TW201041857A - Stable forms of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide - Google Patents

Abstract

Polymorphic forms of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramicle are provided together with a process for the manufacture of said compound.

Description

201041857 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to N-(2,6-dimethyl-4-indolyl-4-yl-phenyl)-3,3-di which has improved properties A specific crystalline form of methyl-butanamine. [Prior Art] The compound N-(2,6-dimethyl-4-morpholine-4-yl-phenyl)-3,3-dimethylbutanamine is disclosed in WO 2005/087754, WO 2007/ 090409 and W0

国际 International Patent Application No. 2009/015667. This compound is an opener of the KCNQ family of potassium channels and is therefore suitable for treating diseases that are responsive to the opening of their channels. More than 70 human genes encode potassium channels, and the family is a family of specific potassium channels containing five members (KCNQ1-5). Based on its extensive performance in the middle sacral nervous system (CNS), this family represents a drug development goal worthy of attention. In fact, the mutations in the KCNQ2 and kcn(1) channels seem to cause a hereditary form of epilepsy called the $familial neonatal convulsion. Retigabme, a compound of KCNQ2 & KCNQ3 if opener, has also been reported to successfully reduce the frequency of seizures in clinical trials [A^wro/., 68, 1 197-1204, 2007]. # Oral dosage forms and especially (iv) 1 常常 are often preferred forms of administration for patients and physicians due to ease of administration and better compliance. For the preparation of tablets, the f-component is preferably crystalline. The compound which exists in a crystalline form may exist in more than one form, i.e., a polymorph. The polycrystalline form can have different properties as the applicability of the drug as a drug. In particular, the polymorphic Form 201041857 can exhibit different properties, such as enthalpy, enthalpy, solubility or dissolution rate, and the need to optimize for drug development. The present invention relates to polymorphs having improved f < Ν_(2,6-dimethyl-4-inocyl-4-yl-phenyl)·3,3 dimethyl-butanamine. SUMMARY OF THE INVENTION The present inventors have discovered that the free base of Ν_(2,6-dimethyl-4-inorganin-4-yl-phenyl)_3,3-dimethyl-butanamine is crystallized. The particular polymorph has an excellent stability and/or dissolution rate. Thus, in one embodiment, the invention relates to ν_(2,6-dimethyl-4-morpholine-4) in crystalline form with XRPD reflection at 1〇36, 12 67, 28.64 and 29.89 (.20) -Base-phenyl)-3,3-dimethyl-butanamine free base. In one embodiment, the present invention relates to ν-(2,6-dimethyl-4-morpholin-4-yl) in crystalline form having XRPD reflection at 8.68, 18.09, 22.60, and 30.62 (.20). • Free base of phenyl)-3,3-dimethyl-butanamine. In one embodiment, the invention relates to ν_(2,6-dimethyl-4-morphin-4-yl-benzene in crystalline form at 8.63, 22.26, 23.40, and 30.49 (2 〇 having XRPD reflection) Free test of -3,3-dimethyl-butanamine. In one embodiment, the invention relates to a pharmaceutical composition comprising a polymorph of the invention. In one embodiment, the invention is Regarding a polymorph of the invention for use as a medicament, in one embodiment, the invention relates to a polymorph of the invention for use in the treatment of a disease selected from the group consisting of: seizure disorder, schizophrenia Disease, depression and bipolar group spectrum disorder (bipolar 201041857 spectrum disorder) 〇

In one embodiment, the invention relates to a polymorph of the invention for use in therapy. X In a specific example, the invention relates to a method of treating a disease which would benefit from the opening of the potassium channel of the KCNQ family, comprising administering to a patient in need thereof a polymorph of the invention. In a specific example, the present ..., m π will benefit 〇

A polymorph of the invention of a disease in which the potassium channel of the KCNQ family is open. In one embodiment, the invention relates to the use of a polymorph of the invention for the manufacture of a drug that will benefit from the opening of the KCNQ family of potassium channels; In a specific example, the present invention relates to a process for producing N-(2 6-methyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butanamine. [Embodiment] Next. The present invention relates to a free form of N-(2,6-dimercapto-4-inmorpholin-4-yl-phenyl)3 decyl-butanamine. The molecular structure thereof is described in 3

〇0Ν Each of these polymorphic forms is referred to as a polymorph of the present invention.

