OA19696A - Stable Forms of N-(2,6-Dimethyl-4Morpholin-4-YL-Phenyl)-3, 3-DimethylButyramide - Google Patents
Stable Forms of N-(2,6-Dimethyl-4Morpholin-4-YL-Phenyl)-3, 3-DimethylButyramide Download PDFInfo
- Publication number
- OA19696A OA19696A OA1201100416 OA19696A OA 19696 A OA19696 A OA 19696A OA 1201100416 OA1201100416 OA 1201100416 OA 19696 A OA19696 A OA 19696A
- Authority
- OA
- OAPI
- Prior art keywords
- dimethyl
- phenyl
- butyramide
- morpholin
- compound
- Prior art date
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Description
Titre : Stable Forms of N-(2,6-Dimethyl-4-Morpholin-4-YL-Phenyl)-3, 3-Dimethyl-Butyramide.
Abrégé :
Polymorphie forms of N-(2,6-dimethyl-4-morpholin-4yl-phenyl)-3,3-dimethyl- butyramideare provided together with a process for the manufacture of said compound.
Formula I
O.A.P.I. - B.P. 887, YAOUNDE (Cameroun) - Tel. (237) 222 20 57 00-Site web: http:/www.oapi.int - Email: [email protected]
Hence, in one embodiment, the invention relates to the free base of N-(2,6-dimethyl-4morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in crystalline form with XRPD reflections at 10.36, 12.67, 28.64 and 29.89 (°2Θ).
In one embodiment, the invention relates to the free base of N-(2,6-dimethyl-4morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in crystalline form with XRPD reflections at 8.68, 18.09, 22.60 and 30.62 (°20).
In one embodiment, the invention relates to the free base of N-(2,6-dimethyl-4morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in crystalline form with XRPD reflections at 8.63, 22.26, 23.40 and 30.49 (°20).
In one embodiment, the invention relates to a pharmaceutical composition comprising the polymorphs of the présent invention.
In one embodiment, the invention relates to a polymorph of the présent invention for use as a médicament.
In one embodiment, the invention relates to a polymorph of the présent invention for curing a disease selected from seizure disorders, schizophrenia, dépressive disorders, and bipolar spectrum disorders.
In one embodiment, the invention relates to a polymorph of the présent invention for use in therapy.
In one embodiment, the invention relates to a method for treating a disease which will benefit from opening of the KCNQ family potassium ion channels comprising the administration of a polymorph of the présent invention to a patient in need thereof.
In one embodiment, the invention relates to a polymorph of the présent invention for use in the treatment of diseases which will benefit from opening of the KCNQ family potassium ion channels.
In one embodiment, the invention relates to the use of a polymorph of the présent invention in the manufacture of a médicament for the treatment of a disease which will benefit from opening of KCNQ family potassium ion channels.
In on embodiment, the invention relates to a process for the manufacture of N-(2,6dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide.
Figures
Figure 1: X-ray powder diffractogram of the α-form of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)3,3-dimethyl-butyramide
Figure 2: X-ray powder diffractogram of the β-form of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)3,3-dimethyl-butyramide
Figure 3: X-ray powder diffractogram of the γ-form of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)3,3-dimethyl-butyramide
Detailed description of the invention
The présent invention relates to polymorphie forms of the free base of N-(2,6-dimethyl-4morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide, the molecular structure of which is depicted below.
Each of these polymorphie forms is referred to as a polymorph of the présent invention.
In one embodiment, the invention relates to crystalline N-(2,6-dimethyl-4-morpholin-4-ylphenyl)-3,3-dimethyl-butyramide in a polymorphie form denoted herein as the a form, exhibiting X-ray powder diffraction (XRPD) reflections at 10.36, 12.67, 28.64 and 29.89 (2°θ). An XRDP of the a form is shown in Figure 1. As shown in the examples, the a form has the lowest solubility (of the polymorphs of the présent invention) from which observation it may be concluded that it is the most stable form.
