阅读说明：本技术 有机化合物 (Organic compounds ) 是由 姚伟 李鹏 于 2017-01-26 设计创作，主要内容包括：本发明涉及特定取代的杂环稠合γ-咔啉,其前药,它们是本发明所述的游离、固体、药学上可接受的盐和/或基本上纯的形式,涉及它们的药物组合物,以及它们用于治疗涉及的5-HT2A受体、5-羟色胺转运蛋白(SERT)、关于多巴胺D1和D2受体信号系统的通路和/或μ-阿片样受体的疾病的方法。(The present invention relates to certain substituted heterocyclic fused gamma-carbolines, prodrugs thereof, which are free, solid, pharmaceutically acceptable salts and/or substantially pure forms thereof as described herein, pharmaceutical compositions thereof, and methods of their use for treating diseases involving the 5-HT2A receptor, the 5-hydroxytryptamine transporter (SERT), pathways involved in the dopamine D1 and D2 receptor signaling system, and/or the μ -opioid receptor.)

1. Use of a compound of formula I, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition comprising said compound in admixture with a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment or prevention of a central nervous system disorder:

wherein:

x is-NH-;

l is O;

z is-CH (O-R)₁) -, -O-or-C (═ O) -;

R₁is H;

wherein the disorder is selected from drug dependence, e.g. opiate dependence and/or alcohol dependence, or drug or alcohol dependence (e.g. opiate dependence) withdrawal, or substance use disorder, e.g. opiate abuse.

2. Use according to claim 1, wherein Z is-CH (O-R)₁) -, and R₁Is H.

3. Use according to claim 1, wherein Z is-C (═ O) -.

4. Use according to claim 1, wherein Z is-O-.

5. Use according to any one of claims 1 to 4, wherein the compound is in isolated or purified free or salt form.

6. Use according to any one of claims 1 to 4, wherein the compound is in the form of a pharmaceutically acceptable salt.

7. Use according to claim 1, wherein the compound is:

in the form of an addition salt with an acid selected from glutamic acid, tartaric acid, malic acid or ascorbic acid.

8. The use according to any one of claims 1-7, wherein the compound is in admixture with a pharmaceutically acceptable carrier.

9. The use according to claim 8, wherein the pharmaceutically acceptable carrier comprises a polymer matrix.

10. Use according to claim 8 or 9, wherein the pharmaceutically acceptable carrier is a pharmaceutically acceptable diluent.

11. Use according to claim 9, wherein the polymer matrix is biodegradable poly (d, l-lactide-co-glycolide) microspheres.

12. Use according to any one of claims 1 to 11, wherein the drug dependence is substance addiction, substance use disorder or substance induction disorder.

13. Use according to claim 12, wherein the substance-induced disorder is selected from the group consisting of intoxication, withdrawal, substance-induced intellectual disorders including substance-induced psychosis, substance-induced bipolar disorder and related disorders, substance-induced depressive disorder, substance-induced anxiety disorder, substance-induced obsessive-compulsive disorder and related disorders, substance-induced sleep disorder, substance-induced sexual dysfunction, substance-induced confusion and substance-induced neurocognitive disorder.

14. Use according to claim 12, wherein the patient suffers from anxiety syndrome or is diagnosed with anxiety as a co-morbid disorder or as a residual disorder, and wherein the method does not comprise further administration of an anxiolytic agent, such as benzodiazepines.

15. Use according to any one of claims 1 to 14, which further comprises administering one or more additional therapeutic agents selected from the group consisting of: opioid agonists or partial opioid agonists, e.g., mu-agonists or partial agonists, or kappa-agonists or partial agonists, including mixed agonist/antagonists (e.g., agents having partial mu-agonist activity and kappa-antagonist activity).

16. Use according to any of claims 1 to 14, which further comprises administering buprenorphine.

Technical Field

The present invention relates to certain substituted heterocycle fused gamma-carbolines, prodrugs thereof, which are in free, solid, pharmaceutically acceptable salt and/or substantially pure form, pharmaceutical compositions thereof, and their use in therapy involving 5-HT_2AReceptor, 5-hydroxytryptamine transporter (SERT), for dopamine D₁And D₂Methods of use in disorders of the receptor signaling system and/or μ -opioid receptors, such as anxiety, psychosis, schizophrenia, sleep disorders, sexual dysfunction, migraine, headache-associated conditions, social phobia, gastrointestinal disorders such as dysfunction of gastrointestinal motility and obesity; depression and mood disorders associated with psychosis or parkinson's disease; psychosis, such as schizophrenia associated with depression; bipolar dysfunction; mood disorders; drug dependence, such as opiate dependence and alcohol dependence, drug withdrawal syndrome, and other psychiatric and neurological disorders, as well as combinations with other agents.

Background

Substituted heterocycle fused gamma-carbolines are known as 5-HT₂Receptors, especially 5-HT_2AAnd 5-HT_2CAgonists or antagonists of the receptor for the treatment of central nervous system disorders. These compounds have been disclosed in U.S. Pat. Nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, 7,183,282, U.S. RE39680 and U.S. RE39679 as novel compounds useful in the treatment of 5-HT_2ADisorders associated with receptor modulation, such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual desireDysfunctions, migraine, conditions associated with headache, social phobia, gastrointestinal disorders such as dysfunction of gastrointestinal motility and obesity. PCT/US08/03340(WO2008/112280) and U.S. application No.10/786,935 also disclose methods of making substituted heterocyclic fused gamma-carbolines and the use of these gamma-carbolines as 5-hydroxytryptamine agonists and antagonists for the control and prevention of central nervous system disorders such as addictive disorders and sleep disorders.

Further, WO/2009/145900 discloses the use of certain substituted heterocyclic fused gamma-carbolines for the treatment of psychosis and depressive disorders, as well as sleep disorders, depression and/or mood disorders in patients with psychosis or parkinson's disease. In addition to disorders associated with psychosis and/or depression, this patent application also discloses and claims the use of these compounds at low doses to selectively antagonize 5-HT_2AReceptor without or with minimal effect on dopamine D₂Use of a receptor, thereby useful for treating sleep disorders without dopamine D₂Side effects of pathways or other pathways associated with conventional sedative hypnotics (e.g., benzodiazepines) (e.g., GABA)_AReceptor), including but not limited to the development of drug dependence, hypotonia, weakness, headache, blurred vision, dizziness, nausea, vomiting, epigastric discomfort, diarrhea, joint pain, and chest pain. WO 2009/114181 also discloses a process for the preparation of crystals of the tosylate addition salt of these substituted heterocyclic fused gamma-carbolines.

Disclosure of Invention

The present invention provides novel compounds that have novel receptor binding characteristics, bind 5-HT_2A、D₁And mu opioid receptors. The unique pharmacological characteristics of these compounds, including 5-HT_2AAntagonism, D₁Activity and morphine antagonism, such that these compounds may be useful in the treatment of various substance use disorders and psychiatric disorders, for example depression, anxiety, sleep disorders, psychosis or dementia, as further described herein, including the treatment of patients suffering from substance use disorders and concomitant psychiatric disorders.

The present invention thus provides compounds of formula I, which may be used for the treatment or prevention of central nervous system disorders. In a first aspect, the present invention relates to a compound of formula I (compound I):

wherein:

x is-NH-or-N (CH)₃)-；

L is selected from O, NH, NR^aAnd S;

z is-CH (O-R)₁) -, -O-or-C (═ O) -;

R₁is H, -C (O) -C_1-21Alkyl (e.g., -C (O) -C)_1-5Alkyl, -C (O) -C_6-15Alkyl or-C (O) -C_16-21Alkyl), preferably said alkyl is linear, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C_1-22Alkoxy (e.g. ethoxy) substituted, e.g. R₁Is C (O) -C₃Alkyl, -C (O) C₆Alkyl, -C (O) -C₇Alkyl, -C (O) -C₉Alkyl, -C (O) -C₁₁Alkyl, -C (O) -C₁₃Alkyl, or-C (O) -C₁₅An alkyl group;

R^athe method comprises the following steps:

halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, or C_3-6Cycloalkyl, each radical independently optionally substituted with up to 3 independently selected R^bSubstituted by radicals, e.g. C_1-3Haloalkyl or C_1-3A hydroxyalkyl group; or

Aryl optionally substituted with up to 5 independently selected R^bSubstitution; and

each R^bIndependently selected from H, halogen, NH₂、NO₂、OH、C(＝O)OH、CN、SO₃And C_1-4An alkyl group;

the compounds are in free or salt form, e.g., isolated or purified.

The present invention provides additional exemplary embodiments of compounds of formula I in free or salt form, e.g., isolated or purified free or salt form, including:

1.1 Compounds I, wherein L is-O-;

1.2 Compounds I or 1.1, wherein Z is-CH (O-R)₁)-；

1.3 compound I or 1.1 wherein Z is-C (═ O) -;

1.4 Compounds I, wherein L is NH.

1.5 Compounds I, wherein L is NR^a；

1.6 Compounds I, wherein L is S;

1.7 Compound I or any one of 1.1-1.5, in solid form, for example in the form of a solid salt;

1.8 Compound I or any one of 1.1-1.7, wherein Z is-CH (O-R)₁)-；

1.9 of compound I or any one of 1.1-1.7, wherein Z is-C (═ O) -;

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

1.11 Compound I or any one of 1.1-1.9, wherein X is-NH-;

1.12 Compound I or any one of 1.1-1.9, wherein X is-N (CH)₃)-；

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

1.14 Compound I or any one 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 one of 1.1-1.14, wherein Z is-CH (O-R)₁) -and R₁Is H;

1.18 Compound I or any one of 1.1-1.14, wherein Z is-CH (O-R)₁) -, and R₁is-C (O) -C_1-5Alkyl, -C (O) -C_6-15Alkyl or-C (O) -C_16-21An alkyl group;

1.19 Compound I or any one of 1.1-1.14, wherein Z is-CH (O-R)₁) -and R₁Is selected from C (O) -C₃Alkyl, -C (O) C₆Alkyl, -C (O) -C₇Alkyl, -C (O) -C₉Alkyl, -C (O) -C₁₁Alkyl, -C (O) -C₁₃Alkyl or-C (O) -C₁₅An alkyl group; for example, wherein R¹Is acetyl, ethylcarbonyl or propylcarbonyl;

1.20 Compound I or any one of 1.1-1.12 or 1.17-1.19, wherein L is NR^aAnd wherein R is^aThe method comprises the following steps:

halogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, or C_3-6Cycloalkyl, each radical independently optionally substituted with up to 3 independently selected R^bSubstituted by groups; or wherein R is^aIs aryl optionally substituted with up to 5 independently selected R^bSubstitution; wherein R is^bIndependently selected from H, halogen, NH₂、NO₂、OH、C(＝O)OH、CN、SO₃And C_1-4An alkyl group;

1.21 Compounds 1.20, wherein R^aIs C_1-4Alkyl or C_3-6Cycloalkyl optionally substituted with up to 3 independently selected R^bSubstituted by groups;

1.22 Compound 1.20, wherein R^aIs aryl, optionally substituted with up to 3 independently selected R^bSubstituted by groups;

1.23 Compound 1.20, wherein R^aSelected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl or phenyl;

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

1.25 Compound 1.24, wherein the carbon atom CH is present substantially in the R configuration or S configuration, for example wherein the diastereomer having the R configuration or S configuration at that carbon is present in a diastereomer excess of greater than 70%, for example greater than 75%, or greater than 80%, or greater than 85%, or greater than 90%, or greater than 95%, or greater than 97%, or greater than 98% or greater than 99%.