In a specific example, the invention relates to a crystalline form of the polymorphic form referred to herein as I, 〇-mercapto-4-morpholine-4-yl, -3,3-di Ketobutanamine, which is at 1.36, 12 bases) • b7 28.64 and 29.8%. X-ray powder diffraction (XRPD) reflection is shown under 2〇 5 201041857. The alpha form of XRDp is shown in Figure 1. As shown in the examples, the oxime: form has the lowest solubility (of the polymorph of the invention) and thus the observations can be inferred to be the most stable form. In one embodiment, the invention relates to crystalline N-(2,6-dimercapto-4-methyllin-4-yl-phenyl)-3, which is referred to herein as a polymorphic form of the 0 form. , 3-dimethyl-butanamine, which exhibits XRPD reflection at 8 68, 18 〇 9, 22 6 〇 and % 62 (° 2 Θ). The XRDp of this Lu form is shown in Figure 2. As shown in the examples, the exhaust form has an intrinsic dissolution rate higher than the alpha form so that the 0 form is expected to enter the solution faster in the gastrointestinal tract than the alpha form and thus may act sooner. In one embodiment, the invention relates to a crystalline Ν-(2,6-diindenyl-4 morpholino-4-ylphenyl)_3,3_ in a polymorphic form referred to herein as the gamma form. Mercapto-butylamine, which exhibits tf XRPD reflection at 8 63, 22 26, 23 4 〇 and 3 〇 49 (. 2 〇. XRDp in the ω γ form is shown in Figure 3. As shown in the example & The gamma form is characterized by a faster intrinsic dissolution rate and is therefore expected to enter the solution faster than the alpha form and the cold form in the monthly intestinal tract and thus may act sooner. The synthesis Ν-(2) disclosed in 〇W〇2005/087754 , 6-dimethyl: phenyl) 3'3-dimethyl-butanamine, and the polymorph of the invention may not be prepared as in the examples. Alternatively, Ν-(2 6 - ® ,--methyl-4-morpholine_4_yl-phenyl)_3,3-dimercaptobutylamine can be produced by the following method, preferably in the presence of A such as Na2C03. Under the solvent, a halogen-halogen, 2,6-didecyl-aniline (such as 4-bromo-2,6-methyl-aniline) is reacted with 33 _, - fluorenyl-butane, to obtain V -(4-bromo-2,6 201041857 dimethyl-phenyl)-3,3-dif-butylamine or phase 4-dentin compound. Thus, in one embodiment, the invention relates to the manufacture of n-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-di-f- A method of butaamine, which comprises reacting 4-dentin-2,6-dimethyl-aniline with diindoyl-butanyl chloride in the presence of a test. In a specific example, under stirring and a nitrogen atmosphere, In an amount of 1 eq. I.1 equivalents of 3,3-dimethyl-butane chloride, and stirring is continued until the desired degree of conversion has been achieved. The resulting compound can be treated by phase extraction and recrystallization. Subsequently, in the presence of a palladium catalyst and a base, The compound (or the corresponding 4-halogen compound) is reacted with morpholine to obtain N_(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butan Amine. Thus, in one embodiment, the invention relates to a process for the manufacture of N_(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butanamine , which is contained in the presence of a palladium catalyst and a base to make ruthenium (4_halogen_2,6_two曱-Benzyl G-based)-3,3-dimethyl-butanamine (such as 4-acting compound) is reacted with morpholine. The palladium catalyst consists of a palladium source and a phosphine ligand. Suitable palladium sources include different oxidation states. Examples of sources that can be used in the method of the invention are Pd2(dba)3, Pd(dba)2 and pd(〇Ac)2. Dba represents the di-subunit acetone and OAc represents acetic acid vinegar. In particular, pd(dba)2 can be mentioned. A source of 0.1-10 mol-%, such as 〇1] m 〇 1%, is typically used. Throughout the present application, 'mol-% is calculated relative to the finite reactants. Many phosphine ligands are known, including monodentate and bidentate. The phosphine ligand for it includes 2-(2-dicyclohexylphosphinophenyl)_N,N-dimethylaminolamine 201041857 (DavePhos), racemic 2,2'-bis-diphenylphosphino. Ij,]binaphthyl (rac-BINAP), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), bis-(2-diphenylphosphinophenyl)ether (DPEphos), three Tert-butylphosphine (Fu's salt), biphenyl-2-yl-di-tert-butyl-phosphine, biphenyl-2-yl-dicyclohexyl-phosphine, (21-dicyclohexylphosphino) Biphenyl-2-yl)-dimethyl-amine, [2, _(di-t-butyl-phosphino)-biphenyl-2-yl]-dimethyl-amine and dicyclohexyl_(2 ,, 4',6'-tripropyl-biphenyl-2-yl)-phosphine. Further, a carbene ligand such as 13_bis-(2,6-diisopropyl-phenyl)-3H-imidazole-1-rust; a vapor compound may be used in place of the phosphine ligand. In one embodiment, the phosphine ligand is DavePhos. The lignin ligand is typically added in an amount of from 0.1 to 10 mol-%, such as from 0.1 to 1 mol-%. Addition to the reaction mixture to increase the pH. In particular, bases selected from the group consisting of NaO(t-Bu), KO(t-Bu) and Cs2C03 are suitable. Organic bases such as ι,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) may also be suitable. Mention may in particular be made of NaO(t-Bu) and KO(t-Bu). It is typically added in an amount of from about 1 to 5 equivalents, such as from 1 to 3 equivalents. In a specific example, '0.1-0.5 mol-% (such as 0.25 mol-%) Pd(dba)2 and 0.1-1 mol-% (such as 0.5 mol-%) DavePhos, 1 equivalent 7V-(4-bromo- 2,6-Dimethyl-phenyl)-3,3-dimercapto-butylamine and 1-2 equivalents (such as 1.6 equivalents) of Na(Oi-Bu) and such as dimethoxyethane (DME) The solvent is mixed 'subsequent to the addition of morpholine and the reaction is allowed to proceed until the desired degree of conversion is achieved. The final product can be treated using phase extraction and recrystallization, and the final polymorph form can be determined by the solvent used. As shown in the examples, recrystallization from water will result in a Q! form. As discussed above, 'KCNQ potassium channel openers have been shown to be suitable for 201041857 treatment of seizures, as the polymorphs of the invention are useful for the treatment of acute seizures, delirium, persistent epilepsy and epilepsy, such as epilepsy syndrome and epilepsy attack. As shown in the Examples, a number of related preclinical models indicate that the polymorphs of the present invention are useful for the treatment of psychotic and affective diseases or conditions. Psychiatric diseases include schizophrenia. Symptoms of schizophrenia fall into four categories: positive, negative, cognitive, and affective, such as camp symptoms. Positive symptoms are one or more of the symptoms of "super" normal behavior, such as hallucinations, delusions, thinking disorders, misinterpretation or exaggeration in language and communication, speech confusion, behavioral confusion, and mental agitation. Negative symptoms indicate symptoms of lack of normal behavior in patients such as blunted affect, aphasia, social disability (sociality), lack of interest (anhedonia), lack of willpower (av〇) Mi〇n ), emotional withdrawal, abstract thinking (difficuUy in abstract thinking), lack of spontaneous (lack spontaneity), stereotyped thinking (stereotyped thinking), lack of speech (al〇gia) and attention to stress disorder One or more of (attenti〇nal impairment). Cognitive symptoms refer to cognitive deficits in schizophrenia, such as lack of one or more of sustained attention, executive function, and memory loss. Affective symptoms of schizophrenia may include depressive symptoms such as general depression, lack of interest, sleep disorders, psychomotor agitation or retardation, sexual dysfunction, weight loss, difficulty concentrating, 2 thoughts Concepts, prostration, lack of value, repetitive death thoughts or suicidal thoughts, depressive symptoms in schizophrenia appear to be associated with general adverse treatment outcomes and have a relatively frequent incidence rate estimated at 25_6〇% 201041857 (Montgomery Λ van Zwieten-Boot, Eur Neuropsychopharmac〇l 2007, 17, 70-77:^ 'Schizophrenia can be subdivided based on clinical conditions. The paranoid subtype of schizophrenia is characterized by significant paradox in the context of cognitive function and relative preservation of emotions. Or auditory hallucinations, words and behaviors are chaotic, dull or inappropriate: for: the basic characteristics of the schizophrenia chaotic subtype. The schizophrenia stress subtype is characterized by a significant spirit that can involve athletic rest and excessive movement. Second movement disorder. Finally, the remaining subtypes of schizophrenia are characterized by a lack of Positive symptoms. Affective disorders include conditions characterized by emotional disturbances. Therefore, such as major depression, sexual affective disorder, (4), mild depression, and transient recurrent depression Symptoms and bipolar group-type disorders such as dimorphism, type II bipolarity, and circulatory affective disorder are classified as affective disorders. Major depression is a relatively high incidence in the general population. Chronic recurrent disease. The disease is classified as depression. The progression of clinical conditions is characterized by lack of symptoms, sleep disorders, psychomotor agitation or retardation, sexual dysfunction, weight loss, difficulty in concentration and delusions. The most serious complication of depressive episodes is suicide mi suicide attempt (DSMIV, Ameriean psyeiJtric

