TW201118102A - Hydroxyasenapine compounds, derivatives thereof and pharmaceutical compositions comprising same - Google Patents

Abstract

The present invention provides isolated or purified hydroxyasenapine compounds, derivatives thereof, especially ester derivatives thereof, and pharmaceutical compositions comprising the same. The present invention provides also methods of treatment using the same.

Description

201118102 VI. INSTRUCTIONS: A novel hydroxyasenapine compound, a derivative thereof and a pharmaceutical composition comprising the same.

The formula is incorporated herein by way of example as fully described herein. [Technical Field of the Invention] The present application describes a novel </ RTI> prior art. The determination of any part or any part of this disclosure is not an admission that the disclosure is prior art to the present invention. Trans-5-chloro-2-indolyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3 is described in Example 3 of U.S. Patent No. 4,145,434 (the '434 patent). ;6,7] The method of oxo [4,5c] ratio η (also known as asenapine, see Merck Index, No. 832), which has the compound of formula A Structure,

The compound of formula A is known to have therapeutic activity in patients suffering from a disease of the middle sacral nervous system (CNs disease). For example, the compound of formula I, as described in the first column, lines 45 to 50 of the '434 patent, generally exhibits significant CNS inhibitor activity (which can be used to treat stress, agitation and anxiety, and therapeutic spirit 149868.doc 201118102 Disease and schizophrenia), and also showed excellent antihistamine and anti-serotonin activity as in the United States on March 9, 1995, the International Application No. (^/£?95/〇〇〇765 Sublingual or buccal administration of arnicapine salt (eg, cepinal maleate) can be used for treatment or treatment, as described in column 5, pp. 43-46 of Patent No. 5,763,476 (the '476 patent). Disorders of mental disorders (such as stress, agitation, anxiety, psychosis, and schizophrenia). The above-mentioned applications and patents are hereby incorporated by reference in their entirety as if their entire disclosures Therapeutic treatment of bipolar disorder and related symptoms with azinazepine or a salt thereof is described in U.S. Patent Application Serial No. 2006/008469, filed on Apr. 20, 2006, the disclosure of Incorporated in this article It has been fully described herein. Compounds having atypical antipsychotic properties for the treatment of various CNS diseases are generally of interest, in particular, useful in injectable compositions or oral compositions. A patient with schizophrenia, bipolar disorder, or manic episodes, depressive episodes, or mixed episodes associated with bipolar disorder provides an acceptable concentration of azepine in a therapeutic concentration. [Invention] For the above, a need is needed. A compound contained in a composition that is stable and provides activity, such as an atypical antipsychotic, when administered to a patient in need of such treatment. The present invention provides such or other objectives and/or advantages of its in-state Provided are isolated and/or purified hydroxy asconapine compounds or derivatives thereof which are therapeutically active against (10) diseases. In some implementations, the isolated single-base aspirin (-π-) I49868 .doc 201118102 Compound is a compound of formula I, hydrazine, or in:

Another aspect of the present invention provides an isolated or/and purified derivative of a hydroxyazinapine compound of the formula π, and hydrazine, especially an ester derivative wherein the hydroxy substituent in the compound of Formula I or II The position is occupied by the ester functional group in the ester derivative, or wherein the position of the compound of formula m occupied by at least one hydroxyl substituent is occupied by the ester functional group in the derivative compound. Another aspect of the invention is a pharmaceutical composition comprising at least one compound of formula I, formula π, or formula III or at least - a derivative of formula I, formula „, or formula 149868.doc 201118102 ΠΙ compound And - or a variety of pharmaceutically acceptable excipients. In some implementations, it is better to make (4) a combination of drugs (for example, as requested in the United States Interim Request No. 61/22_ on June 24, 2009 The pharmaceutical composition of the present invention is incorporated herein by reference in its entirety as if it has been fully described herein. The other aspects of the present invention and the superior ή ι ιν τ , 70~俅 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 傻 【 【 【 【 【 【 人类 【 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类Other oxidation products of aspinapide and its salts have not been noted, such as the hydrazine compound, but it can be produced by metabolic oxidation when exenatine or its salt is administered to humans. In studies using animal models, the inventors have surprisingly found that hydrGxyasenapine compounds and derivatives thereof of formulas I, II, and III have activity as atypical antipsychotic compounds, which are suitable for use in Therapy for CNS disease is provided to patients in need thereof, for example, for the treatment of schizophrenia, bipolar disorder, or manic episodes associated with bipolar disorder, seizures of stagnation, or mixed episodes. The hydroxy compounds of the formulae I, II and III can be prepared by modifying the known exenatine preparation process, for example, as described in U.S. Patent Application Serial No. 12/341,281, filed on December 24, 2008. A method for the preparation of cilastatin, which is incorporated herein by reference, as it is fully incorporated herein by reference in its entirety, in its entirety, in its entirety, in Preparation of azinapine) 'In general, an appropriately substituted aryl compound can be substituted by the method described in the 28 丨 application (for example, Formula Ha or IHa 149868.doc 201118102. The compounds of the invention are prepared from suitable aryl precursors containing a pendant methoxy substituent at the position in the product compound.