In one embodiment, the invention relates to crystalline N-(2,6-dimethyl-4-morpholin-4-ylphenyl)-3,3-dimethyl-butyramide in a polymorphie form denoted herein as the β form exhibiting XRPD reflections at 8.68, 18.09, 22.60 and 30.62 (2°θ). An XRDP of the β form is shown in Figure 2. As shown in the examples, the β form has a higher intrinsic dissolution rate than the a form. The β form is thus expected to enter into solution in the gastrointestinal tract more quickly than the a form and thus potentially give rise to a faster onset of action.
In one embodiment, the invention relates to crystalline N-(2,6-dimethyl-4-morpholin-4-ylphenyl)-3,3-dimethyl-butyramide in a polymorphie form denoted herein as the γ form exhibiting XRPD reflections at 8.63, 22.26, 23.40 and 30.49 (2°θ). An XRDP of the γ form is shown in Figure 3. As shown in the examples, the γ form is characterised by a faster intrinsic dissolution rate and is thus expected to enter into solution in the gastrointestinal tract more quickly than the a form and β-form and thus potentially give rise to a faster onset of action.
N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide may be synthesized as disclosed in WO 2005/087754, and the polymorphs of the présent invention may be prepared as disclosed in the examples.
Alternatively, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide may be manufactured by a process wherein a 4-halogen-2,6-dimethyl-aniline, such as 4-bromo-2,6dimethyl-aniline is reacted in a solvent with 3,3-dimethyl-butyryl chloride preferably in the presence of a base, such as Na2CO3 to obtain A/-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethylbutyramide, or the corresponding 4-halogen compound.
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-butyramide comprising reacting 4-halogen2,6-dimethyl-aniline with 3,3-dimethyl-butyryl chloride in the presence of a base.
In one embodiment, 1 équivalent of 4-bromo-2,6-dimethyl-aniline is mixed with 1-2 équivalent, such as 1.5 équivalent Na2CO3 in tetrahydrofuran (THF) under stirring and nitrogen atmosphère. After 1-2 hours, 1-1.5 équivalents, such as 1.1 équivalent 3,3-dimethyl-butyryl chloride is added, and stirring is continued until a desired degree of conversion has been achieved. The compound obtained may be worked up by phase extractions and recrystallisations. Subsequently, this compound (or the corresponding 4-halogen compound) is reacted with morpholine in the presence of a palladium catalyst and a base to obtain N-(2,6dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide.
Hence, 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-butyramide comprising reacting N-(4halogen-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide (such as the 4-bromo compound) with morpholine in the presence of a palladium catalyst and a base.
The palladium catalyst consists of a palladium source and a phosphine ligand. Useful palladium sources include palladium in different oxidation States, such as e.g. 0 and II. Examples of palladium sources which may be used in a process of the présent invention are Pd2(dba)3, Pd(dba)2 and Pd(OAc)2. dba désignâtes dibenzylideneacetone and OAc désignâtes acetate. Particular mention may be made of Pd(dba)2. The palladium source is typically employed in an amount of 0.1-10 mol-%, such as 0.1-1 mol-%. Throughout this application, mol-% is calculated with respect to the limiting reactant.
Numerous phosphine ligands are known, including both monedentate and bidentate. Useful phosphine ligands include 2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethylaniline (DavePhos), racemic 2,2’-bis-diphenylphosphanyl-[1,1’]binaphtalenyl (rac-BINAP), 1,Tbis(diphenylphosphino)ferrocene (DPPF), bis-(2-diphenylphosphinophenyl)ether (DPEphos), trit-butyl phosphine (Fu’s sait), biphenyl-2-yl-di-t-butyl-phosphine, biphenyl-2-yl-dicyclohexyl-phosphine, (2’-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine, [2’-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and dicyclohexyl-(2’,4’,6’-tri-propyl-biphenyl-2-yl)-phosphane. Moreover, carbene ligands, such as e.g. 1,3-bis-(2,6-di-isopropyl-phenyl)-3H-imidazol-1-ium; chloride may be used instead of phosphine ligands. In one embodiment, the phosphine ligand is DavePhos. The phosphine ligand is typically added in an amount of 0.1-10 mol-%, such as 0.1-1 mol-%.