Association, Washington D.c_ 1994). In addition to major depression, other conditions are characterized by (4) mood, such as low-lying emotional disorders, depressions not listed, mild depression, and recurrent transient depression (dsmiv· American Psychiatric Association, Washington DC 1994) 〇 Low-lying emotional disorders are distinguished from major depression by severity, chronicity, and persistence. Low-lying emotional disorders are characterized by chronic depressions that have been present for many years, 201041857. The category of "not listed separately _, t 夕 出 出 」 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 》 Coarse depression and recurrent transient depression. The basic features of mild depression are the same duration of performance in major depression, but involving fewer symptoms; g h, and one or more periods of depressive symptoms of minor injuries. The recurrent short-term depression is characterized by the same number of times and severity as the recurrent episodes of depressive episodes with the same performance in severe depression and shorter duration of life. Ο ❹ Bipolar group spectrum disorder (formerly W horse & depression) is a group of depressive symptoms S has at least one manic, mild mad or mixed episode of affective disorder. The red madness is characterized by abnormalities and -η _. The different periods of emotions such as continuation, bloating or irritability. Mixed episodes of seizures The prosthetic fit Μ is characterized by a period of at least one week that satisfies the onset of manic episodes and major depressive episodes. Similar to the manic episode, the mild 3 madness is characterized by the presence of η π V. However, there is no difference between a mad sputum and a singular episode compared to a mild manic episode of treatment without the presence of a psychotic characteristic injury or the need for a hospitalized severely suppressed episode. = Symptoms and characterization The initial diagnosis is due to major depression (4). Mm (4) The most mixed type or light-weight jin, and manic, different diagnosis. ^断', and severe depression Bipolar group spectrum disease can be further divided into the first extreme disease, circulatory affective disorder and double: the syndrome of the younger type of bipolar syndrome is characterized by the diarrhea. Type I double TV and ancient or evening = human mad or mixed type seizures and a sepal a also has - or multiple severe depressive episodes. The first and individual ten-learn bipolar syndrome is characterized by 11 201041857 One or more major depressive episodes with at least one mild manic episode. Due to the progressive nature of Type I and Type II bipolar disorder, patients who are untreated have an increased risk of recurrence of symptoms with each new episode and a greater risk of increased duration and severity of subsequent episodes. . To this end, patients with Type J and Type II bipolarity may eventually be classified as a fast-circulating patient, where the patient experiences at least four episodes per year. Circulatory affective disorder is a subgroup of bipolar syndromes characterized by chronic volatility affective disorders involving a number of mild manic periods and periods of depressive symptoms. Bipolar disorder, not elsewhere listed, refers to a class of disorders that have bipolar characteristics but do not meet the criteria for any of the listed bipolarities described above. Bipolar group spectrum disorders are life-threatening conditions' because the risk of suicide in patients diagnosed with bipolar disorder is estimated to be higher than -^ ^ 1 5 Harris ^ Barraclough, 1997, British Journal 吖/^/π· kiss, Ι70:205·228)β Currently, bipolar group-spectrum-type disorders are treated by maintaining the use of mood stabilizers (mainly clock or anti-epileptic drugs) in patients with bipolar disorder, and when the patients relapsed wildly or When you have a seizure, add anti-manic arsenic I (clock or antipsychotic) or anti-depression Qi! (Tricyclic antidepressants or selective serotonin reuptake inhibitors) (eg such as bribery and Goodwm, CW.~2〇〇4, 6:459 65). It is therefore desirable to develop new therapeutic treatments for bipolar group spectrum disorders to meet the need for effective treatment of all three key elements of such disorders with only one therapeutic agent: these novel agents should preferably be rapidly initiating Time to alleviate manic symptoms (anti-manic activity), to reduce the symptoms of depression (anti-depressant activity) with a rapid onset of action to prevent mania and relapse of depressive symptoms (emotional stable activity). Thus, in a specific embodiment, the invention relates to a method of treating a disease selected from the group consisting of a seizure disorder, a psychotic disorder (such as schizophrenia 'inhibition disorder and 12 201041857 bipolar group spectrum disorder), the method comprising The patient is expected to have an effective amount of the polymorph of the invention. χ In need - In the specific case, any of the above diseases is yet to be diagnosed as having the disease. The polymorphic form of the invention having the most "therapeutically effective amount" refers to an amount sufficient to cure, alleviate or partially suppress: the clinical manifestations of the disease and its complications in a therapeutic intervention. The 晋 疋 * 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 「 。 。 The effective amount of each purpose will be determined by the degree of disease or injury and the weight and general condition of the individual. The 7-gauge experiment should be constructed by constructing a matrix of values and (iv) using appropriate doses. It is true that the difference between i and r is achieved within the general skills of the trained physician. In this article, the terms "disease", "disorder" and "synonym use. ^" are used as 〇H = The term "treatment" means to combat silk (such as disease = disease and management and care of the patient. The term is intended to include the full range of treatments for a given condition, such as administration of activity: a compound To alleviate symptoms or complications 'to delay the progression of a disease, disorder or condition = to alleviate or alleviate symptoms and complications, and / or to cure or eliminate the disease, disease = or condition, and to prevent the disease, wherein prevention should be understood as To combat the disease: the management and care of the patient with the condition or condition and including the activation of the disease: to prevent the onset of symptoms or complications. Nevertheless, prevention (prevention =,) and therapeutic (treatment of the more) 4 is the invention The patient is preferably a mammal, especially a human. The treatment of the invention will typically involve the daily administration of the polymorph of the invention. This may involve once daily or daily administration. Injecting twice or even more frequently 13 201041857. In the specific example, the present invention relates to a crystal form system in a method of about iqin ancient... wherein 忒多克克7日与25〇mg Amount between /day, such as about 1 * g / day, such as,,,,, 1 n ^. about 2.5 mg / day, such as about 5 mg / day, such as about 10 mg / day, such as About 50 mg/day, such as hydrazine or about 250 mM/g + brother. In one embodiment, the polymorph of the invention can be administered as the sole therapeutically effective compound. In another embodiment, Taigong aa + n n, a multi-day type of hair can be administered as one of the combination therapies, and the polymorph of the present invention can be combined with one or more others, for example, an anti- The invention relates to a medicine which is a combination of a therapeutically effective compound which is active in the production of erythromycin or sputum. The polymorph of the present invention may be administered alone or in combination with a pharmaceutically acceptable agent or diluent in an earlier dose or in multiple doses. The pharmaceutical composition of the present invention may be according to conventional Remington: The Science and PracUce of Pharmacy. 19th edition, Gennar, ed., pubHshing c〇, E_n, μ, the technology disclosed in the state) 'with pharmaceutically acceptable carriers or diluents and any other known adjuvants Or mix with excipients. The pharmaceutical composition of the present invention may be specifically formulated to be administered by any suitable means such as orally, transrectally, nasally, transpulmonarily, locally, intravitally, sublingually, percutaneously, in the cerebral cistern, Intraperitoneal, vaginal or parenteral (including sublingual, intramuscular, intrathecal, intravenous and intradermal) routes, oral route to slaves. It should be understood that the preferred route will depend on the general condition and age of the individual to be treated. The nature of the condition or disease to be treated and the active ingredient chosen. However, the polymorphs of the invention are especially suitable for the preparation of solid dosage forms, such as troches. 14 201041857 Polymorphs of the invention and pharmaceutically acceptable The pharmaceutical compositions formed by the combination of the received carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The compositions are preferably presented in unit dosage form using methods known in the pharmaceutical art. The pharmaceutical composition may be a solid or a liquid. Solid dosage forms for oral administration include, for example, capsules, lozenges, sugar-coated pills, pills, buccal tablets, Zhengzhou and Zhishou Li], such as in the form of powder or pellets. The gelatin capsule is, for example, in the form of a sugar-coated tablet or a buccal bond. Where appropriate, the pharmaceutical composition for oral administration can be prepared with a coating (such as an enteric coating), or it can be subjected to a method well known in the art. Formulated to provide controlled release of the active ingredient (such as sustained or extended release). Liquid dosage forms for oral administration include, for example, solutions, emulsions, suspensions, syrups and elixirs. The compositions of the present invention suitable for oral administration may be, for example, capsules or granules. The discrete unit forms are presented, each containing a predetermined amount of the active ingredient and may include suitable excipients. In addition, the formulation which can be used orally can be in the form of a powder or granule, a solution or suspension in an aqueous or non-aqueous liquid. Or in the form of an oil-in-water or water-in-oil liquid emulsion. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile j solutions and various organic solvents. Examples of solid carriers are lactose, clay, limonene, cyclodextrin. , talc, gelatin, loam, pectin, acacia, magnesium stearate, stearic acid, low-alkyl ether of cellulose, corn starch, horse starch, gum and Analogs. Examples of liquid carriers are syrup, peanut oil, eucalyptus oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. The carrier or diluent can include any sustained release material known in the art, such as Glycerol monostearate or distearate alone or mixed with a wax 15 201041857 Glycerin s. Any adjuvant or additive commonly used for such purposes (such as coloring agents, flavoring agents, preservatives, etc.) may be used, The restriction is that it is compatible with the active ingredient. 25 mg to about 1 g. The release agent and then the amount of the solid carrier may vary, but will generally be about by mixing the active ingredient with a common adjuvant or The mixture is compressed in a tablet machine to prepare a tablet. Formulations are preferably presented in unit dosage form by methods known to those skilled in the art. Typical units of oral or multiple times per day (such as 1 to 3 times daily) The dosage form may contain from about 1 to about 1000 mg, such as from about 1 to about 1 mg, preferably from about 0.05 to about 500 mg, and more preferably from about 5 to about 2 bar. For parenteral routes (such as intravenous, intrathecal 'intramuscular and similar routes of administration), the typical dose is about one-half of the oral dose. In a particular embodiment, the invention relates to a polymorph of the invention for use in the treatment of a disease selected from the group consisting of seizures, schizophrenia, depression, and bipolar group spectrum disorders. In a particular embodiment, the invention relates to the use of a polymorph of the invention for the manufacture of a medicament for the treatment of a condition selected from the group consisting of seizures, schizophrenia, depression and bipolar group spectrum disorders. All references (including publications, patent applications, and patents) cited herein are hereby incorporated by reference in their entirety in their entirety in their entirety herein in theties 'And all of its contents are set forth herein (maximum extent permitted by law)', regardless of whether any incorporation of a particular document is provided separately elsewhere herein. The use of the terms "a", "an" and "the" are used in the context of the present invention. For example, unless otherwise indicated, the phrase "the compound" is understood to mean a variety of aspects of the invention or particular description. All of the precise values provided herein represent corresponding approximations, unless otherwise indicated (for example, all of the exemplified values provided for a particular factor or measurement result may be considered as providing a corresponding approximation of the "about" modification as appropriate. Measurement results). Unless otherwise stated or apparently inconsistent with the circumstances, the use of such as "including", "having", "including" or "containing" is used in the context of "any" or "inclusive". Describes the intention to help say Ge-(4): to form one or more elements "composition", "substantially" from "specific" or "elemental" elements "composed" or "substantially" to a similar aspect or mode of the invention. For example, the situation is contradictory. Otherwise, the description of a composition containing a specific element is also understood to also describe the composition of the element. Example l Use ί to use calibration * 5 ° / mln TA - Instr ~ s ^ Sit line difference (four) heat (5)