Alternatively, a hydroxyalcinapine compound (e.g., a compound of formula I) can be prepared by direct oxidation of azinapine, for example, acylation of the carbene azide carbon site, followed by, for example, the use of The gas oxybenzoic acid (m_CPBA) oxidizes the resulting ketone to an ester which can be converted to the corresponding alcohol (hydroxyl substituent) by alkaline hydrolysis. In addition, the inventors believe that one or more of the hydroxy substituents of the hydroxyarpineapine compound of the present invention can be converted to a vinegar functional group (e.g., formazan-functional group) as needed to provide a compound having altered metabolism. The activity of, for example, an atypical antipsychotic compound is also provided by dissolving the I1 germ and providing it to the patient in need thereof. Such vinegar-functional compounds may be useful in the preparation of pharmaceutical compositions for the treatment of schizophrenia, bipolar disorder, or bipolar disorder, stagnation episodes, or mixed episodes associated with bipolar disorder. The hydroxyalcinapine compound of formula I, II or III, or a derivative thereof (e.g., an ester derivative thereof), can be combined with one or more pharmaceutically acceptable excipients (e.g., as described in Remington: The Science and Practice 〇fpha café (as in the 21st edition) is mixed to provide a suitable for CNS disease (eg schizophrenia, bipolar disorder, or manic episodes associated with bipolar disorder, depressive episodes or ~ 149868.doc In the treatment of 201118102, the pharmaceutical composition of the compound or the salt of the compound III or a derivative thereof is formed by a general method. s This article uses the term "single-off", which means that the chemical is naturally formed in it: it is obtained from it. The form removed or isolated from the parent is obtained by the use of the term "purified" as used herein, at least about 70% by weight of the intended form. EXAMPLES In the following examples, all reagents are commercially available USP grade items unless otherwise indicated. The following examples are provided to illustrate and not to limit the invention. The zinc-repairing and other methods of solving such methods may be substituted for those of the examples and are still within the scope of the invention. Example 1: Synthesis of Hydroxy Ascipine by Acinapine

Legend of the reaction conditions of Scheme 1: 149868.doc 201118102 (a) Ethyl formate thiophene, reflux: (b) acetonitrile, A1C13, CH2C12' room temperature,