Base is added to the reaction mixture to increase pH. In particular, bases selected from NaO(t-Bu), KO(t-Bu) and Cs2CO3 are useful. Organic bases, such as 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) may be applied as well. Particular mention may be made of NaO(t-Bu) and KO(t-Bu). Typically, the base is added in an amount around 1-5 équivalents, such as 1-3 équivalents.
In one embodiment, 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 équivalent of A/-(4-bromo-2,6-dimethyl-phenyl)-3,3dimethyl-butyramide and 1-2 équivalent, such as 1.6 équivalent of Na(Ot-Bu) are mixed with a solvent, such as dimethoxyethane (DME), after which morpholine is added and the reaction is allowed to proceed until a desired degree of conversion is achieved. The final product may be worked up using phase extractions and re-crystallisations, and the final polymorphie form obtained may dépend on the solvents used. As shown in the examples, re-crystallisation from water will resuit in the a-form.
As discussed above, KCNQ potassium ion channel openers hâve been shown to be useful in the treatment of seizure disorders, for which reason the polymorphs of the présent invention may be useful in the treatment of acute seizures, convulsions, status epilepticus, and epilepsy, such as epileptic syndrome and epileptic seizures.
As shown in the examples, a number of relevant pre-clinical models indicate that the polymorphs of the présent invention may be useful in the treatment of psychotic and mood diseases or disorders.
Psychotic diseases include schizophrenia. The symptoms of schizophrenia fall into four broad categories: positive, négative, cognitive and affective, such as dépressive symptoms. The positive symptoms are those which manifest themselves as an ‘excess of normal behaviour, such as one or more of hallucinations, delusions, thought disorders, distortions or exaggerations in language and communication, disorganized speech, disorganized behaviour and agitation. The négative symptoms are those where patients show a lack of normal behaviour, such as one or more of blunted affect, aphasia, asociality, anhedonia, avolition, emotional withdrawal, difficulty in abstract thinking, lack of spontaneity, stereotyped thinking, alogia and attentional impairment. The cognitive symptoms relate to the cognitive déficits in schizophrenia, such as one or more of lack of sustained attention, déficits in executive function and memory. Affective symptoms of schizophrenia may include dépressive symptoms, such as depressed mood in general, anhedonic symptoms, sleep disturbances, psychomotor agitation or retardation, sexual dysfunction, weight loss, concentration difficulties, delusional ideas, loss of energy, feelings of worthlessness, récurrent thoughts of death or suicidai idéation. Dépressive symptoms in schizophrenia appear to be associated with a generally poor treatment outcome and are relatively frequent with an estimated prevalence of 25-60% (Montgomery and van Zwieten-Boot, Eur Neuropsychopharmacol., 2007, 17, 70-77).
Schizophrenia may be subdivided on the basis ofthe clinical picture. The paranoid subtype of schizophrenia is characterized by the presence of prominent delusions or auditory hallucinations in the context of a relative préservation of cognitive functioning and affect, whereas disorganized speech and behaviour, fiat or inappropriate affect are essential features of the disorganized subtype of schizophrenia. The essential feature of the catatonie subtype of schizophrenia is a marked psychomotor disturbance that may involve both motoric immobility as well as excessive motor activity. Finally, the residual subtype of schizophrenia is characterized by a lack of prominent positive symptoms.