The melting point is used as the starting letter. Αβ名.ώ J ,^ . 9 Under motion, heat about 2 mg of sample in 5Vmin in a loose sealing disk. β (10) χ ^ 末 绕 绕 绕 绕 ( 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用 利用The diffractometer allows Xiao Xing to shoot and measure. Use the detector to measure the sample in the reflection mode in the range of 5_4〇1 17 201041857. All values are ±0.1. . Dimethyl-4-morpholin-4-yl-phenyl)_3,3-dioxime Example 1. N-(2,6-yl-butyramine, or form N-(4-)$; - 2, 6-

Dimercapto-phenyl)-3,3-dimethyl-butanamine

Br

Na2C03, room temperature. (THF)~

300 g (l.5 mol) of 4_molyl,6-di-benzidine and 239 g (2.25 (10) of 1.5 eq) of sodium carbonate in h25 L hydrogen flunan were collected under nitrogen atmosphere at room temperature. liquid. After 1 hour, add mL (mol 1 Λ) 3,3-dimethylbutane gas over a period of 2 hours while maintaining the temperature below 3 (TC ' and then at room temperature (d) for 2 hours. Add 21 [ Tetraaminopyran and 3.6 L of water 'to obtain complete phase separation. Extract the aqueous phase with 2 il tetrahydrogenated bite' and wash the combined organic phase with 1.5 L0_5 MNa2C03 aqueous solution. The solvent was removed from the organic phase and the force was added σ 21 L-Hept was calcined to the obtained solid. The suspension was warmed to (d) and allowed to cool to room temperature. The solid was taken out and washed with 300 mL of heptane. Synthesis of N-(2,6-dimethyl-4-? Porphyrin_4_yl-phenyl)_3 3 dimethylbutazone

Pd(dba)2

DavePhos

NaOf-Bu (DME) 201041857 Add 1.44 g (2.5 mmobu 0.0025 eq) bis-dibenzylideneacetone _ and 1.97 g (5.0 mmol, 0.005 eq) DavePhos, 298 g (1 ·0 mol ) #-(4 -Bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramine and 154 g (16 mol, 1.6 eq) sodium tributoxide to a nitrogen-filled three-necked round bottom flask Add 2.0 L DME. 13 1 mL (1.5 mol, 1.5 eq) morpholine was added and the reaction mixture was warmed to reflux for 2-3 h. 3. 〇 L water was added and the resulting suspension was allowed to be left overnight. The solid was filtered off and washed with 1. L water. The solid was dissolved in 3 L of an aqueous solution of hydrochloric acid together with 40 g of charcoal under reflux. After refluxing for 15 hours, the warm reaction solution was filtered through a filter aid and the filter was washed with 1.0 L of warm water. The aqueous phase was washed sequentially with 1.0 L of ethyl acetate and 1 〇 L toluene. After phase separation, the aqueous phase was added to 690 g 27.7 °/ with vigorous stirring. In the aqueous sodium hydroxide solution (pH 12-13), a precipitate was produced. The resulting solid was filtered and washed with water (2.0 L). The solid was dried in a vacuum oven at 4 ° C for 72 hours to give the title compound. (hplc purity: 99.9% (area)' XRPD diffraction pattern: 〇: polycrystalline plastic). Example 2_ N-(2,6-Dimethyl-4-morphin-4-yl-phenyl)-3,3-dimercapto-butylamine, in the form of 10 ° C / min The heating rate is heated to the alpha form to 17 ° C to obtain the /5 form. Example 3· N-(2,6-dimercapto-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butanamine, γ form dissolved by 70 ° C 1 g of Ν-(2,6-dimercapto-4-morpholin-4-yl-phenyl)-3,3-dimercapto-butanamine was obtained in 3 ml of acetic acid to obtain the γ form. After the addition of 6 ml of water (70 ° C) slowly, the γ form was precipitated. 19 201041857 The following table summarizes the α form, /3 form of N-(2,6-dimethyl-4-morpholine-4-yl-phenyl)-3,3-dimethyl-butanamine free base and The nature of the gamma form. Polymorphic form Thermal properties / enthalpy start (dark melt) Solubility in water at room temperature at pH 7.4 Intrinsic dissolution rate (37 ° C) mg / / cm 2 / min a 0. When heated at 5 C/min, the endothermic reflection at about 150 °C on the DSC was converted to |3 0.06 0.021 β S coverage at 236·9 C. When exposed, it sublimes at about 200 ° C 0.13 0.026 7 4 complex i two. When exposed, it sublimes at about 200 °C. A small amount of sputum was observed at about 145 ° C before melting. 0.13 0.036 polymorphic form

Stable rabbit ^2 is stable in 95% of the phase, day Example 4. Rat electrophysiology journal has shown that *gas inhibits spontaneously active dopaminergic in the ventral tegmental area (VTA) (ie, the midbrain limbic system) The number of guiding neurons may demonstrate the antipsychotic potential of the compounds (Chi〇d〇 and Bunney m3, ^ 5' 2539-2544). In the midbrain limbic system, all clinically used psychotropic inhibitors initially increase the firing rate of dopamine-induced neurons (Tung #Λ, 199!, j. Neural Transm ~'·, 84 (1 -2), 53-64). After long-term administration, these mental inhibitors eventually reduce the trigger rate to less than the pre-treatment level (after #3_4 weeks)