(c) m-CPBA, p-benzoic acid monohydrate, CH2C12, reflux; (d) KOH, EtOH, room temperature; (e) A1C13, LiAlH4, THF, 5 °C Step 1 - Synthesis of compound 2 A solution of gaseous ethyl formate (532 mL, 5.59 mol) in toluene (815 mL) was added dropwise to 1 (245.14 g) in toluene (1900 mL) at room temperature under a nitrogen atmosphere for 30 minutes. ; 858 mmol) in solution. During the addition, a white precipitate and a gas (fluorenyl chloride) were produced from the reaction mixture, and the temperature was raised to 45 °C. The reaction mixture was stirred for 19 hours under reflux and then cooled to room temperature. The resulting solid was removed by filtration. The residue was washed with toluene (1 L), and the filtrate was evaporated to dryness to afford 2 ( 334 g, 976 s s s s s s s s s s s s s s s s s s s s s Chlorination (27.7 g, 207.80 mmol) was mixed in dioxane (220 mL), then acetonitrile (8.14 mL, 114.07 mL) was slowly added at room temperature. The reaction was monitored by TLC (toluene / EtOAc, 8:2) by quenching the sample with saturated NaHC. After 22 hours the reaction was complete and the mixture was poured onto saturated NaCI (350 mL). The organic phase was separated and the aqueous phase was extracted twice with CH2C12. The combined organic layers were washed with aq. NaHC.sub.3, dried over EtOAc. Compound 3 (23.35 g, 60.52 mmol, 80%) was obtained which was used in the next step without further purification. Step 3 - Synthesis of Compound 4 149868.doc 201118102 Add m-CPBA (59.49 g, 344.74 mmol) and p-toluenesulfonic acid monohydrate (11.71) to a solution of compound 3 (23.14 g, 59.96 mmol) heated to reflux. g, 61.56 mmo 1). The reaction was stirred under reflux for 19 hours, then cooled to room temperature and then quenched with water (170 mL). The resulting suspension was poured onto 25% Na2S2O3 (550 mL) and extracted twice with CH2C12. The combined organic layers were washed with aq. NaHC03, dried over EtOAc EtOAc Compound 4 (22.99 g, 57.21 mmol, 95%) was obtained which was used in the next step without further purification. Synthesis of Step Lock 4 - Compound 5 KOH (35.85 g, 639.92 mmol) was added to a solution of Compound 4 (22.99 g, 57.22 mmol) in EtOH (400 mL). The reaction mixture was stirred at room temperature for 3 hours and then poured onto water (400 mL). Concentrated HC1 was added to bring the pH to 1, and some crystals were formed. The mixture was extracted with AcOEt (3 x 2 50 mL). The aqueous layer was filtered to obtain certain products. The combined organic layers were dried over MgS04 and filtered. The solvent was evaporated to about 10% of the original volume and the residue was co-evaporated with toluene (2 x 100 mL). Additional toluene (100 mL) was added and crystallized and filtered. The residue was mixed with the crystals previously obtained from the aqueous layer and dissolved in THF (260 mL). The solid matter remaining in the solution was filtered off, and THF was evaporated to obtain a partial product. The residue on the filter was collected and suspended in additional THF (260 mL). The mixture was stirred at 45 ° C for 30 minutes, filtered and evaporated THF. The combined products were dried in a vacuum oven to give compound 5 (15.23 g, 42.34 mmol, 74%). Step 5 - Compound 6 (target: 11-hydroxyasinapine) Synthesis 149868.doc -10 - 201118102 To a solution of A1C13 (0.895 g, 6.71 mmol) in THF (29 mL) was added to EtOAc (26.5 mL, 1 M THF, 26.5 mmol). After the mixture was mixed for 15 minutes, a solution of the compound 5 (3.43, 9.53 111111 〇1) contained in butyl 11 (34 1111 ) was slowly added to form a suspension. The reaction was stirred at 5 &lt;0&gt;C and was monitored by TLC (CH.sub.2Cl.sub.2/MeOH, 9/1). After completion, the reaction was quenched by dropwise addition of a tartaric acid solution and stirred for 20 minutes. Concentrated HC1 (3 7%) was added until pH = 9, and the mixture was extracted twice with toluene/EtOAc (8/2). The organic layer was separated, dried over MgS04, and evaporated and evaporated. The crude residue was purified by chromatography on EtOAc (EtOAc: EtOAc (EtOAc) • ΗΝΜ^όΟΟ MHz &gt; DMSO-d6) : δ (ppm)=2.45 (3Η) » 2.94 (1Η) » 2.99 (1H), 3.10 (1H), 3.22 (1H), 3.39 (1H), 3.54 (1H ), 6.54 (1H), 6_58 (1H), 7.01 (1H), 7.14 (1H), 7.17 (1H), 7.25 (1H), 9_32 (1H) MS (ESI) m/z : 302 = [M+H ]+ Example 2: Synthesis of 7-hydroxyasinapine

149868.doc 201118102

Scheme 2 Scheme for the reaction conditions of Scheme 2: (a) Org 213361-0 (0.9 eq.), potassium butoxide (22 eq.), THF 'room temperature' 4.5 hrs acetic anhydride (2.5 eq.), room temperature , 15 minutes; (b) trimethylamine N-oxide dihydrate (1.5 equivalents), lithium diisopropylamide (7.7 equivalents) 'THF' room temperature, 3.5 hours; (c) copper telluride (ΐ) (〇) • 3 equivalents), cesium carbonate (1.3 equivalents), N,N-dimethylglycine (〇.3 equivalents), dioxane, reflux, 22 hours; (d) acetic acid (110 equivalents), hydrogen bromide (19 equivalents), reflux, 20 hours Step 1 - Synthesis of Compound 18 Compound 16 in THF (36 mL) was obtained over 20 min at room temperature (according to V. Daukasas, R. Martinkus, V. Kulesius, V. Stelbiene, Zhunal Organicheskoi Khimii, 1983, 19(3), proc. 522-528, prepared by the Dauksas et al.) (7.96 g, 42.68 mmol) solution was added dropwise to THF (40 mL) In the middle of the ΚΟιΒιι solution, the gray suspension turns reddish brown. Compound 17 (11.96 g '38.94 mmol) was taken over 3 minutes (according to J. Kalbitz, E. Leissring, H. Schmidt, Zeitschrift fuer Anorganische und Allgemeine 149868.doc 201118102