Mood disorders include disorders wherein a disturbance in mood is the prédominant feature. Thus, both dépressive disorders, such as major dépressive disorder, dysthymie disorder, dépressive disorder not otherwise specified, minor dépression and brief récurrent dépression mood disorders as well as bipolar spectrum disorders like bipolar I disorder, bipolar Il disorder and cyclothymie disorder are classified as mood disorders. Major dépressive disorder is a chronic recurring disease with considérable morbidity in the general population. The hallmark ofthe disease is a depressed mood. The clinical picture may be further characterised by anhedonic symptoms, sleep disturbances, psychomotor agitation or retardation, sexual dysfunction, weight loss, concentration difficulties and delusional ideas. However, the most serious complication of a dépressive épisode is that of suicidai idéation, leading to suicide attempts (DSM IV, American Psychiatrie Association, Washington D.C. 1994). Besides major dépressive disorder, other disorders are characterized by depressed mood, such as dysthymie disorder, dépressive disorder not otherwise specified, minor dépression and récurrent brief dépressive disorder (DSM IV, American Psychiatrie Association, Washington D.C. 1994). Dysthymie disorder is differentiated from major dépressive disorder on the basis of severity, chronicity and persistence. Dysthymie disorder is characterized by chronic, less severe dépressive symptoms that hâve been présent for many years. The “dépressive disorder not otherwise specified” category includes disorders with dépressive features, like minor dépressive disorder and récurrent brief dépressive disorder that do not meet the criteria for other dépressive disorders like major dépressive disorder or dysthymie disorder. The essential feature of minor dépression is one or more periods of dépressive symptoms that are identical in duration to those expressed in major dépressive disorder but which involve fewer symptoms and less impairment. Récurrent brief dépression is characterised by récurrent brief épisodes of dépressive symptoms that are identical in number and severity to those expressed in major dépressive disorder but with shorter duration.
Bipolar spectrum disorders, previously referred to as manic-depressive illness, are mood disorders where dépressive symptoms are combined with at least one manie, hypomanie or mixed épisode. A manie épisode is characterised by a distinct period of abnormally and persistently elevated, expansive or irritable mood. A mixed épisode is characterized by a period lasting at least one week in which both the criteria for a manie and major dépressive épisode are met. In similarity to a manie épisode, a hypomanie épisode is characterized by a distinct period during which there is an abnormally and persistently elevated, expansive or irritable mood. However, in contrast to a manie épisode, a hypomanie épisode is not severe enough to cause marked impairment in social or occupational functioning or to require hospitalisation and there are no psychotic features. The symptoms of a bipolar dépressive épisode are not different from those characterizing a major dépressive épisode. This is also the reason why many bipolar patients are initially diagnosed as suffering from major dépréssion. As mentioned, it is the occurrence of manie, mixed or hypomanie épisodes that gives rise to a bipolar diagnosis, which is distinct from a major dépréssion diagnosis.
Bipolar spectrum disorders may be subdivided into bipolar I disorder, bipolar II disorder, cyclothymie disorder and bipolar disorder not otherwise specified. Bipolar I disorder is charactrized by the occurrence of one or more manie or mixed épisodes and often individuals hâve also had one or more major dépressive épisodes. Bipolar II disorder is characterized by the occurrence of one ore more major dépressive épisodes accompanied by at least one hypomanie épisode. Due to the progressive nature of bipolar I and II disorder, the patients expérience an increasing risk of récurrence of symptoms with every new épisode, as well as a growing risk of increasing duration and severity of subséquent épisodes, if untreated. For this reason, both bipolar I and bipolar II disorder patients may eventually be classified as rapid cycling patients, where the patient expériences at least four épisodes per year. Cyclothymie disorder is a sub-group of bipolar spectrum disorders where the mood disturbances are characterized by chronic, fluctuating mood disturbances involving numerous periods of hypomania and periods of dépressive symptoms. Bipolar disorder not otherwise specified refers to a category of disorders with bipolar features that do not meet the criteria for any specified bipolar disorder mentioned above. Bipolar spectrum disorders are life-threatening conditions since patients diagnosed with a bipolar disorder hâve an estimated suicide risk that is 15 times higher than in the general population (Harris and Barraclough, 1997, British Journal of Psychiatry, 170:205-228). At présent, bipolar spectrum disorders are treated by maintaining the bipolar patients on mood-stabilisers (mainly lithium or antiepileptics) and adding antimanic agents (lithium or antipsychotics) or antidepressants (tricyclic antidepressants or sélective serotonin re-uptake inhibitors) when the patients relapse into a manie or dépressive épisode, respectively (Liebermann and Goodwin, Curr. Psychiatry Rep. 2004, 6:459-65). Thus, there is a desire to develop novel therapeutic treatments for bipolar spectrum disorders in order to meet the need of effectively treating ali three crucial éléments in these disorders with only one therapeutic agent: such novel agents should preferably alleviate manie symptoms with a fast onset of action (antimanic activity), alleviate dépréssion symptoms with a fast onset of action (antidepressant activity), prevent the récurrence of mania as well as dépréssion symptoms (mood stabilising activity).