1.26 Compound I or any one of 1.1-1.25, wherein the compound is selected from:

1.27 compound I or any one of 1.1-1.26, wherein the compound is selected from:

(i.e., 4- ((6bR,10aS) -2-oxo-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-de ] quinoxalin-8-yl) -1- (4-fluoro-phenyl) -butan-1-one, respectively;

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

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

the compounds are in free or pharmaceutically acceptable salt form.

1.28 compound I or any one of 1.1-1.27, in free form;

1.29 compound I or any one of 1.1-1.28, in the form of a salt, e.g. in the form of a pharmaceutically acceptable salt;

1.30 compound I or any one of 1.1-1.29, which is in solid form;

the compounds are in free or salt form, e.g., isolated or purified.

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

wherein:

x is-NH-or-N (CH)₃)-；

Y is-CH (O-R)₁) -or-C (═ O) -;

R₁is H, -C (O) -C_1-21Alkyl (e.g., -C (O) -C)_1-5Alkyl, -C (O) -C_6-15Alkyl or-C (O) -C_16-21Alkyl), preferably said alkyl is linear, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C_1-22Alkoxy (e.g. ethoxy) substituted, e.g. R₁Is C (O) -C₃Alkyl, -C (O) C₆Alkyl, -C (O) -C₇Alkyl, -C (O) -C₉Alkyl, -C (O) -C₁₁Alkyl, -C (O) -C₁₃Alkyl, or-C (O) -C₁₅An alkyl group;

the compounds are in free or salt form, e.g., isolated or purified.

The present invention provides additional exemplary embodiments of compounds of formula II in free or salt form, e.g., isolated or purified free or salt form, including:

2.1 Compounds II, wherein X is-NH-;

2.2 Compounds II in which X is-N (CH)₃)-；

2.3 compound II or 2.1-2.4 wherein Y is-C (═ O) -;

2.4 Compounds II in which Y is-CH (O-R)₁) -; i.e., having formula II-A:

2.5 Compounds II or 2.1-2.4, where Y is-CH (O-R)₁)-；

A compound II wherein X is NH and Y is-C (═ O) -; i.e., having formula II-B:

2.7 Compounds II, wherein X is-NH-and Y is-CH (O-R)₁)-；

2.8 Compounds II, wherein X is-NH-and Y is-CH (O-R)₁) -, wherein R₁Is H; i.e., having formula II-C:

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

2.10 Compounds II, wherein X is-N (CH)₃) -and Y is-CH (O-R)₁)-；

2.11 Compounds II in which X is-N (CH)₃) -and Y is-CH (O-R)₁) -, wherein R₁Is H; i.e., having the formula II-E:

2.12 Compound II or any one of 2.1-2.11, in solid form, for example in the form of a solid salt.

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

wherein:

x is-NH-or-N (CH)₃)-；

R₁Is H, -C (O) -C_1-21Alkyl (e.g., -C (O) -C)_1-5Alkyl, -C (O) -C_6-15Alkyl or-C (O) -C_16-21Alkyl), preferably said alkyl is linear, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C_1-22Alkoxy (e.g. ethoxy) substituted, e.g. R₁Is C (O) -C₃Alkyl, -C (O) C₆Alkyl, -C (O) -C₇Alkyl, -C (O) -C₉Alkyl, -C (O) -C₁₁Alkyl, -C (O) -C₁₃Alkyl or-C (O) -C₁₅；

The compounds are in free or salt form, e.g., isolated or purified.

The present invention provides additional exemplary embodiments of compounds of formula III in free or salt form, e.g., in isolated or purified free or salt form, including:

3.1 Compounds III, wherein R₁Is H; i.e., having formula III-A:

the compound is in free or salt form, e.g., isolated or purified;

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

3.3 Compounds III or 3.1, where X is-N (CH)₃)-；

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

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

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

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

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

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

3.10 Compound III or any one 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 one of 3.1-3.10, wherein the compound is in solid form, e.g. in the form of a solid salt,

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

wherein:

x is-NH-or-N (CH)₃)-；

R₁Is H, -C (O) -C_1-21Alkyl (e.g., -C (O) -C)_1-5Alkyl, -C (O) -C_6-15Alkyl or-C (O) -C_16-21Alkyl), preferably said alkyl is linear, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C_1-22Alkoxy (e.g. ethoxy) substituted, e.g. R₁Is C (O) -C₃Alkyl, -C (O) C₆Alkyl, -C (O) -C₇Alkyl, -C (O) -C₉Alkyl, -C (O) -C₁₁Alkyl, -C (O) -C₁₃Alkyl or-C (O) -C₁₅An alkyl group;

the compounds are in free or salt form, e.g., isolated or purified.

The present invention provides additional exemplary embodiments of compounds of formula IV in free or salt form, e.g., in isolated or purified free or salt form, including:

4.1 Compounds IV, wherein R₁Is H; i.e., having the formula IV-A:

the compounds are in free or salt form, e.g., isolated or purified.

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

4.3 Compounds IV or 4.1, where X is-N (CH)₃)-；

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

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

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

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

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

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

4.10 Compound IV or any one 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 one of 4.1-4.10, wherein the compound is in solid form.

In a fifth aspect, the present invention provides each of the above-described compound I or 1.1 to 1.30, compound II or 2.1 to 2.12, compound III or 3.1 to 3.11, or compound IV or 4.1 to 4.11 (hereinafter collectively referred to as "compounds of formulae I to IV and below" or "compounds of the present invention") in free or pharmaceutically acceptable salt form. The present invention provides additional exemplary embodiments of compounds of formulas I-IV and the following, including:

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

5.2 Compounds of formulae I-IV and the following wherein the salts are fumaric acid addition salts;

5.3 Compounds of formulae I-IV and the following wherein the salts are phosphoric acid addition salts;

5.4 Compounds of formulae I-IV and the following wherein the salts are the toluenesulfonic acid addition salts;

5.55.1-5.4, wherein the salt is in solid form.

In a sixth aspect, the present invention provides a pharmaceutical composition (pharmaceutical composition 6) comprising any one of compounds according to compound I or 1.1-1.30, compound II or 2.1-2.12, compound III or 3.1-3.11, or compound IV or 4.1-4.11 (collectively referred to as compounds of formulae I-IV and below or compounds of the invention), for example in admixture with a pharmaceutically acceptable diluent or carrier. The present invention provides additional exemplary embodiments of pharmaceutical composition 6, comprising:

6.1 pharmaceutical composition 6 comprising compound I or any one of 1.1-1.30;

6.2 pharmaceutical composition 6 comprising compound II or any one of 2.1-2.12;

6.3 pharmaceutical composition 6 comprising compound III or any one of 3.1-3.11;

6.4 pharmaceutical composition 6 comprising compound IV or any one of 4.1-4.11;

6.5 pharmaceutical composition 6 or any one of 6.1-6.4, wherein the compounds of formulae I-IV and below are in solid form;

6.6 pharmaceutical composition 6 or any one of 6.1-6.5, wherein the compounds of formulae I-IV and below are in the form of pharmaceutically acceptable salts as described in compounds 5.1-5.5;

6.7 pharmaceutical composition 6 or any one of 6.1-6.6, wherein the compounds of formulae I-IV and below are admixed with a pharmaceutically acceptable diluent or carrier.

In a preferred embodiment, the pharmaceutical composition of the 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 compositions of the present invention comprise 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 compositions of the present invention comprise 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, the pharmaceutical composition of the invention is used in a sustained or delayed release formulation, such as a depot (depot) formulation. In one embodiment, the depot formulation (depot formulation 6.8) is a pharmaceutical composition of any one of 6.1 to 6.7, preferably in free or pharmaceutically acceptable salt form, preferably as a mixture with a pharmaceutically acceptable diluent or carrier, e.g. as an injectable depot formulation providing sustained or delayed release.

In another embodiment, the depot composition (depot composition 6.9) comprises the pharmaceutical composition of any one of claims 6.1-6.7, wherein R is₁is-C (O) -C_6-15Alkyl, in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier.

In another aspect, the invention provides pharmaceutical composition 6.10, which is pharmaceutical composition 6 or any one of 6.1-6.9, wherein the compounds of formulae I-IV and below are in a polymer matrix. In one embodiment, the compounds of the present invention are dispersed or dissolved in a polymer matrix. In another embodiment, the polymer matrix comprises a standard polymer used in depot formulations, such as a polymer selected from the group consisting of: polyesters of hydroxy fatty acids and derivatives thereof, or polymers of alkyl alpha-cyanoacrylates, polyalkylene oxalates, polyorthoesters, polycarbonates, polyorthocarbonates, polyaminoacids, hyaluronic acid esters, and mixtures thereof. In another 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 polymers. In another embodiment, the polymer is selected from the group consisting of polyglycolic acid, poly-D, L-lactic acid, poly-L-lactic acid, copolymers of the above, poly (aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxan, polyorthocarbonates, polyacetals, poly (lactic-caprolactone), polyorthoesters, poly (glycolic-caprolactone), polyanhydrides; and natural polymers including albumin, casein and waxes, such as glycerol mono-and di-stearate and the like. In a preferred embodiment, the polymer matrix comprises poly (d, l-lactide-co-glycolide).

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), in free or pharmaceutically acceptable salt form₃) And Y is-C (═ O) -or-C (h) (oh) -. 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 above examples of pharmaceutical composition 6.10, the polymer matrix comprises poly (d, l-lactide-co-glycolide).

The (pharmaceutical) compositions 6 and 6.1-6.10 are particularly useful for sustained or delayed release, wherein the compounds of the invention are released upon degradation of the polymer matrix. These compositions can be configured to provide controlled and/or sustained release of the compounds of the invention (e.g., as a depot composition) over a period of up to 180 days, for example, from about 14 to about 30 to about 180 days. For example, the polymer matrix may degrade and release the compounds of the invention over a period of about 30, about 60, or about 90 days. In another example, the polymer matrix may degrade and release the compounds of the present invention over a period of about 120 or about 180 days.

In another embodiment, a pharmaceutical composition of the invention, e.g., a depot composition of the invention, e.g., pharmaceutical composition 6.10, is formulated for administration by injection.

In a seventh aspect, the present invention provides compounds of formulae I-IV and below as described above in an osmotic controlled release oral system (OROS), see WO 2000/35419 and EP 1539115 (u.s.pub.no.2009/0202631), the contents of each of which are incorporated herein by reference in their entirety. Accordingly, in one embodiment of the seventh aspect, the present invention provides a pharmaceutical composition or device comprising (a) a gelatin capsule containing any of the compounds of formulae I-IV and below, or a pharmaceutical composition of the invention, in free or pharmaceutically acceptable salt form, as described above; (b) a multilayer wall placed on a gelatin capsule comprising, in order from the capsule outwards: (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and (c) a hole formed or formable from the wall. (composition P.1).

In another embodiment, the invention provides a pharmaceutical composition comprising a gelatin capsule containing a liquid of a compound or pharmaceutical composition of formulae I-IV and below thereof, e.g., any of pharmaceutical compositions 6 or 6.1-6.10, in free or pharmaceutically acceptable salt form according to the invention, surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer surrounding the expandable layer, and an exit orifice formed or formable in the wall. (composition P.2).

In a further embodiment of the seventh aspect, the invention provides a composition comprising a gelatin capsule containing a liquid compound or pharmaceutical composition of formulae I-IV and below thereof, e.g. any of pharmaceutical compositions 6 or 6.1-6.10, in free or pharmaceutically acceptable salt form according to the invention, surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer surrounding the expandable layer, and an exit orifice formed or formable in the wall, wherein the barrier layer forms a seal between the expandable layer and the environment at the exit orifice. (composition P.3).