The procedure of Kalbitz et al., Chemie, 1994, 620(12), 2041-2047) was added to the reaction mixture and the temperature was observed to rise from 2 ° C to 3 5 C. The reaction was stirred at room temperature for 4.5 hours and monitored by GC. A slurry of acetic anhydride (1 〇 mL) was added and the slurry was stirred for an additional 5 minutes. The reaction was quenched by the addition of 1 M HCl (1 50 mL). The suspension was cooled to 0 ° C and the crystals formed were filtered off and dried in a vacuum oven to afford compound 18 (14.93 g, &gt; 99%). Step 2 - Synthesis of compound 19 Triammonium N-oxide dihydrate (3.12 g, 28.07 mmol) was slowly added to compound 18 (7〇9 g, obtained in Step 1 in THF (50 mL) In a solution of 18.57 mmol), diisopropylation (2 μ THF / ng Gengyuan solution, 71.5 mL, 143.00 mmol) was then added. The mixture was stirred at room temperature and was monitored by TLC (CH.sub.2Cl.sub.2. After 3.5 hours, the reaction was stopped by adding water (100 mL). The resulting emulsion was treated with 4 M HCl to reduce its pH from 11.5 to 9, and then extracted twice with AcOEt. The combined organic layers were rinsed twice with water and treated with brine. The organic layer was dried on MgS(R) 4 filtered and evaporated to dryness. Dissolve the crude product

Concentrated HCl (370/〇, 10.5 mL) was added to EtOH (32 mL). This solution was stirred at room temperature and 1 mL of water was added. The crystals formed were filtered off and dried in a vacuum oven to give Compound 19 (1.49 g, 2%). Concentrated HC1 was added to the mother liquor to a pH of 1 and extracted twice with heptane. The combined organic layers were dried over MgS(R) 4, filtered and evaporated to give additional compound 19 (4 〇3 g, 10.16 mmo, 55%). Step 3 - Synthesis of Compound 20 149868.doc -13· 201118102 At room temperature, cesium carbonate (1.87 g ' 5.73 mmol), hydrazine, hydrazine-dimercaptoglycine (0.13 g' 1.22 mmol) and angstroms Copper (I) (0.25 g ' 1.29 mmol) was added to a solution of compound 19 (1.75 g, 4.42 mmol) in EtOAc (18 mL). The temperature was raised to 97 ° C and stirring was continued for 22 hours. The reaction mixture was filtered through celite and the residue was washed with dioxane. The solvent was evaporated to give compound 20 (1.25 g, m. Step 4 - Synthesis of target compound 21 (7-hydroxyasinapine) Add 1^1*(5 1111〇 to a solution of compound 20 (1.16 g, 3.67 mmol) in acetic acid (18 1111〇) The mixture was heated to reflux temperature (10 ° C.) The reaction was monitored by GC/MS. When incomplete conversion was observed, additional acetic acid (5 mL) and HBr (5 mL) were added. The solvent was evaporated and the residue was co-evaporated three times with toluene. The crude product was dissolved in AcOEt/NH 4 OH (l/l, pH~10) and extracted twice with AcOEt. The organic layer was filtered and evaporated to dryness purified eluting eluting eluting eluting eluting eluting eluting hNMR (600 MHz, DMSO-d6): δ (ppm) = 2.44 (3H), 2.94 (1H), 3.10 (1Η), 3.09 (1Η), 3.22 (1Η)3·39 (1Η), 3.59 ( 1Η), 6.63 (1H), 6.83 (1H), 7.08 (1H), 7.11 (1H), 7_22 (1H), 7.38 (1H), 9.80 (1H) MS (ESI) m/z : 302 = [M+ H] + Example 3: Synthesis of 10,11-hydroxyacenapine 149868.doc 14 201118102