Hence, in one embodiment, the invention relates to a method for the treatment of a disease selected from seizure disorders, psychotic diseases such as schizophrenia, dépressive disorders and bipolar spectrum disorders, the method comprising the administration of an effective amount of a polymorph ofthe présent invention to a patient in need thereof.
In one embodiment, the patient to be treated for any ofthe above-mentioned disease has initially been diagnosed with the disease.
A therapeutically effective amount of a polymorph of the présent invention refers to an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adéquate to accomplish this is defined as a therapeutically effective amount. Effective amounts for each purpose will dépend on the severity of the disease or injury as well as on the weight and general state of the subject. It will be understood that détermination of an appropriate dosage may be achieved using routine expérimentation, by constructing a matrix of values and testing different points in the matrix, ail of which is within the ordinary skills of a trained physician.
In the présent context, the terms “disease”, “disorder” and “illness” are used as synonyms.
The term treatment and treating as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration ofthe active compound to alleviate the symptoms or complications, to delay the progression ofthe disease, disorder or condition, to alleviate or relieve the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition, as well as to prevent the condition, wherein prévention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration ofthe active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (préventive) and therapeutic (curative) treatment are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human being.
Typically, the treatment of the présent invention will involve daily administration of a polymorph ofthe présent invention. This may involve once daily administration, or administration twice a day or even more frequently.
In an embodiment, the invention relates to a method wherein said polymorph is administered in an amount of between about 1 mg/day and 250 mg/day, such as about 1 mg/day, such as 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 about 100 mg/day or about 250 mg/day. In one embodiment, a polymorph of the présent invention may be administered as the only therapeutically effective compound.
In another embodiment, a polymorph ofthe présent invention may be administered as a part of a combination therapy, i.e. the polymorph ofthe présent invention may be administered in combination with one or more other therapeutically effective compounds having e.g. anticonvulsive properties or mood stabilising activity.
The présent invention also relates to a pharmaceutical composition. A polymorph of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents, in either single or multiple doses. A pharmaceutical composition according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants or excipients in accordance with conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
A pharmaceutical composition of the invention may be specifically formulated for administration by any suitable route, such as the oral, rectal, nasal, pulmonary, topical, buccal, sublingual, transdermal, intracisternal, intraperitoneal, vaginal or parentéral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will dépend on the general condition and âge of the subject to be treated, on the nature of the disorder or disease to be treated, and on the active ingrédient chosen. However, polymorphs of the présent invention are particularly suited for the préparation of a solid dosage form, such as tablets.
Pharmaceutical compositions formed by combining a polymorph of the invention and the pharmaceutical acceptable carriers is then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The composition may conveniently be presented in unit dosage form employing methods known in the art of pharmacy.
Pharmaceutical compositions for oral administration may be solid or liquid. Solid dosage forms for oral administration include e.g. capsules, tablets, dragees, pills, lozenges, powders, and granules e.g. placed in a hard gélatine capsule in powder or pellet form or e.g. in the form of a troche or lozenge. Where appropriate, pharmaceutical compositions for oral administration may be prepared with coatings such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingrédient, such as sustained or prolongea release, according to methods well known in the art. Liquid dosage forms for oral administration include e.g. solutions, émulsions, suspensions, syrups and élixirs.