In a further embodiment of the seventh aspect, the present invention provides a composition comprising a gelatin capsule containing a liquid compound or pharmaceutical composition of formulae I-IV and below thereof, e.g. pharmaceutical composition 6 or any of 6.1-6.10, in free or pharmaceutically acceptable salt form according to the present invention, surrounded by: a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer surrounding at least the expandable layer, and an exit orifice formed or formable in a dosage form extending from the outer surface of the gelatin capsule to the environment of use. (composition P.4). The expandable layer may be formed in one or more discrete segments, such as two segments located on opposite sides or ends of the gelatin capsule.

In a particular embodiment of the seventh aspect, the compounds of the present invention in an osmotic controlled release oral system (i.e., composition p.1-P.4) are in a liquid formulation, which may be a neat liquid active agent, a liquid active agent in a solution, suspension, emulsion or galactized composition, and the like.

Further information on osmotic controlled release oral system compositions including gelatin capsules, barrier layers, expandable layers, semipermeable layers and pores may be found in WO 2000/35419, the contents of which are incorporated herein by reference in their entirety.

Other osmotic controlled release oral systems for the compounds of formulae I-IV and below or pharmaceutical compositions thereof used in the present invention can be found in EP 1539115 (u.s.pub.no.2009/0202631), the contents of which are incorporated herein by reference in their entirety. Thus, in another embodiment of the seventh aspect, the present invention provides a composition or device comprising (a) two or more layers comprising a first layer comprising a compound or pharmaceutical composition of formulae I-IV and below, in free or pharmaceutically acceptable salt form, as described above, and a second layer comprising a polymer; (b) an outer wall surrounding the two or more layers; and (c) an aperture in the outer wall. (composition P.5).

Composition p.5 preferably uses a semipermeable membrane surrounding a three-layer core: in these embodiments, the first drug layer is referred to as the first drug layer and contains a small amount of a drug (e.g., compounds of formulas I-IV and below) and an osmotic agent such as a salt; the middle layer, referred to as the second drug layer, contains a larger amount of drug, excipients and no salt; and a third layer, called the push layer, contains the osmotic agent and no drug. At least one hole is drilled from the layer on the end of the first drug layer of the capsule-type tablet. (composition P.6).

The composition p.5 or P.6 may comprise: a membrane for defining a chamber, the membrane surrounding an inner protective coating in which at least one outlet orifice is formed or formable, and at least a portion of the membrane being semi-permeable; an expandable layer located within the chamber distal to the exit orifice and in fluid communication with the semi-permeable portion of the membrane; a first drug layer adjacent the exit orifice; and a second drug layer disposed in a chamber between the first drug layer and the expandable layer, the drug layers comprising a compound of the present invention in free or pharmaceutically acceptable salt form. Different release profiles are obtained depending on the respective viscosities of the first drug layer and the second drug layer. It is necessary to confirm the optimum viscosity of each layer. In the present invention, the viscosity is adjusted by adding a salt, i.e., sodium chloride. The delivery characteristics from the core depend on the weight, formulation and thickness of each drug layer. (composition P.7).

In a specific embodiment, the present invention provides composition p.7, wherein the first drug layer comprises a salt and the second drug layer comprises no salt. Compositions p.5-p.7 may optionally comprise a flow promoting layer between the membrane and the drug layer.

Compositions p.1-p.7 will generally be referred to as osmotic controlled release oral system compositions.

In an eighth aspect, the invention provides a method (method 1) of treating or preventing a central nervous system disorder comprising administering to a patient in need thereof a compound or pharmaceutical composition 6 or 6.1-6.10 or p.1-p.7 of formulae I-IV and below, e.g., in method 1, the compound or composition administered is:

1.1 Compound I or any one of 1.1-1.30, in free or pharmaceutically acceptable salt form;

1.2 compound II or any one of 2.1-2.12, in free or pharmaceutically acceptable salt form;

1.3 compound III or any one of 3.1-3.11, in free or pharmaceutically acceptable salt form;

1.4 compound IV or any one of 4.1-4.11, in free or pharmaceutically acceptable salt form;

1.5A compound of embodiment 5 or any one of 5.1 to 5.5,

1.6A 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;

1.7A 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 the pharmaceutical composition of any one of compositions 6 and 6.1-6.10;

1.10 a pharmaceutical composition comprising 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 comprising 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 comprising 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 a depot composition as described in depot composition 6.09 or 6.10;

1.14 pharmaceutical composition P.1-P.7;

1.15 osmotic controlled release oral system compositions as described above;

in another embodiment of the eighth aspect, the invention provides method 1 or any one of methods 1.1-1.15, wherein the method is further described as follows:

1.16 method 1 or any one of methods 1.1-1.15, wherein the central nervous system disorder is a disorder selected from: obesity, anxiety, depression (e.g., refractory depression and MDD), psychosis (including psychosis associated with dementia, such as hallucinations in late parkinson's disease or paranoia), schizophrenia, sleep disorders (particularly sleep disorders associated with schizophrenia and other psychiatric and neurological diseases), sexual dysfunction, migraine, conditions associated with headache, social phobia, aggressive behavior in dementia (e.g., aggressive behavior in alzheimer's disease), aggressive behavior in autism and related autistic disorders, gastrointestinal disorders such as dysfunction of gastrointestinal motility, and dementia, such as dementia in alzheimer's disease or parkinson's disease; mood disorders; and drug-dependent, e.g., opiate-dependent and/or alcohol-dependent, or drug-or alcohol-dependent (e.g., opiate-dependent) withdrawal; or binge eating disorder; syndromes such as mood disorders and substance use disorders, such as opiate abuse, for example in patients with substance use disorders and co-morbid central nervous system disorders, such as depression, including bipolar depression, anxiety, sleep disorders, psychosis, such as schizophrenia, or dementia, including alzheimer's disease;

1.17 method 1 or any one of methods 1.1-1.16, wherein the central nervous system disorder is related to 5-hydroxytryptamine 5-HT₂A. Dopamine D2 receptor system and/or 5-hydroxytryptamine reuptake transporter (SERT) pathway disorders, similar to those described in WO/2009/145900, the contents of which are incorporated herein by reference in their entirety;

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

1.19 method 1 or any one of methods 1.1-1.18, wherein the central nervous system disorder is a disorder selected from: (i) psychosis in patients with depression, such as schizophrenia; (2) depression in patients with psychiatric disorders, such as schizophrenia; (3) mood 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) substance addiction, substance use disorders, and/or substance induction disorders, optionally wherein the patient has anxiety or a residual syndrome of anxiety disorders;

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

1.21 method 1 or any of methods 1.1-1.20, wherein the patient is intolerant of the side effects of conventional antipsychotics, such as chlorpromazine, haloperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone (zipasidone);

1.22 method 1 or any one of methods 1.1-1.20, wherein the patient is intolerant of the side effects of conventional antipsychotics, such as haloperidol, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone;

1.23 method 1 or any one of methods 1.1-1.22, wherein the disorder is depression and the patient is a patient suffering from a psychiatric disorder such as schizophrenia or parkinson's disease;

1.24 method 1 or any one of methods 1.1-1.22, wherein the disorder is a sleep disorder and the patient has depression;

1.25 method 1 or any one of methods 1.1-1.22, wherein the one or more disorders is a sleep disorder and the patient has a psychiatric disorder, e.g., schizophrenia;

1.26 method 1 or any one of methods 1.1-1.22, wherein the one or more disorders is a sleep disorder and the patient has parkinson's disease;

1.27 method 1 or any one of methods 1.1-1.22, wherein the one or more disorders is a sleep disorder and the patient has depression and a psychiatric disorder, e.g., schizophrenia or parkinson's disease.

1.28 method 1 or any one of methods 1.1-1.27, wherein the patient has a drug-dependent disorder, optionally in combination with any of the above disorders, e.g., wherein the patient has opiate-dependent and/or alcohol-dependent, or has a drug-or alcohol-dependent withdrawal condition, optionally wherein the patient has anxiety or residual syndrome of anxiety disorders;

1.29 of any one of the above methods, wherein the effective amount is 1mg to 1000mg, preferably 2.5mg to 50 mg;

1.30 of any one of the above methods, wherein the effective amount is 1mg to 100mg daily, preferably 2.5mg to 50mg daily;

1.31 of any one of the above methods, wherein the condition to be treated is a movement disorder, e.g. in a patient receiving dopaminergic drug treatment, e.g. a drug selected from the group consisting of levodopa and levodopa co-drugs (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergic drugs, e.g. levodopa;

1.32 of any one of the above methods, wherein the patient has parkinson's disease.

Substance use Disorders and substance-induced Disorders are two classes of substance-related Disorders, defined by the fifth edition of DSM (Diagnostic and Statistical Manual of Mental Disorders). Substance use disorder is a syndrome caused by the continued use of the substance by an individual despite the occurrence of problems. Substance-induced disorders are disorders caused by the use of such substances. Substance-induced disorders include intoxication, withdrawal, substance-induced intellectual disorders including substance-induced psychosis, substance-induced bipolar disorder and related disorders, substance-induced depressive disorder, substance-induced anxiety disorder, substance-induced obsessive-compulsive disorder and related disorders, substance-induced sleep disorder, substance-induced sexual dysfunction, substance-induced confusion and substance-induced neurocognitive disorder.

DSM-V includes criteria for classifying substance use disorders as mild, moderate or severe. In some embodiments of the methods of the present invention, the substance use disorder is selected from the group consisting of a mild substance use disorder, a moderate substance use disorder, and a severe substance use disorder. In some embodiments, the substance use disorder is a mild substance use disorder. In some embodiments, the substance use disorder is a moderate substance use disorder. In some embodiments, the substance use disorder is a severe substance use disorder.

Anxiety is a very common comorbid disorder in patients undergoing substance use or substance abuse therapy. The conventional treatment for substance abuse disorders is the combined use of the partial opioid agonist buprenorphine (buprenorphine) and the opioid antagonist naloxone (naloxone), but these drugs have no significant effect on anxiety, thus leading to the use of conventional third drugs, such as benzodiazepines anxiolytics. This makes treatment regimens and patient compliance more difficult. In contrast, the compounds of the present invention provide opioid antagonism as well as 5-hydroxytryptamine antagonism and dopamine modulation. This may significantly improve the treatment of patients suffering from disorders of use or abuse accompanied by anxiety.

Thus, in some embodiments, the invention provides a method according to method 1 or any one of methods 1.1-1.32, wherein the central nervous system disorder is substance addiction, a substance use disorder, and/or a substance induction disorder, or a substance use disorder, for example in a patient with anxiety syndrome or a patient diagnosed with anxiety as a co-morbid disorder or as a residual disorder, wherein the method does not include further administration of an anxiolytic agent, for example, benzodiazepine. Benzodiazepines are compounds that modulate GABA, including those described in methods 3.1 and 3.2 below.

In another embodiment, the present invention provides method 1 or any one of methods 1.1-1.32, wherein compound or pharmaceutical composition 6 or 6.1-6.10 or p.1-p.7 of formulae I-IV and below comprises:

1.33 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;

1.34 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;

1.35 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, the present invention provides method 1 or any one of methods 1.1-1.35 as described above, wherein the disorder is schizophrenia or sleep disorder.