28 Scheme 3 Legend of the reaction conditions of Scheme 3: (a) i) P(〇Et)3 ' 一曱' ii) 5-Chlorohydrazine, k〇1Bu, THF; (b) Tridecylamine N - oxide ' LDA, THF ; (c) CsC〇3, 2,2,6,6-tetramethyl-3,5-heptanedione, vaporized copper (1), 〇]^8; ((1) III"; boron odor, CH2C12. Step 1 - Synthesis of compound 25 2-bromo-2,5-dimethoxygangyl desert 22 (20.0 g, 64.5) contained in p-xylene (20 mL) Methyl) and triethyl phosphite (1〇8, 64 mmol) were heated to reflux' while stirring under &amp; atmosphere for 3 days "cooling the solution to room temperature" and added to THF (375 mL) 5-Chlorohydrin aldehyde 24 (1 〇〇g, 64 mmol '1.0 eq.) solution. Cool the solution to 149868.doc •15- 201118102 Add ΚΟιΒιι (15.68 g, 140 mmol, 2.19 eq. The reaction mixture was stirred at 0 ° C for 1 hr and allowed to warm to room temperature overnight. Water (100 mL) and brine (40 mL) were then weighed and the mixture was extracted with AcOEt (160 mL). Acidified the mixture with an aqueous solution of HC1 (40 mL) and separated the organic layer 'in Na2S〇4 Dry, filter and concentrate in vacuo to give EtOAc (EtOAc:EtOAc) Pure compound 25 (12.8 g, 32.3 mmol, 50%) was obtained as a white solid. Step 2 - Synthesis of compound 26 <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; And a solution of trimethylamine N-oxide (10.93 g, 95.0 mmol, 3.06 equivalent) was cooled to 0 ° C. Then 1.8 M LDA (115 mL, 207 mmol, 6.7 equivalents) in THF was added dropwise over about 15 hours. After stirring at room temperature for 3 days, the reaction mixture was further cooled to 0 ° C, and 1.8 M LDA (34.6 mL, 62.2 mmo, 2.0 equivalent) in THF was added dropwise. After the night, the reaction mixture was neutralized with EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) And precipitated in pentane (35 〇mL). The precipitate was filtered off, rinsed with pentane and borrowed Silica column chromatography ((: 112 (: 12 /] ^ 011,97_5 / 2.5) for further purification to obtain 26 (1.02 g, 2.39 mmo BU 13%) of pure compound as a colorless oil standard. Step 3 - Synthesis of Compound 27 149868.doc .16 - 201118102 'Compound 26 (456 mg, 1.09 mmol) in anhydrous DMA (5 mL) under N2 atmosphere, (711 mg, 2.18 mmol, 2.0 Equivalent) and a mixture of 2,2,6,6-tetradecyl-3,5-heptanedione (40 mg, 0.218 mmol, 0.2 when I) was heated to 150 °C. Copper chloride (1) (43 mg, 0.436 mmol, 0.4 eq.) was added to the suspension and the mixture was stirred for 1.5 hr. The hot reaction mixture was passed through a glass filter and the residue was washed with dioxane (20 mL). Η2〇 (5 mL), 250/〇 NH4OH (20 mL), AcOEt (25 mL), and TBME (25 mL) were added to the filtrate and the layers were separated. The aqueous layer was extracted with 5 mL of TBME/AcOEt (l/l). The combined organic layers were dried over NadCU, filtered and concentrated in vacuo. The brown crude product was purified by EtOAc EtOAc (EtOAc) (EtOAc) Slowly cure. Example 4: In vivo study The ability of compounds of formulas I and II to inhibit amphetamine-stimulated activity compared to acifluorin was investigated in a rat model. The rat model is believed to reflect dopamine receptor antagonism, which is expected to be effective against CNS diseases such as schizophrenia, bipolar disorder, or manic episodes associated with bipolar disorder, seizures, or mixed episodes. . Acinatrine is a novel psychopharmacological agent that acts as an antagonist of the dopamine D2 receptor subtype and various serotonin and adrenergic receptor subtypes, such as M. Shadid Μ and EHF Wong in "Asenapine has Unique human receptor binding signature", World J. Biol Psychiatr 2005; 6 (suppl i): 3〇6, which is incorporated herein by reference to 149868.doc -17- 201118102, as it is fully described This article is general. Such as Mano and Kapur in "Kapur S, Mano D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2003 · 27 : 1081-90" (which is by reference As described herein, as described in the general description herein, it is believed that D2 receptor antagonism or a decrease in dopamine activity is the primary mechanism of action of a drug having anti-schizophrenia symptoms. Functional D2 antagonism can be performed by measuring the inhibition of its ability to act when a rat is stimulated by an indirect (d-amphetamine) or direct (apomorphine) dopaminergic agonist in an open field. Internal evaluation, as described in "Serpa KA, Moore CL, Meltzer LT. Effects of the Novel Psychopharmacological Agent Asenapine on Amphetamine-Stimulated and Spontaneous Locomotor Activity in the Rat, 2006, March 22", which is cited Modes are incorporated herein as if they have been fully described herein. When d-amphetamine is administered to rats, it causes the release of dopamine and results in a substantial increase in mobility or activity (which can be measured by the distance traveled in an open space), such as Marston et al. in "Asenapine effects". In animal models of psychosis and cognitive function", Psychopharmacology (published on May 22, 2009, "springerlink.com" published online before 0033-3 158 publication), which is incorporated herein by reference, As has been fully explained in this article. For example, Roberts et al., "Roberts DCS, Zis AP and Fibiger HC, Ascending catecholamine pathways and amphetamine-induced locomotor activity: Importance of dopamine and apparent 149868.doc -18- 201118102 noninvolvement of norepinephrine, Brain Research 1975; 93 441- 54. ", and Niemegeers CJE, Janssen PAJ in "A systematic study of the pharmacological activities of dopamine antagonists. Life