Compositions of the présent invention suitable for oral administration may be presented as discrète units such as capsules or tablets, each containing a predetermined amount of the active ingrédient, and which may include a suitable excipient. Furthermore, an orally available formulation may be in the form of powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid émulsion.
Suitable pharmaceutical carriers include inert solid diluents or fillers, stérile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gélatine, agar, pectin, acacia, magnésium stéarate, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, gums and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
The carrier or diluent may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
Any adjuvants or additives usually used for such purposes, such as colouring agents, flavours, preservatives etc. may be used provided that they are compatible with the active ingrédients.
The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g.
Tablets may be prepared by mixing the active ingrédient with ordinary adjuvants or diluents and subsequently compressing the mixture in a conventional tabletting machine.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day, such as 1 to 3 times per day may contain from 0.01 to about 1000 mg, such as about 0.01 to 100 mg, preferably from about 0.05 to about 500 mg, and more preferably from about 0.5 mg to about 200 mg.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar routes of administration, typical doses are in the order of about half the dose employed for oral administration.
In one embodiment, the invention relates to a polymorph ofthe présent invention for use in the treatment of a disease selected from seizure disorders, schizophrenia, dépressive disorders and bipolar spectrum disorders.
In one embodiment, the invention relates to the use of a polymorph of the présent invention for the manufacture of a médicament for the treatment of a disease selected from seizure disorders, schizophrenia, dépressive disorders and bipolar spectrum disorders.
Ail references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), regardless of any separately provided incorporation of particular documents made elsewhere herein.
The use ofthe terms “a” and “an” and “the” and similar référents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase the compound is to be understood as referring to various compounds of the invention or particular described aspect, unless otherwise indicated.
Unless otherwise indicated, ail exact values provided herein are représentative of corresponding approximate values (e.g., ail exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by about, where appropriate).
The description herein of any aspect or aspect ofthe invention using terms such as “comprising”, “having,” “including,” or “containing” with reference to an element or éléments is intended to provide support for a similar aspect or aspect ofthe invention that “consists of’, “consists essentially of’, or “substantially comprises” that particular element or éléments, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).
Examples
The melting points were measured by Differential Scanning Calorimetry (DSC), using a TA-Instruments DSC-Q1000 instrument calibrated at 57min to give the melting point as onset value. About 2 mg of sample was heated 57min in a loosely closed pan under nitrogen flow.
X-Ray powder diffractograms (XRPD) were measured on a PANalytical X’Pert PRO XRay Diffractometer using CuKa1 radiation. The samples were measured in reflection mode in the 29-range 5-40° using an X’celerator detector. Ail values ±0.1°.
Example 1, N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide, g form
Synthesis of N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide
300 g (1.5 mol) 4-bromo-2,6-dimethylaniline and 239 g (2.25 mol, 1.5 eg) sodium carbonate in 1.25 L tetrahydrofuran were stirred under a nitrogen atmosphère at room température. After 1 h, 230 mL (1.65 mol, 1.1 eq) 3,3-dimethylbutyryl chloride was added over a period of 2 h while the température was kept below 30 °C, and the mixture was then stirred for 2 h at room temperatufe. 2.1 L tetrahydrofuran and 3.6 L water were added in order to get a clean phase séparation. The water phase was extracted with 2.1 L tetrahydrofuran, and the combined organic phases were washed with 1.5 L 0.5 M aq. Na2CO3 solution. The solvent from the organic phase was distilled off and 2.1 L heptane was added to the resulting solid. The suspension was warmed to reflux, and allowed to cool down to room température. The solid was filtered off and washed with 300 mL heptane.