(Skarsfeidt 1992, Synapse, 1〇, 25_33; position (6) and i9J 20 201041857

Sczewce, 221, 1054-1057). The inhibition of dopamine-induced neurons mediated by depolarisation blockade is believed to have therapeutic implications for the antipsychotic effects of psychotropic inhibitors (Grace and Bunney 1986, £ 238, 1092-1100). By inferring, compounds that cause a sharp decrease in the spontaneous trigger rate of dopamine-exciting neurons at the midbrain margin are expected to have a rapid onset of anti-psychiatric potential. The presence of KCNQ subunits on t>A neurons in VTA in rodents has been well documented, but its functionality is unknown (Saganich et al., 2〇〇j, Ο 21(13) 4609-4624; Cooper et al., 2001 , #(9)r〇Ki.,21(24)9529-9540). Therefore, it is in vivo to study whether the KCNQ opener of the present invention can significantly inhibit the spontaneous activity of DA neurons in VTA. Individuals • Male Wistar rats (Harlan, The Netherlands) weighing 270-340 g were used. Under controlled conditions of fixed indoor temperature (2i soil 2. 〇) and humidity (55 ± 5%), the animals were maintained under the i2 hour light/dark cycle, and food and tap water were freely available. ❹ Experimental procedure • Rats were anesthetized with intraperitoneal injection of chloral hydrate (400 mg/kg). A femoral vein catheter was then inserted to supplement anesthetic injection (1 mg/kg) and drug administration. The animals were then mounted in a stereotactic frame, exposed to the bone, and drilled above the ventral side of the covered area (〇.5x〇.5 cm). Extracellular single cell recording was performed using an electrode that was pulled by a glass capillary and filled with 2% Pontamine Sky Blue in 2 M NaCl. The tip of the electrode is destroyed under microscope control and produces an impedance of 2.0-8.0 Ω Ω at 135 Hz. The electrode was then lowered into the brain using a hydraulic microdrive for the following coordinates: 5.5_5 〇 mm after the front sill; 0.5-0.9 mm on the side of the midline 21 201041857. Use an oscilloscope and monitor to amplify, differentiate, and monitor extracellular action potentials. The differentiated spikes were collected and analyzed using Spike 2 software (Cambridge Electronic Design Ltd., Cambridge, UK) using a PC-based system (Cambridge Electronic Design Ltd.) connected to the CED 1401 interface unit. It is hypothesized that dopamine-exciting neurons are typically found 7.0-8.5 mm below the surface of the brain and are characterized by (1) slow and irregular triggering patterns (0.5-10 Hz) and (2) with major positive components, negative The component is followed by a three-phase action potential of a minor positive component with a total duration of greater than 2.5 ms (Bunney et al., 1973, j. p/jar_c〇/five r/jer, 185, 560-571). Compound administration. Once a stable basic trigger rate is obtained, a cumulative dose of N-(2,6-dimethyl-4-isomorpholine-4-yl_phenyl)_3,3·dimethyl is administered intravenously. Dilute amine (agent 篁红〇〇.03_0·5 mg/kg; volume range om 〇ml/kg), at least 3 minutes between each injection. These intravenous doses correspond to a subcutaneous dose range of 0-10 mg/kg. First, the first chance is to evaluate the efficacy by statistical comparison of the average trigger rate calculated from the 2 3 knives period (baseline) and the average trigger rate calculated by the maximum efficacy of at least 60 seconds. The single factor factor analysis (〇 way ANOVA) was followed by Student_Newman_Ke post-mortem statistical analysis. A p value less than 〇 〇 5 is considered significant. , as can be seen from Table 1, after the acute administration of the compound, N-(2,6-diyl4-horrinolin-4-yl-phenyl)_3'3-dimercaptobutylamine is significantly and dose-dependently Inhibition of spontaneous da|bj cell triggering in anesthetized rat VTA. This funding demonstrates the rapid onset of antipsychotic potential of this compound. 22 201041857 Table 1. Effect on triggering of spontaneous DA cells in anesthetized rat Vta. Cumulative dose (mg/k&, N-(2,6-diamidino-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butanthine) ) ------ 97.5 ± 0.8 (10) 0.03 89.8 ± 4.5 (5) 0.1 ---- ----- 81.0 ±4.0(5)** 0.25 74.1 ±6.3 (4)*** 0.3 0.5 68.1 ±6.0(4)*** 0.6 _ 0.9 1.0 ---------- 57.1 ±7.9 (3)*** 2.0 ~—--- - 4.0 —--- 6.0 -- -- Average ± standard error of the mean. Spontaneous da cell trigger rate is expressed as a percentage of the baseline trigger rate; 11 is indicated in parentheses; *p<〇.〇5, compared to baseline (drug donation as active) **p<〇.〇i, ***p<〇〇〇1. Example 5. Rat Amphetamine stimulates D_amphetamine administration to rodents via the nucleus accumbens Edge dopamine receptors stimulate increased motility. Although mental illness may not mimic all forms of schizophrenia, the applicability of paranoid schizophrenia (phrnh) and non-schizophrenia psychiatric disorders (Krystal et al. 0/ '" to, ISBN 19 51 1265 2, pp. 214-224) °Shenxin inhibits the increase in amphetamine-induced motor activity as a reliable method for assessing the antipsychotic potential of compounds (Ggren et al., P. iarmaco Zl 984, 1〇2, 45) 9-464) In the following experiment, it was tested whether the inhibition of spontaneous DA neurons in the brain limbic system circuit can be converted into a behavioral antipsychotic endpoint in the above evaluation. Individuals. Male Wistar with a weight of 17〇_24〇g is used. Rats (Tac〇nic, Denmark). Under the conditions of fixed indoor temperature (21 ± 2 〇 c) and humidity (55 ± 5%), the animals were kept under a 2 hour light/dark cycle, food and tap water. It can be taken at will. Eight rats are used at each dose and in the parallel control group receiving d-amphetamine and the vehicle-only injection group. Experimental procedure. In the undisturbed room Under normal light conditions, the subcutaneous main injection d-femata sulphate (〇5 mg/kg) was injected 3 minutes before the test substance. Immediately after the injection of d_amphetamine, the rats were individually placed in the test cage. Waiting for the cage to be equipped with 4 External light source and photocell of the square-shaped holder. The beam passes through the cage 4 cm above the cage floor. The activity count _ is to interrupt the adjacent beam, thus avoiding the rat induced by fixed movement: ten. The activity (count) is up to 2 hours. In the absence of & feminine, the average activity induced by the agent (using your "^ water" treatment is used as a baseline. Therefore, the total living green is subtracted from the base (four). From the total activity, the reaction in the group of the test compound is expressed as a percentage of the similar result of the test. The recorded percentage of the reaction is converted into a suppression knife. The log-probability splitting handle r 1 calculates ED such as ^ Oog-probit anaylse) 舁 50 value. In a set of parallel data, no d is requested to be non-into + shows at the beginning of the exercise evaluation • Fantasy In addition to sulphate 'Use basically the same procedure to evaluate 24 201041857 Test: Potential sedative properties of the mouth (activity inhibition) Ο Result. Can be seen from Table 2, Ν-(2,6-dimethyl_4_? Porphyrin_4_yl" stupid:), 3-methyl-butanamine produced in rats induced by d-amphetamine: inhibition of kinetics. The efficacy of functioning is stronger than the inhibition of motor activity, that is, the inhibition of amphetamine-induced high activity cannot be explained by the sedative nature of the compound. In fact, this effect reflects the antipsychotic potential of 2,6-dimercapto-4, dimethylamino-butanamine, which is considered to be effective for lithium. Treatment of acute mania and prevention of bipolar disorder (Goldberg 2000, coffee. ρ (10) Xin Shao 61 (Supp. 13), 12-18)' and Glanzapine is recognized for its efficacy in treating schizophrenia Olanzapine is effective in this model, so the data is a Chuming N-(2,6-dimethyl-4-morpholin-4-ylphenyl)-3,3·dimethyl-but The potential of guanamine to treat mania and bipolar disorders as well as schizophrenia. Table 2. Effect of compound on amphetamine-induced hyperactivity in rats Compound amphetamine antagonism ED50 (mg/kg) ± standard deviation active inhibition ED50 (mg/kg) Soil standard deviation N-(2,6-two Mercapto-4-morpholin-4-yl-phenyl)-3,3·dimethyl-butanamine 2,1 (1,5) 7,6 (4,8) Lithium hydride 12 (1, 7) >40 olanzapine, 21 (1,7) 0,72 (2,4) Example 6. Rat microdialysis is well known as a psychostimulant by increasing the nucleus accumbens (which is the midbrain edge DA projection Extracellular da content in the terminal region) increases motor activity (guix et al., 1992, //wr like Ze"., 138(1), 137-140; Moghaddam et al. 25 201041857, 1989, do nape, 4 (2), 156-161). It is also known that the antagonism of antipsychotic drugs against stimulant-induced hyperlocomotion is related to the anti-psychotic drug's inhibition of stimulated DA content in the nucleus accumbens (Broderick, Prog. Neuropsychopharmacology and Biol.