Sci 1979; 24:2201-15" (both of which are incorporated herein by reference in its entirety as if fully described herein) A metric for D2 antagonism. Using these models, the anti-dopaminergic properties of the selected anazepine hydroxy metabolite relative to azinapine were determined by measuring its effect on the acceleration of amphetamine-induced rat activity. Methods The principles and procedures used in this study were performed according to the 1st Guidelines f〇r the Care and Use of Laboratory Animals. Test animals Male Sprague Dawley rats (Harlan) weighing 13 〇 to 〇 5 〇 g were used. Rats were housed in groups of 5 for 7 to 1 day before the test and rats were weighed 180 to 200 g at the time of the test. Maintain the enclosure in a 12-hour light/dark cycle (6: 0G on, 18: _light). Free access to food and water. Test between 〇〇 and 16 · 。. All rats were fasted overnight before the test. The rats were randomly assigned to (d) or the drug-treated group. Drug Preparation D-amphetamine was dissolved in a 9%·9% saline solution. Dissolve or suspend the test or control drug (asinapine, 11-hydroxyasinapine (compound of formula I), or 7-hydroxyazepine (compound of formula III)) in 丨% crem〇ph〇r EL,1 % 1 N HC and 5% methylcellulose contained in water (which is used as a vehicle pair 149868.doc • 19. 201118102) All test compounds are solutions. The dosage is expressed as the active ingredient (instant test) and the dosage is 5 mL/kg. Test Devices Rats were tested for activity (LMA) using a 16-beam digital scanning animal activity monitor (Accuscan Eiectr〇nics, Columbus' Ohio). Each laboratory consisted of a 16x16x16 inch PLEXIGLAS® box surrounded by an infrared light beam (16/side, 1 inch apart) to measure the activity monitor. Place each box in a stainless steel vented sound attenuating chamber (SAC). The room was illuminated by two incandescent lamps and tested in one mouse per room. Procedure The rats were weighed and administered in a test room. The rats were orally administered (p〇) with a drug or vehicle and then placed in the test chamber. After an adaptation/absorption period (30 minutes), each rat was injected subcutaneously with 丄mg/kg d-phenylisoamine and placed back in the test chamber, then began recording activity 35 liters (lma) within two hours. ' Record every 5 minutes - LMA. The rats were euthanized after the end of the test period. Tests Each test included 4 groups, one vehicle control group and three dose groups. All groups received the same d-amphetamine treatment. Data Analysis The LMA was measured by the number of movements (four) and expressed as the inhibition of LMA measured for the animals of the (four) medium. . The single 2-inch ANOVA and the subsequent Duunett test (using the dose of bamboo ', F Feng early factors, set the ridgeability to p < 0.05) for the complete 2 hour test. w J total moving distance (c 149868.doc) -20- 201118102 Perform statistical analysis. Use jandei sigmastat for statistical analysis, which performs normality and variance test as part of ANOVA.