In another embodiment, the invention provides a method of any one of methods 1.1 to 1.35, wherein a depot composition of the invention (e.g., a depot composition of any one of 6.8 to 6.10), or (drug) composition 6 or 6.1 to 6.7, or composition p.1 to p.7 is administered for controlled and/or sustained release of a compound of the invention over a period of about 14 days, about 30 days to about 180 days, preferably about 30, about 60 or about 90 days. Controlled release and/or sustained release may be particularly useful in avoiding premature discontinuation of treatment, particularly for treatment with antipsychotics, where noncompliance or non-compliance with a treatment regimen often occurs.

In another embodiment, the present invention provides method 1 or any one of methods 1.1-1.35, as described above, wherein the depot composition of the invention is administered for controlled and/or sustained release of the compound of the invention over a period of time.

In a ninth aspect, the present invention provides a method (method 2) for preventing or treating one or more sleep disorders comprising administering to a patient in need thereof a compound or pharmaceutical composition 6 or 6.1-6.10 or p.1-p.7 of formulae I-IV and below (method 2), e.g. the compound or composition administered in method 2 is:

2.1 Compound I or 1.1-1.30 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 to 3.11 in free or pharmaceutically acceptable salt form;

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

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;

2.7A 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;

2.8A 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 the pharmaceutical composition of any one of compositions 6 and 6.1-6.10;

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

2.11 a pharmaceutical composition comprising 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 comprising 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 a depot composition as described in depot composition 6.09 or 6.10;

2.14 pharmaceutical composition P.1-P.7;

2.15 osmotic controlled release oral system compositions as described above;

in another embodiment of the ninth aspect, the present invention provides method 2 or 2.1-2.15, wherein the sleep disorders include sleep maintenance insomnia, frequent wakeups and post-wake discomfort, such as:

2.16 any one of the above methods, wherein the sleep disorder is sleep maintenance insomnia;

2.17 any one of the above methods, wherein the effective amount is 1-5mg per day, preferably 2.5-5mg per day;

2.18 any one of the above methods, wherein the effective amount is 2.5mg or 5mg daily;

2.19 any one of the above methods, wherein the sleep disorder is in a patient suffering from or at risk of dyskinesia, e.g., in a patient receiving dopaminergic medication, e.g., a drug selected from levodopa and levodopa co-drugs (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergic drugs, e.g., in a patient receiving levodopa;

2.20 any one of the above methods, wherein the patient has parkinson's disease.

In another embodiment of the ninth aspect, the invention provides any one of methods 2 or 2.1-2.20, wherein the sleep disorder comprises sleep maintenance insomnia, frequent wakeups, and post-wake discomfort.

The compounds of the present invention, the pharmaceutical compositions of the present invention or the depot compositions of the present invention may be used in combination with a second therapeutic agent, particularly in lower amounts than when the agents are used alone as a monotherapy, thereby improving the therapeutic activity of the combined agents and not causing the adverse side effects often seen in conventional monotherapies. Thus, the compounds of the present invention may be administered simultaneously, sequentially or contemporaneously with other antidepressants, antipsychotics, other hypnotics and/or agents used to treat parkinson's disease or mood disorders. In another example, side effects may be reduced or minimized by administering a compound of the invention in free or salt form in combination with one or more second therapeutic agents, wherein (i) the dose of the one or more second therapeutic agents or (ii) the dose of the compound of the invention and the second therapeutic agent together is lower than the agent/compound administered as monotherapy. In a particular embodiment, the compounds of the invention are used for the treatment of dyskinesia in a patient receiving dopaminergic drug treatment, e.g. a drug selected from the group consisting of levodopa and levodopa co-drugs (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergic drugs, e.g. for use in the treatment of parkinson's disease;

thus, in a tenth aspect, any one of method 1 or method 1.1-35, or any one of method 2 or method 2.1-20, further comprises one or more therapeutic agents selected from the group consisting of: compounds that modulate GABA activity (e.g., enhance activity and promote GABA transport), GABA-B agonists, 5-HT modulators (e.g., 5-HT1a agonists, 5-HT_2AAntagonists, 5-HT2a inverse agonists, and the like), melatonin agonists, ion channel modulators (e.g., blockers), 5-hydroxytryptamine-2 antagonists/reuptake inhibitors (SARI), orexin receptor antagonists, H3 agonists or antagonists, noradrenergic agonists or antagonists, galanin agonists, CRH antagonists, human growth hormone, growth hormone agonists, estrogens, estrogen agonists, neurokinin-1 drugs, antidepressants, opioid agonists and/or partial opioid agonists, and antipsychotics such as atypical antipsychotics (methods I-a and II-a, respectively, collectively referred to as "method 3").

In another embodiment of the tenth aspect, the invention provides method I-A or II-A as described below, further comprising one or more therapeutic agents.

3.1 methods I-A or II-A, wherein the one or more therapeutic agents is a compound that modulates GABA activity (e.g., enhances activity and promotes GABA transport);

3.2 method I-A or II-A or 3.1 wherein the GABA compound is one or more selected from the group consisting of: doxepin, alprazolam, bromoazepam, clobazam, clonazepam, chlordiazepoxide, diazepam, flunitrazepam, fluazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201(Evotec Pharmaceuticals) and estazolam;

3.3 method I-a or II-a, wherein the therapeutic agent is an additional 5HT2a antagonist;

3.4 method I-a or II-a or 3.3 wherein the additional 5HT2a antagonist is selected from one or more of: ketanserin, risperidone, elinserin, flurarserin (volinanserin) (Sanofi-Aventis, france), prevanserin, MDL 100907(Sanofi-Aventis, france), HY10275(Eli Lilly), APD125(arena pharmaceuticals, san diego, CA), and AVE8488(Sanofi-Aventis, france);

3.5 methods I-a or II-a, wherein the therapeutic agent is a melatonin agonist;

3.6 methods I-a or II-a or 3.5, wherein the melatonin agonist is selected from one or more of: melatonin, ramelteon (a)Takeda Pharmaceuticals, Japan), VEC-162(Vanda Pharmaceuticals, Rockwell, Md.), PD-6735 (Discovery, Inc. II), and agomelatine;

3.7 methods I-A or II-A, wherein the therapeutic agent is an ion channel blocker;

3.8 method I-a or II-a or 3.7, wherein the ion channel blocker is one or more of lamotrigine, gabapentin and pregabalin.

3.9 method I-A or II-A, wherein the therapeutic agent is an orexin receptor antagonist;

3.10 method I-a or II-a or 3.9 wherein the orexin receptor antagonist is selected from orexin, 1, 3-diaryl urea, SB-334867-a (GlaxoSmithKline, uk), GW649868(Glaxo SmithKline), and a benzamide derivative;

3.11 method I-A or II-A, wherein the therapeutic agent is a 5-hydroxytryptamine-2 antagonist/reuptake inhibitor (SARI);

3.12 methods I-a or II-a or 3.11, wherein the 5-hydroxytryptamine-2 antagonist/reuptake inhibitor (SARI) is selected from one or more of Org 50081 (Organon-netherlands), ritanserin, nefazodone (nefazodone), nefazodone (Serzone), and trazodone;

3.13 methods I-a or II-a, wherein the therapeutic agent is a 5HTIa agonist;

3.14 methods I-a or II-a or 3.13, wherein the 5HTIa agonist is selected from one or more of rapinotan, sarzoltan, itapirone, buspirone and MN-305 (medicinanova, san diego, CA);

3.15 method I-A or II-A, wherein the therapeutic agent is a neurokinin-1 drug;

3.16 methods I-a or II-a or 3.15, wherein the neurokinin-1 drug is casoproitant (GlaxoSmithKline);

3.17 method I-A or II-A, wherein the therapeutic agent is an antipsychotic;

3.18 method I-a or II-a or 3.17 wherein the antipsychotic is selected from chlorpromazine, haloperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

3.19 method I-A or II-A wherein the therapeutic agent is an antidepressant;

3.20 methods I-a or II-a or 3.19 wherein the antidepressant is selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline (protiptyline), sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine (velafaxine);

3.21 method I-a or II-a, 3.17, or 3.18, wherein the antipsychotic is an atypical antipsychotic;

3.22 method any one of I-a or II-a or 3.17-3.21, wherein the atypical antipsychotic is selected from clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

3.23 methods I-a or II-a, wherein the therapeutic agent is selected from any one of methods 3.1-3.22, e.g., selected from modafinil, amofenib, doxepin, alprazolam, bromodiazepam, clobazazepam, clonazepam, chlordiazepine, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitreDiazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Emotec Pharmaceuticals), estazolam, ketanserin, risperidone, etirin, flurescerin (Sanofi-Aventis, France), preverin, MDL 100907(Sanofi-Aventis, France), HY10275(Eli Lilly), APD125(Arena Pharmaceuticals, san Diego, CA), AVE8488(Sanofi-Aventis, France), Repinotan, Salizotan, Meditarone, buspirone, MN-305 (san IiNova, san Diego, CA), melatonin, RameitiamineTakeda Pharmaceuticals, Japan), VEC-162(Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Discovey, Inc.), agomelatine, lamotrigine, gabapentin, pregabalin, orexin, 1, 3-diaryl urea, SB-334867-a (GlaxoSmithKline, UK), GW649868(GlaxoSmithKline), benzamide derivatives, Org 50081 (Organon-Netherlands), ritanserin, nafmazolone, nefazodone, trazodone, casoprotein (GlaxoSmithKline), amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, propizine, clozapine, meprobamate, bepotamorex, meprobamate, doxepin, paroxetine, fluoxetine, fluvoxamine, fluvone, fluvoxiline, propiconazole, bevacizine, clomipramine, bevacizine, naphazoline, bevacizine, naphazoline, bevacizine, naphazil, bevacizine, naphazoline, naphazil, naphazoline, bevacizine, naphazoline, naphazil, naphazoline, naphazil, naphazoline, naphazil, naphazoline, naphazil, naphazoline, naphazil, naphazoline, naphazil, naphazoline, naphazil, naphazoline, naphazil, naphazoline, naphazil, Trimipramine, venlafaxine, chlorpromazine, haloperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

3.24 method I-A or II-A, wherein the therapeutic agent is an H3 agonist;

3.25 method I-a or II-a, wherein the therapeutic agent is an H3 antagonist;

3.26 method I-A or II-A, wherein the therapeutic agent is a noradrenergic agonist or antagonist;

3.27 method I-a or II-a, wherein the therapeutic agent is a galanin agonist;

3.28 method I-A or II-A, wherein the therapeutic agent is a CRH antagonist;

3.29 method I-A or II-A, wherein the therapeutic agent is human growth hormone;

3.30 method I-A or II-A, wherein the therapeutic agent is a growth hormone agonist;

3.31 method I-a or II-a, wherein the therapeutic agent is an estrogen;

3.32 method I-A or II-A, wherein the therapeutic agent is an estrogen agonist;

3.33 method I-A or II-A, wherein the therapeutic agent is a neurokinin-1 drug;

3.34 method I-a or II-a, wherein the therapeutic agent is combined with a compound of formula (I), and the therapeutic agent is an anti-parkinson agent such as L-dopa, Co-careldopa, doodpa (Duodopa), entacapone, carbidopa and levodopa Co-formulation (stalova), amantadine hydrochloride syrup (symmetrel), benztropine (benzzotropine), biperiden, bromocriptine (bromocriptine), entacapone, pergolide, pramipexole, propiconazole, ropinirole, selegiline and tolcapone.

3.35 methods I-A or II-A, wherein the therapeutic agent is an opioid agonist or a partial opioid agonist, e.g., a mu-agonist or a partial agonist, or a kappa-agonist or a partial agonist, including mixed agonists/antagonists (e.g., agents having partial mu-agonist activity and kappa-antagonist activity);

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

3.37 methods I-a or II-a, wherein the compound of formula (I) may be used for the treatment of sleep disorders, depression, psychosis or any combination thereof in patients with the listed diseases and/or parkinson's disease.