Pac/ί" 28, 1 5 7-17 1 ). Therefore, the nucleus accumbens is the neuroanatomical site for the reversal of positive symptoms of psychosis. Therefore, the following experiment was conducted to study N-(2,6-dimethyl Effect of -4-morphin-4-yl-phenyl)-3,3-dimethyl-butanamine on baseline and amphetamine-induced da content in nucleus accumbens of free-moving rats. It can be related to the behavior data obtained above. Individuals. Male Sprague_ with an initial weight of 275-300g

Dawley rat (Charles River). Under controlled conditions of fixed indoor temperature (21 ± 2 〇) and humidity (55 ± 5%), the animals were maintained under a 12-hour light/dark cycle, and food and tap water were freely available. Surgery • Anesthetized animals with hypnorm/d〇rmicum (2 ml/kg 'subcutaneously) and stereotactically implanted intracerebral guide tubes (CMA/12)' position the dialysis probe tip In the nucleus accumbens (coordinates: 1.7 mm before the anterior iliac crest, -1.2 mm on the anterior temporal iliac crest, and 8 cumples on the ventral surface of the dura mater). Use a base bolt and an acrylic adhesive to secure the guide tube. The body temperature of the animal was maintained at 37 rpm by means of a rectal probe and a heating plate. Rats were housed in cages from day to day. Complex 2

Experimental procedure. On the day of the experiment, a microdialysis probe (cma/i2, diameter 0.5 mm, length 2 mm) was inserted through the guide tube of the conscious animal. The probe is connected to microinjection 1 via a two-channel rotary joint, allowing the animal to move unrestricted. Constant flow rate of i卟/_ during the duration of the experiment J 26 201041857