The Hochbergs evening control program, Fiigner_p〇ijceii〇, is applied to the data for the normality-variance test failure. The original data series is shown in 丨3. Results Subcutaneous administration of 1 mg/kg d-amphetamine (AMP) in vehicle-treated rats stimulated mobility. It peaked approximately 45 minutes after administration and most ended after two hours. In the test, the average total movement distance of the vehicle + AMP treated group was similar, which was between 255 〇 9 and 30 624 during the two hour test period. Aspirin is inhibited by 1 mg/kg AMP (subcutaneously) in a dose-dependent manner of 〇.3 mg/kg (oral) at the lowest effective dose (MED, which is defined as the lowest dose of LMa that produces a statistically significant decrease). ) induced LMA stimulation. The MED dose was reduced by 83 〇/〇 of LMA' compared to the vehicle-treated control group, and the high dose of 〇 mg/kg (oral) was reduced by 97% of lma (Table 4). 11-hydroxyasinapine was found to inhibit LMA stimulation induced by i mg/kg AMP (subcutaneous) in a dose-dependent manner with MED of 1. 〇mg/kg (oral), which was compared with vehicle-treated The control group reduced LMA by 75% (Table 4), and 7-no acenapine was inhibited by 1 mg/kg AMP (subcutaneous) in a dose-dependent manner with MED of 1.0 mg/kg (oral). Induced LMA stimulation was reduced by 39% of LMA compared to the vehicle treated group (Table 5). There is a minimal difference in effect between the 1.0 mg/kg MED dose and the other lowest dose 0.3 mg/kg. The LMA reduction for the 1.0 mg/kg (MED) and 0.3 mg/kg vehicle treatment groups was 39% and 34% (Table 5). In this analysis, approximately 30% of the reductions were 149868.doc •21-201118102 often reached statistical significance. However, in the tests described herein, the reduction caused by 0.3 mg/kg did not reach a significant level at the level of 〇5. Discussion The current treatment of schizophrenia relies mainly on the use of atypical antipsychotics. The common feature of most atypical drugs is the property of dopamine D2 receptor antagonism with moderate to potent serotonergic, adrenergic and muscarinic activities, but aspirin and its derivatives have dopaminergic properties, A novel psychopharmacological agent with serotonin b and adrenaline anti-aging effects, which has a pre-clinical receptor binding profile that binds to the dopamine D2 receptor and a high affinity for various serotonergic and adrenergic receptors. The inhibitory effect of 胄xin benzene# propylamine-stimulated activity is a measure of D2 antagonism and it shows anti-psychotic efficacy. In previous studies, azinazepine was characterized by its ability to inhibit d-amphetamine-stimulated activity after it was administered subcutaneously in rats. The results of these studies showed that azinazepine was similar to the atypical antipsychotic drug 芏金 (萨 (5) anzapine and 必必(四) eHdGne) (iv) and the southern dose of d-amphetamine. In the study of the present invention, the in vivo (1) receptor activity of the cathiconine compound studied in the present invention showed potent inhibition of the potency of diazepam-stimulated rat LMA, and thus showed cardiac therapy and Treatment of CNS diseases (eg, 'schizophrenia, bipolar disorder, or bipolar disorder-related manic episodes, camping episodes, or mixed episodes) associated with activity. 149868.doc 22- 201118102 Table 1 - Inhibition of activity capacity of azinazepine Test time after administration of d-amp (minutes)

Vehicle control group PO

Asinapine 0,1 mg/kg, PO

Aspirin 0.3 mg/kg, PO mobile CM (mean)

SEM moving CM (mean)

SEM moving CM (mean)

SEM

Ashenapride 1.0 mg/kg, PO mobile CM (mean)