3.38 method I-a or II-a, wherein the disorder is selected from at least one or more psychosis, such as schizophrenia, depression, mood disorders, sleep disorders (e.g., sleep maintenance and/or falling asleep), or any combination of these disorders;

3.39 of any one of the above methods, wherein the disorder is a sleep disorder;

3.40 of any one of the above methods, wherein the disorder is a sleep disorder associated with psychosis such as schizophrenia or parkinson's disease; the therapeutic agent is in free or pharmaceutically acceptable salt form.

In an eleventh aspect of the invention, a combination of a compound of the invention as described in any of methods I-A, II-a or methods 3 or 3.1-3.40 and one or more second therapeutic agents can be administered as a pharmaceutical composition or depot composition as described above. Such a combined composition may include a mixture of each drug combined, as well as two or more separate compositions of drugs, where each individual composition may be administered to the patient, for example, together.

In particular embodiments, methods I-A, II-a, 3, or 3.1-3.40 comprise administering to a patient in need thereof a compound of the invention in free or pharmaceutically acceptable salt form and an atypical antipsychotic, such as a compound selected from clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, or paliperidone, for example wherein the dosage of the atypical antipsychotic is reduced and/or side effects are reduced.

In another embodiment, methods I-A, II-a, 3, or 3.1-3.40 comprise administering to a patient in need thereof a compound of the invention and an antidepressant in free or pharmaceutically acceptable salt form, e.g., amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, or venlafaxine. Alternatively, antidepressants may be used as adjunctive agents in addition to the compounds of the invention.

In another embodiment, methods I-A, II-a, 3, or 3.1-3.40 comprise administering to a patient in need thereof a compound of the invention and a compound that modulates GABA activity, e.g., a compound selected from doxepin, alprazolam, bromazepam, clobazam, clonazepam, chlordiazepine, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (exotpharmaceuticals), estazolam, or any combination thereof, in free or pharmaceutically acceptable salt form. In other embodiments, the presently disclosed methods no longer comprise administering a GABA compound, benzodiazepine, or any other anxiolytic agent.

In another preferred embodiment, method I-A, II-A, 3, or 3.1-3.40 comprises administering to a patient in need thereof a compound of the invention and doxepin in free or pharmaceutically acceptable salt form. The dosage of doxepin can vary within any range known to one of ordinary skill in the art. In one example, a 10mg dose of doxepin can be combined with any dose of a compound of the invention.

In another embodiment, methods I-A, II-a, 3, or 3.1-3.40 comprise administering to a patient in need thereof a compound of the invention in free or pharmaceutically acceptable salt form and an atypical stimulant (including as part of a daily dosing regimen), such as modafinil, adrofil, or amofenil. Regimens comprising the compounds of the invention and the drugs promote more regular sleep and avoid side effects such as psychosis or mania associated with higher levels of the drugs, for example in the treatment of bipolar depression, cognition associated with schizophrenia, and excessive sleepiness and fatigue in conditions such as parkinson's disease and cancer.

In some embodiments, each of the compounds of formulas I-IV and below; pharmaceutical compositions 6 and 6.1-6.8; depot compositions 6.9 and 6.10; compositions P.1 to P.7; methods 1 and 1.1-1.35; and methods 2 and 2.1-2.20; the compounds of the present invention are substantially free of compounds of formula a.

In a twelfth aspect, the invention provides the use of a compound (in the manufacture of a medicament) as described below for the treatment or prevention of one or more disorders as described above:

11.1 Compound I or 1.1-1.30 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 in free or pharmaceutically acceptable salt form or 4.1-4.11;

11.5 Compound 5 or 5.1-5.5;

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

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

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

11.9 pharmaceutical compositions 6 and 6.1-6.10;

11.10 pharmaceutical composition P.1-P.7;

11.11 osmotic controlled release oral system composition as described above,

for example in any one of method 1 or 1.1 to 1.35, method 2 and 2.1 to 2.20, and method 3 or 3.3 to 3.40, or any one of the methods of the eleventh aspect.

In a thirteenth aspect, the present invention provides the use of a pharmaceutical composition as described above for the treatment or prevention of one or more disorders as described above, for example:

12.1 pharmaceutical compositions 6 and 6.1-6.10;

12.2 pharmaceutical composition P.1-P.7;

12.3 osmotic controlled release oral system compositions as described above;

for example in any one of methods 1 and 1.1 to 1.35, methods 2 and 2.1 to 2.20, methods I-A, II-a, 3 or 3.3 to 3.40, or any one of the methods described in the eleventh or twelfth aspects.

Detailed Description

As used herein, the following terms, unless otherwise specifically or specifically indicated, have the following meanings:

as used herein, "alkyl" is a saturated or unsaturated hydrocarbon moiety, e.g., having a length of 1 to 21 carbon atoms, which may be straight-chain or branched (e.g., n-butyl or t-butyl), and is preferably straight-chain, unless otherwise specified. E.g. "C_1-21Alkyl "denotes an alkyl group having 1 to 21 carbon atoms. In one embodiment, alkyl is optionally substituted with one or more hydroxy or C_1-22Alkoxy (e.g., ethoxy) substitution. In another embodiment, the alkyl group contains 1 to 21 carbon atoms, preferably is straight chain and is optionally saturated or unsaturated, e.g., in some embodiments, wherein R is₁Are alkyl chains containing from 1 to 21 carbon atoms, preferably from 6 to 15 carbon atoms, from 16 to 21 carbon atoms, for example such that together with-C (O) -to which they are attached (for example when cleaved from a compound of formula I), a residue of a natural or unnatural, saturated or unsaturated fatty acid is formed.

The term "pharmaceutically acceptable diluent or carrier" is used to indicate diluents and carriers which may be used in pharmaceutical formulations and which do not contain substances known to cause allergy, fever or disease which are potentially capable of causing or promoting the condition. Thus, pharmaceutically acceptable diluents or carriers exclude bodily fluids, such as blood, urine, spinal fluid, saliva, etc., as well as their constituent components, such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers may be found in the processing of any of several well known pharmaceutical formulations, such as Anderson, Philip o; knoben, James e.; troutman, William G eds, Handbook of Clinical Drug Data, 10 th edition, McGraw-Hill, 2002; pratt and Taylor editors, Principles of Drug Action, 3 rd edition, churchilll Livingston, New York, 1990; katzung et al, Basic and Clinical Pharmacology, 9 th edition, McGraw Hill,20037 ybg; edited by Goodman and Gilman, Pharmacological Basis of Therapeutics, 10 th edition, McGraw Hill, 2001; remington's Pharmaceutical Sciences, 20 th edition, Lippincott Williams & wilkins, 2000; and Martindale, Extra Pharmacopoeia, 32 th edition (The Pharmaceutical Press, London, 1999); these are incorporated herein by reference.

The terms "purified", "purified form" or "isolated and purified form" as applied to a compound refer to the physical state of the compound after isolation from a synthetic process (e.g., from a reaction mixture), or natural source, or a combination thereof. Thus, the terms "purified", "in purified form" or "isolated and purified form" refer to the physical state of a compound (e.g., chromatography, recrystallization, LC-MS and LC-MS/MS techniques, etc.) after it has been obtained from one or more purification processes described herein or known in the art, which is of sufficient purity to be characterized by standard analytical techniques described herein or known in the art.

Compounds of formula I, including for example compounds of formulae II-B and II-C, wherein Z is- (C ═ O) -or- (ch (oh)) -are obtainable as metabolites of compounds of formula a and/or metabolites of compounds of formula B:

compounds of formula A are known to provide 5-HT_2ASERT and/or D₂Effective treatment of receptor-related disorders without significant extrapyramidal side effects is similarly disclosed and described in WO2009/145900, the entire contents of which are incorporated herein by reference. However, plasma levels of compounds of formula II-B and II-C resulting from the metabolism of compounds of formula A are quite low and may not contribute significantly to the therapeutic activity of compounds of formula A. The compounds of the formulae II-D and II-E may also be present as metabolites, but have not been detected to date. It has unexpectedly been found that the compounds of formula I have activity as antagonists of the μ -opioid receptor. This is unexpected because the compound of formula a is not known or understood to have any mu-opioid receptor activity or binding. Compounds of formula I wherein X is-NH-and wherein L is-O-have been shown to have particularly good mu-opioid receptor antagonism. Thus, such compounds of formula I may be useful in the treatment of drug dependence, e.g., opiate dependence and/or alcohol dependence, by inhibiting endogenous opiate responses to adverse drug administrationAnd by inhibiting the direct elimination of the undesirable opioid drug.

Surprisingly, the metabolites of the compound of formula a have a corresponding receptor binding affinity that differs to some extent from the compound of formula a. For example, the receptor binding characteristics of the compounds of formula II-B are quite unique, as compared to 5-HT_2A、D₁And antagonist activity at the Mu opioid receptor, making this compound highly interesting for use in the treatment of mood disorders. For example, the compound of formula a is inactive at the Mu opioid receptor.

Unless otherwise indicated, compounds of the invention, such as compound I or 1.1-1.30, compound II or 2.1-2.18, compound III or 3.1-3.13, or compound IV or 4.1-4.13 (collectively referred to as compounds of formulae I-IV and below) may exist in free or salt form, e.g., as acid addition salts. Acid addition salts of the compounds of the invention which are sufficiently basic are, for example, those with inorganic or organic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, toluenesulfonic acid, propionic acid, succinic acid, diglycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like. In addition, salts of the compounds of the invention which are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases which provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. In one embodiment, the salt of the compound of the present invention is the toluenesulfonic acid addition salt. In another embodiment, a salt of a compound of the invention is a fumaric acid addition salt. In one embodiment, the salts of the compounds of the present invention are the phosphate addition salts.

The compounds of the invention are intended for use as medicaments and are therefore preferably pharmaceutically acceptable salts. Salts not suitable for pharmaceutical use may be useful, for example for isolating or purifying the free compounds of the invention, and are therefore also included.

The compounds of the present invention may contain one or more chiral carbon atoms. Thus, the compounds exist in various stereoisomeric forms, such as enantiomeric or diastereomeric forms, or as mixtures of such forms, such as racemic/diastereomeric mixtures. Any isomer may exist wherein the asymmetric center is in the (R) -, (S) -or (R, S) -configuration. In the present invention is understood to include various optically active isomers as well as mixtures thereof (e.g., racemic/diastereomeric mixtures). Thus, the compounds of the present invention may be racemic mixtures, or they may be predominantly, e.g., in pure or substantially pure, isomeric form, e.g., greater than 70% enantiomeric/diastereomeric excess ("ee"), preferably greater than 80% ee, more preferably greater than 90% ee, and most preferably greater than 95% ee. Purification of the isomers and separation of the isomeric mixtures may be accomplished by standard techniques well known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed, etc.).

Geometric isomers with respect to the nature of the double bond or ring substituents may exist in either the cis (Z) or trans (E) form, both isomeric forms being included within the scope of the present invention.