Maintain filtered Ringer's solution (Ringer s〇luti〇n) (145 mM

A microdialysis probe was perfused with NaCb 3 mM Κα, 1 mM MgCl 2 , 1.2 mM CaCl 2 ). After 180 minutes of stabilization, the experiment was started. The dialysate was collected every 2 minutes. After the experiment, the rats were sacrificed by decapitation, their brains were removed, frozen and sectioned for probe placement verification. Compound administration · Subcutaneous administration of n-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butanamine in a volume of 2.5 ml/kg (5 mg/kg) or vehicle (10% 2-hydroxy-propyl-/5-cyclodextrin, isotonic, pH 5-7). Thirty minutes after the first administration, d-amphetamine sulfate (〇·5 mg/kg, subcutaneous) was administered. Dialysate analysis. The concentration of dopamine (DA) in the dialysate was evaluated by electrochemical detection by means of HPLC. The dialysate fraction was separated by reverse phase liquid chromatography (〇ds i5〇x3 mm, 3 μΜ). The mobile phase consisted of 9 mM NaH2P〇4, 50 mM sodium citrate, 367 mg/1 1-octanoic acid sodium, 5 〇 EDTA, and 8% acetonitrile (pH 4.0). The flow rate was 0.5. Electrochemical detection of DA was performed using a coulometric detector; the potential was set to El = -75 mV and E2 = 300 mV (guard cells at 350 mV) O (Coulochein®, ESA). The DA dialysate content in the three dialysis samples before administration of the compound was averaged and used as the DA baseline content (1%). Statistical analysis. The amount of da dialysate in the three dialysis samples before administration of the compound was averaged and used as the DA baseline content (1% by weight). Where appropriate, repeated measures of variance analysis followed by post-test (Tukey test) analysis. *p<0.05 is considered significant. Results · As can be seen from Table 3, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-didecyl-butanamine was significant (p=〇〇〇2 It inhibits the increase in extracellular DA content induced by amphetamine in the nucleus accumbens of freely moving rats. N_(2,6_dimercapto_4_ 27 201041857 morphine-4_yl-phenyl)j 3 - tiangan basic extracellular DA content, (two;: 7 guanamine does not significantly affect N in this region) - From dimethyl two: exhibition '). These data indicate that the above-mentioned antagonism (i.e., antipsychotic residence) of the activity of sinensis in rats is actually related to glare, and the nucleus is excited by DA. The inhibition of the content is related, which in one step enhances the antipsychotic potential of the compounds>. The observations only affect the influence of 'D on the Α content without affecting the 曰', and the basic DA si, indicating a lack of interest: low risk' This is a short-term but frequently observed characteristic of antipsychotic drugs for clinical use. . Effect of 5 substances on the increase of DA content caused by amphetamine in the nucleus accumbens of freely moving rats (minutes) ------- -40 -20 ----- 0 ------ Baseline of amphetamine + vehicle baseline Fantas + N-(2,6-Dimethyl_4_morpholin-4-yl-benzene)-3,3-dimercapto-butylamine (5 mg/ Kg) Baseline 0/〇91±6 108 ±5 96±5 100 ±3 112±7 91±4 20 168 ± 19 112±12 40 ---- 338 ±27 227 ± 46 60 -*-- 375 ± 46 262 ± 53* 80 -- 319 ± 59 195 ± 38 * 100 232 ± 48 172 ± 24 120 ------- 162 ± 37 166 ± 32 140 1----- 129 ± 27 129 ± Μ Display The corrected DA content in the nucleus accumbens of the freely moving rat. The same 4 were compared with the amphetamine-vehicle group, *P < 0.05. Example 7. Amphetamine Sensitization in Mice Clinical data indicate that schizophrenia and bipolar disorder in which amphetamine has not been used 28 201041857 Patients showed an amplification response to the first dose of amphetamine, indicating that these patients can exhibit dopamine motility Sensitization (Strakowski et al, 1996, Biol. Psychiatry 40, 872-880; Lieberman 1987, 91, 415-433; Strakowski et al, 2001, CTO 15, 701-708). This phenomenon is mimicked in rodents when repeated intermittent administration of amphetamine leads to a progressive increase in the behavioral response to amphetamines (this phenomenon is called behavioral sensitization) (R〇bins〇n and Berridge, 1993, 18(3) :247-91 ). The dopamine pathway at the edge of the brain is the main neural circuit associated with this behavioral sensitization (Robinson and Becker, iiaearc/! 1986, 396(2): 157-98). Inhibition of the behavioral response to acute amphetamine challenge in sensitized animals has been proposed as a model for assessing the antipsychotic or anti-manic potential of a compound. Individuals • Male NMRI mice (Charles River) weighing approximately 35 g were used. Under controlled conditions of fixed indoor temperature (21 ± rc) and humidity (55 ± 5 〇 / 〇), animals were housed in 6 mice per cage for 12 hours light/dark cycle. 'Food and tap water are optional. Take it. Twelve small air were used in each experimental group. Experimental procedure. All mice were pretreated daily with d-amphetamine sulfate (2_5 mg/kg, subcutaneous) or saline (10 ml/kg) for a total of $ days. There were 17 days between the last day of pretreatment and the test day, leaving the animals in their caged home for standard care as described above. Experiments were performed under normal light conditions in undisturbed rooms. Mice were treated with test substance or vehicle and individually placed in test cages for 30 minutes. Mice were then challenged with D_amphetamine sulfate (125 mg/kg, subcutaneous) or saline (5 ml/kg) and placed in test cages and data acquisition was initiated. 5x8 infrared light source and photocell monitoring occupying 4 cm space 29 201041857 Sport activity. The beam passes through the cage at 8 cm above the bottom of the cage. The recording of the activity count needs to interrupt the adjacent beam, #this avoids the count induced by the fixed movement of the mouse. Compound administration · 30 minutes before data acquisition, N_(2,6-dimethyl-4-oxalin-4-yl-phenyl)_3,3-dimethyl-butanamine (〇_5mg/ Kg) or vehicle (shaved-ureo-propyl + cyclodextrin' isotonic ^... small ^ ^ ^ subcutaneous treatment of mice treated with amphetamine and mice pretreated with vehicle. The total counts obtained in each group of animals in the 3 minute test were averaged and used to calculate the efficacy in the following manner: the average activity induced by amphetamine in the animals pretreated with amphetamine was used as a sensitization reaction. The median activity induced by vehicle challenge in vehicle pretreated animals was used as a baseline active response. The self-sensitized amphetamine reaction value was subtracted from the baseline value and set to 1 GG% ', ie sensitization reaction. Repeat for each dose group The values for each dose group are calculated and then expressed relative to the 100% value. That is, the response in the amphetamine-sensitized group of the test compound is determined by sensitization minus baseline activity to sensitize the records in the amphetamine-responsive group. A hundred-knife ratio of similar results is expressed. The percentage of reaction is converted to a hundred Ratio and carry out logarithm_probability analysis to thereby obtain e〇5q which inhibits the sensitization reaction. Similarly, by phase: active activity in the baseline is indicated by vehicle pretreatment, vehicle challenged, drug-treated animals. The active response to calculate the ED that inhibits baseline activity. The therapeutic index value is then calculated by dividing the first ΕΕ > 5 〇 by the second ε 〇 5 。. Results · Visible from Table 4. (2,6-dimercapto_4_morpholine-4-ylphenyl) 3,3-methyl-butanamine and anti-manic lithium and antipsychotic olanzapine inhibited sensitized mice High activity induced by amphetamine 201041857. The potency of these compounds is stronger than the potency of these compounds to inhibit baseline activity. That is, these compounds have a calming effect that can be separated from their sedative effects, ie Antipsychotic/anti-manic action (ie therapeutic index > ι). This separation is characteristic of a psychoactive inhibitor (Kapur and Mam〇h less cA, 27(7), 1081-1090) and thus proves N_(26_ Antipsychotic/anti-manic madness of dimethyl-4_maline 4-yl-phenyl)_3,3-dimethyl-butanamine Potential. 0 Table 4. Effect of compound on amphetamine sensitization behavior in mice. Inhibition of amphetamine sensitization ED50 (±SD) (mg/kg) Baseline activity inhibition ED50 (±SD) (mg/kg ) Therapeutic index N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimercapto-butylamine 1.6(1.2) >2.5 >1 Chlorination钟34 (7.2) »40 »1 Olanzapine 0-11 (1.4) >0.31 >3 Example 8 • Conditional avoidance in rats 'training rats in a conditional avoidance response (CAR) model at fixed time Respond to stimuli by moving from one place to another to avoid electric shock from the foot. Antipsychotic drugs selectively inhibit avoidance response within a specific dosage range without inhibiting escape behavior caused by the occurrence of foot shocks. The Car model is considered a predictive and reliable animal model that is sensitive to compounds with antipsychotic potential. All clinically effective antipsychotics have been shown to inhibit CAR (Wadenberg and Hicks, "V and ev 23, 851-862, 1999" ° 31 201041857 individuals. At the beginning of the study, a male war plus rats weighing 150 g were used ( TaC〇niC, Denmark. Rats were maintained in pairs and maintained in a 12-hour light/dark cycle (lighting at 06:00). | Feeding animals once a day (about 6 pellets per rat) to keep the rats It is free to feed the weight. The water can be used with the sound. The temperature is automatically controlled (21 ± 1. 〇 and relative humidity (55 ± 5%). w Experimental procedure • Use four automatics placed in the sound attenuation chamber The shuttle was (ENV-010M, MED_Ass〇ciates) for conditional avoidance testing. Each cartridge was divided into two compartments by a spacer with an opening. II was detected by two photocells placed on either side of the barrier wall. Location and crossing from one compartment to another - in the case of conditional stimuli (cs), tone and light, the animal has 10 ^/time crossing to the other compartment of the shuttle box to avoid cs (test knot And avoid unconditional stimuli (ucs). If the rats stay in the same area for more than 10 seconds Then it is presented as a 0 5 mA scrambled foot shock (4) until escaping or 10 seconds maximum duration. The following behavioral variables are evaluated: avoidance (responding to CS within 10 seconds); evasion (#cs+ucs response); escaping Failure (no response); inter-assay traversal and motor activity. Rats were acclimated to the shuttle box at each test _ 3 minutes. During the training period, each test period consisted of 30 trials with intervals between seconds and %. Randomly changed between seconds. Training was performed until the rats showed an evasive rate of more than 80% for 3 consecutive days (four). Pre-tests were performed on the day before the test to obtain baseline values for each animal, so the animals served as their own controls. 7 to 8 rats were used. A parallel control group containing the test compound was also included. Compound administration · Subcutaneous administration of N-(2,6-dimethyll) in a volume of 5 ml/kg 30 minutes before the test Base_4_morpholine_4_yl-phenyl)_3,3-dimethyl-butanamine (2.5 mg/kg & 5 mg/kg). Dissolve the compound in 1% 2 hydroxypropyl 32 201041857 -] S-cyclodextrin in vehicle (isotonic with glucose, pH 5-7). Statistical analysis Two-way repeated measures ANOVA followed by post hoc comparison (Student-Newman-Keuls method) to statistically evaluate the effects of compounds on avoidance and escape failure behavior. P value less than 0.05 Statistically significant. Results. It can be seen from Table 5 that 'N-(2,6-dimethyl-4-norlin-4-yl-phenyl)-3,3-didecyl-butanamine significantly reduces avoidance frequency. None of the test doses caused any escape failure to occur, corresponding to no effect on athletic performance (data not shown). In summary, the information demonstrates the antipsychotic potential of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimercapto-butylamine. Table 5. Effect of Compounds on Conditional Avoidance Response in Rats Treatment % of avoidance inhibition relative to baseline (Standard) Vehicle (10% Hpbeta) -2 (4.2) N-(2,6-Dimethyl_ 4_morpholin-4-yl-phenyl)-3,3-dimercapto-butylamine, 2.5 mg/kg _ - - 1 (14) N-(2,6-dimercapto-4-? Physo-4-yl-phenyl)-3,3-dimercapto-butylamine, 5 mg/kg 71 (26)*** P<0.001 Experiment 9. Mice forced swimming test schizophrenia symptoms range involved A series of negative symptoms, including lack of interest, social withdrawal, and emotional apathy. These symptoms are not suitable for treatment with currently available antipsychotics (Duncan et al, 2004, Sc/nzop A. and 71. 2-3, 239-248). The forced swimming test is a widely and frequently used model for pre-clinical assessment of antidepressant activity (P〇rs〇lt et al., 1977, vol. 229, 327-336). To test whether N_(2,6-dimethylmorpholin-4-yl-phenyl)_3,3-dimethyl-butanamine has a class of antidepressant or mood-induced 33 201041857 struggling, forced swimming test in mice The compound was tested in. Individuals • Male NMRI mice (Charles River) weighing 23-25 g were used. Under controlled conditions of fixed indoor temperature (21 ± 2 ° C) and humidity (55 ± 5 〇 / 〇), mice were kept in a cage for 8 hours under light/dark cycle, food and tap water. Feel free to use. Eight mice were used in the mother experimental group. Experimental procedure J-shaped mice were placed in a 2000 ml beaker containing 1200 mi of tempered water (25 〇) and allowed to swim for 6 minutes. The performance of the mice was recorded by means of a digital analysis system = (Bi〇〇bServe) video recording, digitization and analysis. Dingdan The time it takes for each mouse to remain in the last 3 minutes of the test period. Treatment. 30 minutes before the test 'by N_(2,6-diindolyl-phenyl-phenyl)-3,3-dimethyl-butanamine or vehicle (1% 2 〇 丙基 丙基 产Earth essence, 10 reading g) subcutaneous treatment of mice. In addition, as a positive pair of Zhaotu, = propionate-HC1 (40mg/kg) and saline control (1〇 ..., 匕 analysis, by means of single factor variance analysis, statistical ratio relative to the relevant control group The time spent not moving. And after the test (Student_Newman_Keuis). The p value is small ^ ' 吏 use the result. It can be seen from Table 6 that it is significant in + _ φ + ' .05. ~ A: 4 2: Wide 6 During the minute of swimming, the time spent in the immobility was reduced. This is compared with the effect of butylamine on the significant effect of propanol. In contrast, the dose has only a weak effect, which is The combination of the Austrian gas level: the observation of the insufficiency of the effect of the same level? In the class of negative 沁 (2,6-di-f-group _4_morpholine _ with specific information to prove the potential of depression, its transferable servant...), The potential of butyric acid amines. 34 of the negative symptoms 201041857 Table 6. Effect of compounds on immobility in the J rat strong stroke test Dose: mg/kg J base · 4 _ _ _ _ 4- yl - phenyl) —Methyl·'Butamine immobility% (soil sn) olanzapine immobility% (± SD) acetaminophen-HC1 immobility % (±SD) vehicle - --^00 (6.6) 100 (6.61) 100(7.1) 0.31 96 (14) --------- - 1.3 102 (4.6) 95(11) 2.5 ---^ (7.5) 5.0 82.3 ( 20) * 40 - - 73.8 (22)* [Simple description of the diagram] Figure 1 N(2,6--methyl- 4-methyl--4-yl-phenyl)-3,3-dimethyl The ruthenium of butyramine: a diffraction pattern of the χ ray powder in the form. Figure 2: X-ray powder diffraction pattern of /5-form of Ν-(2,6-dimethyl-4-isomorpholine-4-ylphenyl)-3,3 dimethyl-butanamine. Figure 3: Diffraction pattern of χ-ray powder in the gamma form of Ν·(2,6-dimethyl-4-isomorpholine-4-yl-phenyl)_3,3-diindenyl-butanamine. [Main component symbol description] None 35