SEM 050505050505050505) 0) 50520 1122334455667788991010ππ12 886544369293129815269763995964865644373348 18467483101417171818181761491251161089661817157454231 97869757596153586 3 396 ^ 0746192415044228 ^ 902 4967464474945398389801014118511541122110411791023958977836819793742666663545611 150186ss128216244240260244228230183170175 ^ 110116102124105130w 3 4 5 0 * 3489939364758142458 240 ^ 635017794921903567840 11 111122121222122211111 608738052458322054027952 561444357444965467743453 13 9 3 2 3 3 6 4- ο 5 8 3 4 ο? 4 2 9 9 3 4 8 5 4 ( 12 1 -34125535949324142 9061213112243918332715335212715141592111 CM of data system movement = average number of centimeters moving within five minutes; N=8 Table 2-11 - Inhibition of activity by hydroxyasinapin D-amp vehicle control Π-jing Ϊ: Axiana $ 11 - test time after kealoxipine II hydroxyaroxibine _PO_0.1 mg/kg, PO_0.3 mg/kg , PO_1.0 mg/kg, PO (min) Moving CM SEM Moving CM SEM Moving CM SEM Moving CM SEM (Average) (Average) (Average) (Flat Number) 5101520253035404550556065707580859095100105110115120 as 2475438221125146118571877191717161658114311329110859461031923626589582313373 31988088107901591201361101507711294139168183190168951781498686 I 468436256269068424371130622713445: 2230304484113132166156150138142133121231068482797650503341 6311050761212163172942452902092382631851981741599684132931094976 42171055076078,8210036904859129 20354152749512014512714013813811111092847179555941454230 139948977146163205171145150142160186951121191116463125716790 2 8 175721680833461566015404 ^^ 474523000005157105748 (ί112222333443432342222 443627,2,910} 8692884130} 28585 643547nn11K998797898lc763 7 of the mobile data-based CM = Mean centimeters moves within five minutes; N = 8 149868.doc •23- 201118102 Used as a restraining force to move to the Pingnaisiaki I between ¥ -7 7 d 1 3-颂I Table 4 after the group | Photo 3 for the P0 agent

The mean shift and shift of My LC number I is flat SJ base mg -M0.1 Pinnaxi k:, i base mi hydroxy 0. 101520253035404550556065707580859095100105110115120 1:650666^13621607168116641655166211407142412851216944949^914710 certificate692527753806333334583549 03031143243599219952633 11112222222221221111111 832500168838435531004780223078718)86414587333730 18375901316182020201917191715131310109478836353 均7-hydroxyl a.Omg/ke. Ρη SEM~~ (Average) 5 6 J 9 3 9 3 ό 5 6 9 3 7 4 2 4 9 1 5 6 5 5 8 ^30337680068605552133943 ^65765992010666536138777 ^80^12091753578906459^ /12 611911212222222222111- 1 1 11413338359743342ΐ636807479344870 154247698710311813511712312411410310894978984695770475935 141|44556083696811431231123711621087_103810938389057808306255355234448443337 34101113681151541231701531631611461641741718117710688114709767111 Data system moving CM=average number of centimeters moving within five minutes; N=8 Table 4 - Aspirin and warp against inhibition of stupid isopropylamine-stimulated activity Comparison of doses of keasiatin

Dosage (ms/kg.p〇) azinapine η-hydroxyasinapine 7-hydroxyazinapine agent 0.1 0.3 1.0 25509±2774 (0.0±10.9) 19929±3174 (21.9±12.4) 4429± 678 (82.6±2.7)b · 7.9±172 (97.2±0.7)6 25555士1698 (0.0±6.6) 21945±3035 (14.1±11.9) 19538±1888 (23.5±7.4) 6498±1352 i74.6±5.3&gt ;b 30624士3693 (0.0±12.1) 26050土3132 (14.9±1〇·2) 20158±4047 (34.1±13.2) 18562±2200 Π9.4+7 Bold part=Minimum effective dose (MED) The LMA a data is the average number of centimeters ± SEM within 120 minutes; (the average hundred lbs b reduced from the control group versus the vehicle control ρ &lt;0.05; one-way ANOVA) It is intended that the above description of the invention is illustrative. Various changes and modifications may be made to the embodiments described herein, and such changes may be made without departing from the scope or spirit of the invention. -24· 149868.doc

Claims (1)

201118102 VII. Patent application scope: 1. An isolated compound of formula I, II, or III, 2. An ester derivative of a compound of formula I, II, or III. 3. A pharmaceutical composition comprising at least one of the following: (i) a compound of formula I, II, or III 149868.doc 201118102 HO HO Formula III; (ii) an ester derivative of a compound of formula I, II, or III, or or (ii) a salt of the compound, and one or more pharmaceutically acceptable excipients. 4. A method of treating schizophrenia, bipolar disorder, or manic episodes, depressive episodes, or mixed seizures associated with bipolar disorder comprising administering a pharmaceutical composition according to claim 3. 149868.doc 201118102 IV. Designated representative map (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the characteristics that can best show the invention. Chemical formula: 149868.doc