It is also to be understood that the compounds of the present invention encompass stable and unstable isotopes thereof. Stable isotopes are non-radioactive isotopes that contain one additional neutron compared to the abundant nuclides (i.e. elements) of the same species. It is expected that the activity of compounds containing such isotopes will be retained and that such compounds may also be useful for detecting the pharmacologic kinetics of non-isotopic analogs. For example, a hydrogen atom at a particular position on a compound of the invention may be replaced by deuterium (a stable isotope, which is non-radioactive). Examples of well known stable isotopes include, but are not limited to, deuterium,¹³C、¹⁵N、¹⁸And O. Or unstable isotopes, which are radioactive isotopes containing additional neutrons compared to the abundant nuclides (i.e. elements) of the same species, e.g.¹²³I、¹³¹I、¹²⁵I、¹¹C、¹⁸F, can replace I, C and the corresponding abundant matter of F. Another example of a useful isotope of a compound of the invention is¹¹Isotope of C. These radioisotopes may be used for radiographic and/or pharmacokinetic studies of the compounds of the invention. In addition, substitution of atoms with natural isotopic distributions with heavier isotopes can result in the desired pharmacokinetic rate changes when these substitutions are at sites of facile metabolism. For example, introduction of deuterium (²H) Instead of hydrogen, metabolic degradation can be slowed when the site of the hydrogen is an enzymatically or metabolically active site.

In addition to the unique properties of the compounds of the present invention, compounds of formula I wherein Y is-C (H) (OH) -may also be esterified to form physiologically hydrolyzable and acceptable ester prodrugs. As used herein, "physiologically hydrolyzable and acceptable ester" means an ester of a compound of the present invention that is capable of hydrolyzing under physiological conditions to yield, on the one hand, a hydroxyl group and, on the other hand, an acid such as a carboxylic acid, which is itself physiologically tolerable at the dosage to be 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 wherein R₁is-C (O) -C_1-21An alkyl group. In some preferred embodiments, R₁is-C (O) -C_1-21Alkyl, for example acyl acid esters, such as heptanoate, octanoate, decanoate, dodecanoate, tetradecanoate or hexadecanoate.

Similarly, when a compound of the invention contains an amine group, prodrugs of such amines may also be present, for example, methyl amine prodrugs, wherein the prodrugs are cleaved after administration to release the amine metabolites in vivo.

Prodrugs of the compounds of the present invention, wherein R₁is-C (O) -C_1-21Alkyl, preferably-C_6-21Alkyl, more preferably C_6-15Alkyl, more preferably linear, saturated or unsaturated and optionally substituted with one or more hydroxy or alkoxy groups, is particularly useful for sustained and/or delayed release to achieve long-acting effects, e.g., wherein the compounds of the present invention are released over a period of about 14 to about 30 to about 180 days,e.g., about 30 or about 60 or about 90 days, e.g., as described in any of the depot compositions described herein. Preferably, the sustained and/or extended release formulation is an injectable formulation.

Alternatively and/or additionally, a compound of the invention may be included as a depot formulation, for example by dispersing, dissolving or encapsulating the compound in a polymer matrix, as described in any of compositions 6 and 6.1 to 6.10, such that the compound is released continuously as the polymer degrades over time. The release of the compound of the invention from the polymer matrix provides for a controlled and/or delayed and/or sustained release of the compound, e.g. from a drug depot composition, to the target to which the drug depot is administered, e.g. a warm-blooded animal such as a human. Drug depots deliver a compound of the invention to a target at a concentration effective for treating a particular disease or medical condition for a sustained period of time, e.g., 14 to 180 days, preferably about 30 days, about 60 days, or about 90 days.

Polymers of the polymeric matrix useful in the compositions of the invention (e.g., the depot compositions of the invention) may include polyesters of hydroxy fatty acids and derivatives thereof, or other agents such as polylactic acid, polyglycolic acid, polycitric acid, polylapple trees, poly-beta-hydroxybutyric acid, epsilon-caprolactone ring-opening polymers, copolymers of lactic acid and glycolic acid, copolymers of 2-hydroxybutyric acid and glycolic acid, copolymers of polylactic acid and polyethylene glycol or copolymers of polyglycolic acid and polyethylene glycol, polymers of alkyl alpha-cyanoacrylates (e.g., poly (2-butylcyanoacrylate)), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polypropylene carbonate), poly (ortho carbonates), poly (amino acids) (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid, or poly-y-methyl-L-glutamic acid), hyaluronic acid esters, and the like, and one or more of these polymers may be used.

If the polymers are copolymers, they may be any random, block and/or graft copolymer. When the above-mentioned α -hydroxycarboxylic acid, hydroxydicarboxylic acid and hydroxytricarboxylic acid have optical activity in their molecules, any of D-isomer, L-isomer and/or DL-isomer may be used. Among them, an α -hydroxycarboxylic acid polymer (preferably lactic acid-glycolic acid polymer), an ester thereof, poly α -cyanoacrylate, and the like can be used, and preferably a lactic acid-glycolic acid copolymer (also referred to as polylactide- α -glycolide), or poly (lactic acid-co-glycolic acid), hereinafter referred to as PLGA). Thus, in one aspect, the polymer that can be used in the polymer matrix is PLGA. The term PLGA as used herein includes polymers of lactic acid (also known as polylactic acid, poly (lactic acid), or PLA). Most preferably, the polymer is a biodegradable poly (d, l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymer material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not significantly cause inflammation of body tissues. The matrix material should be bio-disposable, wherein the polymeric material should degrade under body pressure into products that can be broken down by the body and should not aggregate in vivo. The products of biodegradation should also be biocompatible with the body, wherein the polymer matrix is biocompatible with the body. Particularly useful examples of polymeric matrix materials include: poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, copolymers of the above, poly (aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxans, polyorthocarbonates, polyacetals, 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 present invention is dl (polylactide-co-glycolide). Preferably, the molar ratio between lactide and glycolide in such copolymers is in the range of about 75:25 to 50: 50.

Useful PLGA polymers may have a weight average molecular weight of about 5,000 to 500,000 daltons, preferably about 150,000 daltons. Depending on the degradation rate to be achieved, polymers of different molecular weights may be used. For the diffusion mechanism of drug release, the polymer should remain unchanged until all of the drug is released from the polymer matrix and then degraded. The drug may also be released from the polymer matrix upon bioerosion of the polymer excipient.

PLGA may be prepared by any conventional method, or may be commercially available. PLGA can be prepared, for example, by ring-opening polymerization from cyclic lactide, glycolide, etc. with a suitable catalyst (see EP-0058481B 2; effect of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

PLGA is believed to be biodegradable by degradation of the entire solid polymer composition, since hydrolysable and enzymatically cleavable ester linkages are cleaved under biological conditions (e.g., in the presence of water and biological enzymes present in the tissues of warm-blooded animals such as humans) to form lactic acid and glycolic acid. Lactic acid and glycolic acid are both water-soluble, non-toxic products of normal metabolism that can be further biodegraded to form carbon dioxide and water. In other words, PLGA is believed to degrade by hydrolysis of its ester groups in the presence of water, for example in the body of a warm-blooded animal such as a human, thereby producing lactic and glycolic acids, and producing an acidic microclimate. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of warm-blooded animals such as humans under normal physiological conditions and are therefore well tolerated and produce minimal systemic toxicity.

In another embodiment, the polymer matrix useful in the present invention may comprise a star polymer, wherein the structure of the polyester is star-shaped. These polyesters have a single polyol residue as the central moiety, which is surrounded by a chain of acid residues. The polyol moiety may for example be glucose or for example mannitol. These esters are well known and can be found in GB 2,145,422 and U.S. Pat. No.5,538,739, the contents of which are incorporated herein by reference.

Star polymers can be prepared using a polyol as a starter, such as a polyol, e.g., glucose or mannitol. The polyol contains at least 3 hydroxyl groups and has a molecular weight of up to about 20,000 daltons, wherein at least 1, preferably at least 2, e.g. an average of 3, of the hydroxyl groups of the polyol are in the form of ester groups, which contain polylactide or co-polylactide chains. Branched polyesters, such as poly (d, l-lactide-co-glycolide) have a central glucose moiety with a linear arrangement of linear polylactide chains.

The depot compositions of the invention as described above (e.g., compositions 6 and 6.1-6.10, in a polymer matrix) can comprise a polymer in the form of microparticles or nanoparticles or in liquid form in which the compounds of the invention are dispersed or encapsulated. "microparticles" means solid particles containing a compound of the invention in solution or solid form, wherein such compound is dispersed or dissolved in a polymer that serves as the matrix of the particles. By appropriate selection of the polymeric material, a microparticle formulation can be produced in which the resulting microparticles exhibit both diffusional and biodegradable release properties.

When the polymer is in particulate form, the particles may be prepared using any suitable method, for example by solvent evaporation or solvent extraction methods. For example, in a solvent evaporation process, the compounds and polymers of the invention may be dissolved in a volatile organic solvent (e.g., ketones such as acetone, halogenated hydrocarbons such as chloroform or dichloromethane, halogenated aromatics, cyclic ethers such as bisAn alkyl, an ester such as ethyl acetate, a nitrile such as acetonitrile, or an alcohol such as ethanol) and dispersed in an aqueous phase (e.g., polyvinyl alcohol, PVA) containing a suitable emulsion stabilizer, and then evaporating the organic solvent to provide microparticles in which the compounds of the present invention are encapsulated. In solvent extraction processes, the compounds and polymers of the present invention may be dissolved in a polar solvent (e.g., acetonitrile, dichloromethane, methanol, ethyl acetate, or methyl formate) and then dispersed in an aqueous phase (e.g., a water/PVA solution). An emulsion is prepared to provide microparticles in which the compounds of the present invention are encapsulated. Spray drying is another production technique used to prepare microparticles.

Another method for preparing microparticles of the present invention can also be found in U.S. Pat. No.4,389,330 and U.S. Pat. No.4,530,840.

The microparticles of the present invention can be prepared by any method that can produce microparticles having a size range useful in injectable compositions. One preferred method of preparation is described in U.S. Pat. No.4,389,330. In this method, the active agent is dissolved or dispersed in a suitable solvent. To the medium containing the agent is added a polymeric matrix material in an amount relative to the active ingredient that provides a product having the desired active agent loading. Optionally, all of the ingredients of the particulate product may be blended together in a solvent medium.

Solvents that may be used in the present invention for the compounds of the present invention and the polymeric matrix material include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, dichloromethane, and the like; an aromatic hydrocarbon compound; a halogenated aromatic hydrocarbon compound; a cyclic ether; alcohols, such as benzyl alcohol; ethyl acetate; and so on. In one embodiment, the solvent useful in the present invention may be a mixture of benzyl alcohol and ethyl acetate. Additional information regarding the preparation of microparticles useful in the present invention can be found in U.S. patent application No.2008/0069885, the contents of which are incorporated herein by reference in their entirety.

The amount of the compound of the present invention incorporated in the fine particles is usually about 1 to 90% by weight, preferably 30 to 50% by weight, more preferably 35 to 40% by weight. Wt% means the fraction of the compound of the invention based on the total weight of the microparticles.

The drug depot composition may comprise a pharmaceutically acceptable diluent or carrier, for example a water-miscible diluent or carrier.

Details of osmotic controlled release oral system compositions can be found in EP 1539115 (u.s.pub.no.2009/0202631) and WO 2000/35419, the contents of which are incorporated herein by reference in their entirety.

A "therapeutically effective amount" is an amount of a compound of the invention (e.g., contained in a drug depot) that is effective to reduce, alleviate or regress the disease or disorder over the expected treatment period when administered to a subject suffering from the disease or disorder.

The dosage employed in the practice of the present invention will, of course, vary depending upon, for example, the particular disease or condition being treated, the particular compound of the invention employed, the mode of administration, and the desired treatment. Unless otherwise indicated, the amount of a compound of the invention for administration (administered as the free base or as a salt) means or is based on the amount of the compound of the invention in the form of the free base (i.e., the amount is calculated based on the amount of the free base).

