ratio 3.3 2.8

[0166] Together, these results indicate that the compounds of the present invention are well absorbed and distributed in the brain and tissues and persist with a sufficiently long half-life to allow once-daily therapeutic doses to be administered.

Example 16: functioning of the gastrointestinal tract

[0167] The effect of the compound of Example 3 on gastrointestinal motility in rats was tested by monitoring the rate of intestinal transit of an activated charcoal bolus. Rats were treated with (1) aqueous carboxymethylcellulose medium, (2) morphine (5 mg/kg, s.c.), or (3) Example 3 compound (at 0.3, 1.0, or 3.0 mg/kg, s.c.) for 30 minutes to an oral bolus of 15% aqueous activated charcoal. The measured result is the degree of mobility, calculated as the distance traveled by the coal as a fraction of the total length of the animal's intestines. The results are shown in the table below:

Group (n=10 each) treatment Degree of mobility one Wednesday 0.55 2 Compound of example 3, 0.3 mg/kg 0.50 3 Compound of example 3, 1 mg/kg 0.55 four Compound of example 3, 3 mg/kg 0.50 5 Morphine, 5 mg/kg 0.27

[0168] These results show that the compound of Example 3 does not have a significant effect on gastrointestinal motility at doses up to 3 mg/kg. On the contrary, and as expected, morphine resulted in an approximately 50% decrease in gastrointestinal motility.

[0169] In the following experiment, rats were pretreated 60 minutes prior to the bolus with charcoal medium, morphine (5 mg/kg) or compound of example 3 (3 mg/kg), each subcutaneously, followed by treatment with morphine (5 mg/kg) , morphine plus the compound of example 3 (0.3 mg/kg or 3 mg/kg) or only the compound of example 3 (3 mg/kg). The results are shown in the table below. For groups 2 and 3, morphine was administered first, followed by an immediate injection of the compound of example 3:

Group (n=8 each) Preprocessing treatment Degree of mobility one Wednesday Morphine, 5 mg/kg 0.21 2 No Morphine, 5 mg/kg + compound of example 3, 0.3 mg/kg 0.26 3 No Morphine, 5 mg/kg + compound of example 3, 3 mg/kg 0.32 four Morphine, 5 mg/kg Compound of example 3, 3 mg/kg 0.41 5 Compound of example 2, 3 mg/kg Morphine, 5 mg/kg 0.30

[0170] The results show that the compound of Example 3 reverses the inhibition of gastrointestinal motility induced by morphine when administered either simultaneously or sequentially before morphine, with the blockade of the effect of morphine being greater when pretreatment is applied.

[0171] Without being bound by theory, it is believed that these differences are due to the fact that the compounds of the present invention act as a displaced MOP ligand and their inability to activate beta-arrestin signaling pathways further down the cascade that have been shown to mediate opiate-related side effects, including constipation and respiratory depression.

Example 17: lung function

[0172] The effect of the compound of example 3 on lung function in rats was assessed by monitoring the respiratory rate, tidal volume and minute volume in rats after subcutaneous administration of the compound of example 3 at 0.3, 1.0 and 3.0 mg/kg, compared with control with the environment. Measurements were taken at 0, 15, 60, 120 and 240 minutes after compound administration. It was found that there were no significant differences between the environment group and any of the test groups at any given time. The results are shown below for 60 minutes, which is typical of the results obtained:

RR (breaths/min) TV (ml) MV (m/min) Wednesday 188 1.10 195 Compound of example 3, 0.3 mg/kg 181 1.06 181 Compound of example 3, 1.0 mg/kg 203 0.86 169 Compound of example 3, 3.0 mg/kg 190 0.97 179

Claims (37)

1. A method of treating or preventing a disorder of the central nervous system, comprising administering to a patient in need a compound of formula I

Formula I wherein: X is -NH-; L is O; Z is -CH(OR ₁ )-, -O- or -C(O)-; R ₁ is H; in free or pharmaceutically acceptable salt form; where the disorder is a pain disorder selected from neuropathic pain, idiopathic pain, chronic pain, fibromyalgia, toothache and traumatic pain; or where the disorder is a pain disorder in a patient also suffering from a gastrointestinal disorder and/or a pulmonary disorder, or in a patient also suffering from an opioid use disorder; or where the disease or disorder is an opiate overdose or an opioid use disorder. 2. The method of claim 1 wherein Z is -CH(OR ₁ )-. 3. The method of claim 1 wherein Z is -C(=O)-. 4. The method of claim 1 wherein Z is -O-. 5. The method of claim 1, wherein the compound is selected from the group consisting of:

. 6. The method of claim 1, wherein the compound is selected from the group consisting of:

. 7. The method of claim 1, wherein the compound is:

. 8. The method according to any one of paragraphs. 1-7, in which the compound is in the form of a salt, for example, in the form of a pharmaceutically acceptable salt. 9. The method of any one of the preceding claims, wherein the central nervous system disorder is a pain disorder selected from neuropathic pain, idiopathic pain, chronic pain, fibromyalgia, dental pain, and traumatic pain. 10. The method of any one of the preceding claims, wherein the central nervous system disorder is a pain disorder, and wherein the patient is also suffering from a gastrointestinal and/or pulmonary disorder. 11. The method of any one of the preceding claims, wherein the central nervous system disorder is a pain disorder, and wherein the patient also suffers from an opioid use disorder. 12. The method of any one of the preceding claims, wherein the central nervous system disorder is an opioid use disorder. 13. The method according to any one of paragraphs. 1-8, where the disorder of the central nervous system is an opiate overdose. 14. The method of any one of the preceding claims, wherein said patient does not respond to or cannot tolerate side effects from treatment with non-narcotic analgesics and/or opioid drugs, or where the use of opioid drugs is contraindicated in said patient. 15. The method according to any one of paragraphs. 1-13, where said patient does not respond to or cannot tolerate side effects from treatment with opioid drugs, or where the use of opioid drugs is contraindicated for said patient, and said opioid drugs are selected from morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanil, trefantinil, bryfentanil, remifentanil, octfentanil, sufentanil, carfentanil, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, deocine, pentazocine, phenazocine, butorphanol, nalbuphine, leforphanol, lefomethorphan, tramadol, tapentadol and anileridine, or any combination thereof. 16. Use of a compound of formula I:

Formula I wherein: X is -NH-; L is O; Z is -CH(OR ₁ )-, -O- or -C(O)-; R ₁ is H; in free or salt form; in obtaining a medicinal product for the treatment or prevention of disorders of the central nervous system, where the disorder is a pain disorder selected from neuropathic pain, idiopathic pain, chronic pain, fibromyalgia, toothache and traumatic pain; or where the disorder is a pain disorder in a patient also suffering from a gastrointestinal disorder and/or a pulmonary disorder, or in a patient also suffering from an opioid use disorder; or where the disease or disorder is an opiate overdose or an opioid use disorder.

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