Claims (1)

201041857 VII. Patent application scope: 1. A compound in the form of crystal N-(2,6-diamidino-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butanamine It has XRPD reflection at 10.36, 12.67, 28.64, and 29.98 (°20). 2. A compound as claimed in claim 1 wherein the compound exhibits an XRPD pattern as shown in Figure 1. 3' a compound in the form of a crystalline form of n-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butanamine at 8.68, 18.09, There are XRPD reflections at 22.60 and 3 0.62 (.20). 4. A compound according to claim 3, wherein the compound exhibits an xrpd pattern as shown in FIG. 5. a compound in the form of a crystalline form of n-(2,6-dimethyl-4-morphin-4-yl-benyl)-3,3-diindenyl-butanamine which is at 8.63, 22.26, There are XRPD reflections under 23.40 and 30.49 (.20). 6_ A compound of claim 5, wherein the compound is represented by the xrpd pattern as shown in FIG. 7 A compound according to any one of claims 1 to 6, which is for use in therapy. 8. A compound according to any one of claims 6 to 6, which is for use as a medicament. A pharmaceutical composition comprising a compound according to any one of claims 6 to 6. 1 〇 ·- treatment of a disease selected from seizure dis〇rder, schizophrenia, depression and bipolar spectrun (hsorder) disease, the method 3 ^ The patient in need has 36 201041857 efficacy as the compound of any one of the patent scopes 1 to 6. U. For the application of the patents (4) to 6 of the towel, the compound is used. For the treatment of diseases selected from the group consisting of seizures, schizophrenia, camping disorders and bipolar group spectrum diseases. 12. For the compound of the scope of the patent application range 至! to item 6, for the treatment A disease selected from the group consisting of seizures, schizophrenia, camping disorder, and bipolar group spectrum diseases. 13. Use of a phlegm sigma such as any one of claims 1-6 to It is used in the manufacture of a medicament for the treatment of diseases selected from the group consisting of seizures, schizophrenia, depression and bipolar group spectrum disorders. 14. A process for the manufacture of bismuth-(2,6-dimethyl-4-morpholine) a method of 4--4-phenyl-phenyl)_3,3-dimethyl-butanamine, which comprises a base The 4th-element 2,6-dimethyl-aniline is reacted with 3,3-dimercapto-butanyl chloride. 15. The method of claim 12, wherein the 4_halogen_2, 6_-mercapto-amine is 4-,; odor-2,6-dimercapto-aniline 16. Preparation of bismuth-(2,6-dimethyl-4-morpholin-4-yl-benzene a method of -3,3-diindole fluorenyl-butanamine which comprises ruthenium-(4-halo-2,6-dimercapto-phenyl)_3,3_ in the presence of a palladium catalyst The reaction of dimercapto-butylamine with morpholine. The method of claim 14, wherein the halogen-2,6-dimercapto-phenyl)-3,3-dimercapto-butanyl The amine is αγ-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimercapto-butylamine. 18. The method of claim 12, wherein the 4-bromo-2,6-dimethyl-aniline is reacted with 3,3-dimercapto-butenyl chloride in the presence of a base to produce Ν-(4) -Bromo-2,6-dimethyl-phenyl)-3,3-dimercaptobutylamine, and wherein the oxime-(4-bromo-2,6-dimercapto-phenyl)-3 , 3-dimercapto-butanamine is then reacted with ruthenium in the presence of palladium catalyst 37 201041857 to produce NTM (2,6-diamidino-4-morphin-4-ylphenyl)- 3,3-Dimercapto-butylamine. Eight, the pattern: (such as the next page) 38