The compounds of the invention may be administered by any suitable route, including orally, parenterally (intravenously, intramuscularly or subcutaneously) or transdermally, but preferably orally. In a particular embodiment, the compounds of the invention, e.g. depot formulations, are preferably administered parenterally, e.g. by injection.

Generally, for the above uses of method 1 or and 1.1-1.35, method 2 and 2.1-2.20, and method 3 and 3.1-3.40, or compounds of the invention as described above, e.g. for the treatment of a combination of diseases, such as at least depression, a combination of psychiatric disorders, e.g.: as described above (1) psychosis of patients suffering from depression, such as schizophrenia; (2) depression in patients with psychiatric disorders, such as schizophrenia; (3) mood 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) substance addiction, substance use disorders and/or substance induction disorders, indicating that satisfactory results are obtained with oral administration at a dose of about 1mg to 100mg, preferably 2.5mg to 50mg, such as 2.5mg, 5mg, 10mg, 20mg, 30mg, 40mg or 50mg, approximately once daily, preferably by oral administration.

For method 2 or 2.1-2.20 as described above or the use of a compound of the invention, e.g. for the sole treatment of sleep disorders, it is indicated that oral administration of a compound of the invention in free or pharmaceutically acceptable salt form at a dose of about 2.5mg-5mg once daily, e.g. 2.5mg, 3mg, 4mg or 5mg once daily, preferably by oral administration, gives satisfactory results.

For any of methods I-a or methods II-a or 3.1-3.40, it is shown that satisfactory results are obtained with administration at a dose of less than 100mg once daily, preferably less than 50mg, e.g. less than 40mg, less than 30mg, less than 20mg, less than 10mg, less than 5mg, less than 2.5 mg. For any of methods II-a or 3.1-3.40, it was shown that satisfactory results can be obtained with oral administration at a dose of less than 5mg, preferably less than 2.5 mg.

For the treatment of the disorders disclosed herein, wherein the depot composition is used to achieve a longer duration of action, the dosage will be higher than for shorter acting compositions, e.g., higher than 1-100mg, e.g., 25mg, 50mg, 100mg, 500mg, 1000mg, or greater than 1000 mg. For example, the duration of action of the compounds of the invention can be controlled by controlling the polymer composition, i.e., the polymer to drug ratio and the particle size. When the composition of the invention is a depot composition, administration by injection is preferred.

Pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, the salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or an organic solvent or a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Further details of the preparation of these salts, such as the amorphous or crystalline form of p-toluenesulfonate, may be found in PCT/US08/03340 and/or U.S. provisional application No.61/036,069.

Pharmaceutical compositions comprising a compound of the invention may be prepared using conventional diluents or excipients (examples include, but are not limited to, sesame oil) and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

Methods of preparing the compounds of the invention:

wherein X is-NH-or-N (CH)₃) Compounds of the invention in which-and Y is-C (═ O) can be prepared by (6bR,10aS) -2-oxo-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4,5]Pyrrolo [1,2,3-de]Quinoxaline or 1-methyl analog thereof is prepared by reaction with 4-chloro-4' -fluorobutyrophenone according to scheme 1 below:

x is-NH-or-N (CH)₃)-

Scheme 1

Wherein X is-NH-or-N (CH)₃) -andcompounds of the invention wherein Y is-CH (OH) -may be prepared by reacting 4- ((6bR,10aS) -2-oxo-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4,5]Pyrrolo [1,2,3-de]Quinoxalin-8-yl) -1- (4-fluoro-phenyl) -butan-1-one (or its 1-methyl analog) is prepared by reaction with a reducing agent according to scheme 2 below:

x is-NH-or-N (CH)₃)-

Scheme 2

The reducing agent may be a metal hydride, such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diisobutyl aluminum hydride, preferably sodium borohydride. Other reagents for the reduction of ketones can be found in Jerry March, Advanced Organic Chemistry, reaction Mechanisms and Structures (Advanced Organic Chemistry, Reactions Mechanisms and Structures), page 910, 911 (1992, John Wiley & Sons, Inc.), 4 th edition, the contents of which are incorporated herein by reference.

Separation or purification of diastereomers of the compounds of the invention may be accomplished by conventional methods well known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, crystallization, titration, simulated moving bed, and the like.

Wherein Y is-CH (O-R)₁) -and R₁Compounds of formula I other than hydrogen may be prepared by some common esterification method, such as alcoholysis of acid halides, anhydrides, or active esters. For example, wherein R₁Compounds of formula I which are-c (o) -alkyl may be prepared by the reaction of:

(a)L–C(O)-C_1-21alkyl, wherein L is a leaving group, e.g. a halogen group (e.g. chloro or bromo), trifluoromethylsulfonyloxy (-OSO)₂CF₃) Tosyloxy (-O-S (O))₂-C₆H₄-CH₃) Methylsulfonyloxy (-O-S (O))₂-CH₃) 1H-benzo [ d ]][1,2,3]Triazol-1-yloxy or succinimidyloxy, with

(b) Wherein Y is a compound of formula I of-C (H) (OH),

this reaction is preferably carried out in the presence of a base such as diisopropylamine, triethylamine or pyridine. For example L-C (O) -C_1-21Alkyl is acetyl, decanoyl or heptanoyl halide, which can be prepared by HO-C (O) -C_1-21Alkyl, for example, with thionyl chloride, P (X')₃Or P (X')₅Reaction preparation, wherein X' is Cl or Br. When L is tosyloxy-C (O) -C_1-21Alkyl or methylsulfonyloxy-C (O) -C_1-21When alkyl, these compounds may be represented by HO-C (O) -C_1-21Alkyl groups are prepared by reaction with tosyl chloride or mesyl chloride, preferably in the presence of a base such as pyridine. Wherein R is₁The synthesis of compounds of formula II-A other than H can be seen in scheme 3 below:

scheme 3

Or, wherein R₁The compounds of formula II-A other than H can be synthesized by HO-C (O) -C_1-21Alkyl with (I) a compound of formula I wherein Y is-C (H) (OH) in the presence of a base such as DIEPA and NEt₃With (ii) a dehydrating agent or a coupling agent such as 2-fluoro-1-ethylpyridine tetrafluoroborate(FEP), tetramethylammonium hexafluorophosphate (TFFH) or 1,1,3, 3-bis (tetramethylene) ammonium hexafluorophosphate (PyClU).

Salts of the compounds of the present invention may be prepared in analogy to the methods described in the following documents: U.S. patent nos. 6,548,493; 7,238,690, respectively; 6,552,017, respectively; 6,713,471, respectively; 7,183,282, respectively; u.s.re39680; U.S. re39679; and WO 2009/114181, the contents of each of which are incorporated herein by reference in their entirety.

Diastereomers of the compounds prepared may be used, for example, by HPLCAY-H,5 μ,30X250mm separation at room temperature10% ethanol/90% hexane/0.1% dimethylethylamine. A peak can be detected at 230nm, giving diastereomer in 98-99.9% ee.

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

(6bR,10aS) -2-oxy-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4, 5)]Pyrrolo [1,2,3-de]Ethyl quinoxaline-8-carboxylate (6.4g, 21.2mmol) was suspended in HBr in acetic acid (64mL, 33% w/w). The mixture was heated at 50 ℃ for 16 hours. After cooling and treatment with ethyl acetate (300mL), the mixture was filtered. The filter cake was washed with ethyl acetate (300mL) and then dried under vacuum. The resulting HBr salt was then suspended in methanol (200mL) and cooled in isopropanol with dry ice. To the suspension was slowly added ammonia solution (10mL,7N in methanol) with vigorous stirring to adjust the pH of the mixture to 10. The resulting mixture was dried under vacuum and without further purification to give crude (6bR,10aS) -2-oxo-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4,5]Pyrrolo [1,2,3-de]Quinoxaline (8.0g), which was used directly in the next step. MS (ESI) M/z 230.2[ M + H ]]⁺。

Crude (6bR,10aS) -2-oxo-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4, 5)]Pyrrolo [1,2,3-de]Quinoxaline (1.4g) was dissolved in DMF (14mL), and KI (2.15g) and 4-chloro-4' -fluorobutyrophenone (2mL) were added successively. The mixture was degassed with argon and then N, N-diisopropylethylamine (DIPEA, 2mL) was added. The mixture was heated at 78 ℃ for 2 hours. After cooling, the solvent was removed under reduced pressure. The dark brown residue was suspended in dichloromethane (100mL) and then extracted with water (30 mL). Separating the organic layer with K₂CO₃And (5) drying. After filtration, the solvent was removed under reduced pressure. The obtained crude product is purified by silica gel column chromatography, wherein the crude product is used in the process of purifyingElution with 0.1% 7N ammonia in methanol with 0-10% methanol in ethyl acetate gave 4- ((6bR,10aS) -2-oxo-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4,5]Pyrrolo [1,2,3-de]Quinoxalin-8-yl) -1- (4-fluoro-phenyl) -butan-1-one, as a light yellow solid (767 mg).¹H NMR(500MHz,DMSO-d₆)δ10.3(s,1H),8.1–8.0(m，2H),7.3(dd,J＝8.86Hz,2H),6.8(d，J＝7.25Hz,1H)，6.6(dd,J＝7.55Hz,1H)，6.6(d，J＝7.74Hz,1H),3.8(d,J＝14.49Hz,1H),3.3–3.3(m,1H),3.2–3.2(m，1H)，3.1–3.0(m,1H),3.0(t，J＝6.88Hz,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＝6.99Hz,2H)，1.6(t，J＝11.25Hz，2H).MS(ESI)m/z 394.2[M+H]⁺。

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

4- ((6bR,10aS) -2-oxyl-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4, 5)]Pyrrolo [1,2,3-de]Quinoxalin-8-yl) -1- (4-fluoro-phenyl) -butan-1-one (50mg,0.127mmol) was dissolved in methanol (5 mL). Adding NaBH in portions under stirring₄(31mg,0.82 mmol). After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Methanol was evaporated under reduced pressure. The residue was dissolved in dichloromethane (10mL) and then extracted with water (2 X0.5mL). For the combined organic phases K₂CO₃And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and then further dried under vacuum to give 4- ((6bR,10aS) -2-oxo-2, 3,6b,9,10,10 a-hexahydro-1H, 7H-pyrido [3 ', 4': 4,5]Pyrrolo [1,2,3-de]Quinoxalin-8-yl) -1- (4-fluoro-phenyl) -butan-1-ol was a light yellow foaming solid (45mg, 90% yield).¹H NMR(500MHz，DMSO-d₆)δ10.3(s,1H),7.4–7.3(m，2H),7.2–7.1(m，2H),6.7(d，J＝7.29Hz,1H),6.7–6.6(m，1H),6.6(d，J＝7.74Hz，1H),5.4(s，1H),4.7–4.4(m,1H),3.8(d,J＝14.49Hz,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: synthesis of (6bR,10aS) -8- (3- (4-fluorophenoxy) propyl) -6b,7,8,9,10,10 a-hexahydro-1H-pyrido [3 ', 4': 4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Reacting (6bR,10aS) -6b,7,8,9,10,10 a-hexahydro-1H-pyrido [3 ', 4': 4,5]Pyrrolo [1,2,3-de]A mixture of quinoxalin-2 (3H) -one (100mg,0.436mmol), 1- (3-chloropropyloxy) -4-fluorobenzene (100. mu.L, 0.65mmol) and KI (144mg,0.87mmol) in DMF (2mL) was degassed with argon for 3 min and DIPEA (150. mu.L, 0.87mmol) was added. The resulting mixture was heated to 78 ℃ and stirred at this temperature for 2 hours. The mixture was cooled to room temperature and then filtered. The filter cake is purified by silica gel column chromatography using methanol/7N NH₃A gradient of 0-100% ethyl acetate in a mixture in methanol (1:0.1v/v) as eluent gave a partially purified product which was further purified with a semi-preparative HPLC system for 16 minutes using a gradient of 0-60% acetonitrile in water containing 0.1% formic acid to give the title product as a solid (50mg, 30% yield). MS (ESI) M/z 406.2[ M +1 ]]⁺。¹H NMR(500MHz，DMSO-d₆)δ10.3(s，1H),7.2–7.1(m,2H),7.0–6.9(m，2H),6.8(dd,J＝1.03,7.25Hz,1H)，6.6(t,J＝7.55Hz,1H),6.6(dd,J＝1.07,7.79Hz，1H),4.0(t，J＝6.35Hz，2H),3.8(d，J＝14.74Hz,1H),3.3–3.2(m，3H),2.9(dd,J＝6.35,11.13Hz,1H),2.7–2.6(m，1H),2.5–2.3(m,2H),2.1(t,J＝11.66Hz，1H),2.0(d,J＝14.50Hz,1H)，1.9–1.8(m，3H)，1.7(t，J＝11.04Hz,1H)。

Pharmacological characteristics:

as mentioned above, the compounds of the present invention have unique pharmacological profiles, in combination with 5-HT_2A、D₁And mu opioid receptors.

For example, the compound of example 3 for 5-HT_2A、D₁And mu opioid receptors have low nanomolar affinities with Ki values of 8.3nM, 50nM and 11nM, respectively.

Example 3 pharmacological characterization of Compounds Using in vitro receptor binding and cell-based functional assays and for 5-HT_2A、D₁、D₂And functional activity of mu opioid receptors, including DOI-induced cephalpasm, morphine-induced hyperactivity, Western blotting (Western blotting) assays of brain phosphorylating protein levels (tyrosine hydroxylase and GluN2B), and blockade of morphine activity in classical mouse pain tail flick assays.

The compound of example 3 showed oral activity and excellent metabolic stability in animals. Example 3 oral administration of the Compound potentially blocks DOI-induced cephalic spasm (EC) in mice₅₀0.23mg/kg, p.o.), was demonstrated as 5-HT_2AStrong functional activity of the antagonist. The compound of example 3 did not disrupt striatal dopamine neurotransmission at the doses tested, which was shown by a lack of effect on striatal tyrosine hydroxylase, a rate-limiting enzyme for dopamine synthesis. The compound of example 3 (0.3mg/kg, p.o.) showed potential in vivo antagonism as compared to its 5-HT_2AThe dose with comparable receptor effect blocked morphine-induced hyperactivity and morphine-induced analgesia in mice (i.e., 0.1mg/kg and greater, p.o.).

The following examples describe further details regarding the pharmacological characteristics of the compounds of the present invention.

Example 4: functional analysis of cell and nuclear receptors

According to Wang, j.b. et al (1994), FEBS lett, 338: 217-222 the procedure described for the compounds of formulae II-B and II-C was performed for the analysis of cell and nuclear receptor function. These compounds were tested at several concentrations to determine their IC₅₀Or EC₅₀. The cellular agonist effect is calculated as a percentage of the control response to each target relative to a known control agonist, the cellular antagonismThe effect of the agent is calculated as the percentage inhibition of the response to each target relative to the control agonist.

The following assay was performed to determine the effect of compounds of formula II-B on the μ (MOP) (h) receptor:

for antagonists, the apparent dissociation constant (K) was calculated using a modified Cheng Prusoff equation_B)：

Wherein a ═ the concentration of the control agonist in the assay, and EC_50AEC of control agonist₅₀The value is obtained.

Compounds of formula II-B were found to have μ (MOP) (h) (antagonist effect), where IC₅₀Is 1.3x10^-6M，K_BIs 1.4x10^-7M; and finding the IC of the Compound of formula II-C₅₀Is greater than 1x10^-5This is the highest concentration detected.

This result is expressed as a percentage of the control agonist response obtained in the presence of a compound of formula II-B or II-C:

and percent inhibition of control agonist response:

EC₅₀value (concentration at which half of the maximum response value occurs) and IC₅₀The value (the concentration at which half of the maximal inhibition of the control agonist response is elicited) is determined by non-linear regression analysis of the concentration-response curve generated with the average of the replicates using a Hill metricFitting a curve of the formula:

where Y is the response, a is the left asymptote of the curve, D is the right asymptote of the curve, C is the concentration of the compound, and C is the concentration of the compound₅₀＝EC₅₀Or IC₅₀And nH is a skew factor. This analysis is performed using software developed internally in the institution and by using it forBusiness software of4.0(1997, SPSS Inc.) was generated.

Example 5: receptor binding characteristics of Compounds of formulas II-B and II-C

The receptor binding of the compounds of formula II-A and II-B and the compound of example 3 was tested using the tosylate salt of the compound of formula A as a control. The following literature procedures were employed, each of which is hereby incorporated by reference in its entirety: 5-HT_2A: bryant, h.u. 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, q.y. et al (1990), Nature, 347: 76-80; and (4) SERT: park, y.m. et al (1999), anal. biochem., 269: 94-104; mu opioid receptors: wang, j.b. et al (1994), FEBS lett, 338: 217-222.

In general, this result is expressed as a percentage of specific binding obtained in the presence of the compound being tested relative to the control:

and expressed as percent inhibition of specific binding relative to control:

IC₅₀values (concentration at which half of the maximal inhibition of control specific binding is caused) and Hill coefficient (nH) are determined by non-linear regression analysis of the competition curve generated with the mean replicate values, using Hill formula curve fitting:

y-specific binding, a-left-evolvent of the curve, D-right-evolvent of the curve, C-concentration of the compound, C₅₀＝IC₅₀And nH is a skew factor. This analysis is performed using software developed internally in the institution and by using it forBusiness software of4.0(1997, SPSS Inc.) was generated. The inhibition coefficient (Ki) was calculated using the Cheng Prusoff equation:

wherein L ═ the concentration of radioligand in the assay, and K_DThe affinity of a radioligand for the receptor. Scatchard plot for determining K_D。

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

example 6: model of DOI-induced Head spasm (Head Twitch) in mice

R- (-) -2, 5-dimethoxy-4-iodophenylpropylamine (DOI) is 5-hydroxytryptamine 5-HT₂Agonists of the receptor family. When administered to mice, it produces behavioral characteristics associated with frequent head spasms. The frequency of these head spasms over a predetermined time can be used to estimate 5-HT of the brain₂Receptor agonism. Instead, this behavioral analysis can be used to determine 5-HT of the brain₂Receptor antagonism by administering DOI with or without an antagonist and recording a reduction in DOI-induced cephalic spasm following administration of the antagonist.

Such as Darmani et al, Pharmacol Biochem Behav. (1990) 36: 901-906 (the contents of which are incorporated herein by reference in their entirety) are used with some modifications. Subcutaneous injections were performed with (±) -DOI HCl and the mice were immediately placed in conventional plastic cages. The number of head spasms was counted over 6 minutes, starting 1 minute after DOI administration. The tested compounds were administered orally at 0.5 hours prior to DOI injection. The resulting area was calculated as EC50 for reducing DOI-induced cephalic spasm. The results are shown in table 1 below:

compound (I)	EC50(mg/kg,p.o.)
		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

This result indicates that the compounds of examples 1 and 3 potentially block DOI cephalic spasm, which is comparable to the control compounds of formulas a and C, and corresponds to the in vitro 5-HT shown in example 5_2AAnd (6) obtaining the result. In contrast, the compound of example 2 was weaker in this functional assay, which corresponds to the in vitro data in example 5, indicating that this compound is at its 5-hydroxytryptamine receptor (5-HT)_2A) The antagonistic aspect is weaker than other structurally similar compounds.

Example 7: tail flick analysis of mice

Mouse tail flick analysis was used to detect analgesia, as indicated by the nociceptive reflectance threshold of restricted mice. The tails of male CD-1 mice were placed under a concentrated beam of a high intensity infrared heat source, resulting in heating of the tails. The time between turning on the heating instrument and the tail of the mouse being thrown out of the heat source path (latency) was recorded. Morphine administration resulted in analgesia, which produced a delay in the response of the mice to heat (increased latency). Before the administration of the morphine antagonist, i.e. naloxone, the effect is reversed and a normal latency time is obtained. This experiment was used as a functional assay to assess antagonism of mu-opioid receptors.

10 male CD-1 mice (age about 8 weeks) were assigned to each of five treatment groups. These groups were treated as follows: group (1) [ negative contrast ]: 0.25% methylcellulose media p.o. was applied 60 minutes prior to tail flick experiments and saline media was applied 30 minutes prior to tail flick experiments; group (2) [ positive contrast ]: 0.25% methylcellulose medium p.o. was administered 60 minutes prior to the experiment and 5mg/kg morphine in saline at 30 minutes prior to the experiment; group (3) [ positive contrast ]: 3mg/kg naloxone in saline 50 minutes prior to the experiment and 5mg/kg morphine in saline 30 minutes prior to the experiment; groups (4) to (6): 0.1mg/kg, 0.3mg/kg or 1mg/kg of the test compound in 0.25% methylcellulose medium p.o. was administered 60 minutes prior to the experiment and 5mg/kg morphine was administered 30 minutes prior to the experiment. This experiment was repeated for the compounds of example 1 and example 3. The results are presented in the following table as the mean latency in seconds:

the results demonstrate that the compounds of example 1 and example 3 both have a dose-dependent blocking effect on morphine-induced mu-opioid receptor activity.

Example 8: CNS phosphorylated protein characterization

Comprehensive molecular phosphorylation studies were also conducted to examine Central Nervous System (CNS) characteristics of the compounds of example 1 and example 3. The extent of protein phosphorylation on selected key central nervous system proteins in mouse Nucleus accumbens (nucleous accumbens) was examined. The proteins tested included ERK1, ERK2, Glu1, NR2B and TH (tyrosine hydroxylase), and the compounds of examples 1 and 3 were compared to the antipsychotic drugs risperidone and haloperidol.

Mice were treated with the compound of example 1 or 3 at a dose of 3mg/kg or with 2mg/kg haloperidol. Mice were sacrificed 30 minutes to 2 hours post injection by focused microwave cranial irradiation, which preserved the brain phosphorylated protein present at the time of death. Nucleus accumbens were then dissected from the brain of each mouse, sectioned and frozen in liquid nitrogen. The samples were further prepared for phosphoprotein analysis via SDS-PAGE electrophoresis followed by phosphoprotein-specific immunoblotting, such as Zhu H, et al, Brain res.2010jun 25; 1342: 11-23. Phosphorylation at each position was quantified and normalized to total protein levels (non-phosphorylated) and expressed as phosphorylation levels in vehicle-treated control mice.

The results demonstrate that neither the compound of example 1 nor the compound of example 3 has a significant effect on tyrosine hydroxylase phosphorylation at 30 or 60 minutes for Ser40, where haloperidol produced more than a 400% increase and risperidone produced more than a 500% increase in TH phosphorylation compared to haloperidol and risperidone. This demonstrates that the compounds of the invention do not disrupt dopamine metabolism.

The results also demonstrate that neither the compound of example 1 or example 3 has a significant effect on NR2B phosphorylation at 30-60 minutes for Tyr 1472. These compounds resulted in a slight increase in phosphorylation of Ser845 in GluR1 and a slight decrease in phosphorylation of Thr183 and Tyr185 in ERK 2.