Synthesis of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide
Br
Pd(dba)2 DavePhos NaOf-Bu (DME)
1.44 g (2.5 mmol, 0.0025 eq) bis-dibenzylideneacetone-palladium and 1.97 g (5.0 mmol, 0.005 eq) DavePhos, 298 g (1.0 mol) /V-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butyramide and 154 g (1.6 mol, 1.6 eq) sodium-tert-butoxide were added to a nitrogen filled 3-neck 10 L round bottom flask. 2.0 L DME was added. 131 mL (1.5 mol, 1.5 eq) morpholine was added and the reaction mixture was warmed to reflux for 2-3 hours. 3.0 L water was added, and the resulting suspension was stirred overnight. The solid was filtered off and washed with 1.0 L water. The solid, together with 40 g charcoal, was then dissolved in 3 L 1 M aq. hydrochloric acid at reflux. After 1.5 h at reflux the reaction was blank filtered warm over filter aid and the filter was washed with 1.0 L warm water. The aqueous phase was washed with 1.0 L ethyl acetate and then with 1.0 L toluene. After phase séparation, the aqueous phase was added to 690 g 27.7% aq.
sodium hydroxide under vigorous stirring (pH 12-13), leading to précipitation. The resulting solid was filtered off and washed with 2.0 L water. The solid was dried in a vacuum oven at 40 °C for 72 h to give the title compound. (HPLC purity: 99.9% (area), XRPD diffractogram: □polymorph).
Example 2. N-(2,6-Dimethyl-4-morpholin-4-vl-phenyl)-3,3-dimethyl-butyramide, β form
The β-form was obtained by heating the α-form to 170 °C with a heating rate of 10 °C/min.
Example 3, N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethvl-butyramide, yform
The γ-form was obtained by dissolving 1 g N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3,3dimethyl-butyramide in 3 ml acetic acid at 70 °C. Upon slow addition of 6 ml water (70 °C), the γ-form précipitâtes.
The tables below summarise properties of the α-, β- and γ-forms of N-(2,6-Dimethyl-4morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide free base.
| Polymorphie form | Thermal properties/ Tonset (melting) | Solubility in water at RT at pH 7.4 | Intrinsic dissolution rate (37C) mg//cmz/min |
| et | Transforme into β. Endotherm on DSC | 0.06 | 0.021 |
| around 150°C when heated at 5°C/min reflects transformation into beta | |||
| β | 236.9°C when covered. When uncovered it sublimâtes at around 200°C | 0.13 | 0.026 |
| Y | 237.3°C when covered. When uncovered it sublimâtes at around 200°C. A small endotherm is seen around 145°C prior to melting | 0.13 | 0.036 |
| Polymorphie form | Stability |
| a | Solid form stable for >90 days at 60°C at a relative humidity of 95% |
| β | Solid form stable for >90 days at 60°C at a relative humidity of 95% |
| Y | Solid form stable for >14 days at 60°C at a relative humidity of 95% |
Example 4. Electrophysiology, rat.
Reports hâve suggested that inhibition of the number of spontaneously active dopaminergic neurones in the ventral tegmental area (VTA), i.e. the mesolimbic system, in rats may account for an antipsychotic potential of a compound (Chiodo and Bunney 1983, J. Neurosci., 5, 25392544.). In the mesolimbic system, ail clinically used neuroleptics initially increase the firing rate of dopaminergic neurons (Tung et al., 1991, J. Neural Transm. Gen Sect., 84(1-2), 53-64, ).
After chronic administration, such neuroleptics eventually (after 3-4 weeks of treatment) decrease the firing rate to below pre-treatment levels (Skarsfeldt 1992, Synapse, 10, 25-33; White and Wang 1983, Science, 221, 1054-1057). This inhibitory effect on dopaminergic neurons, which is believed to be mediated by a depolarisation blockade, is thought to be of therapeutic significance to the antipsychotic effect of neuroleptics (Grâce and Bunney 1986, J. Pharmacol. Exp. Ther. 238, 1092-1100). By inference, a compound that causes an acute decrease in spontaneous firing rate of mesolimbic dopaminergic neurones could be anticipated to possess a fast-onset antipsychotic potential. The presence of KCNQ subunits on DA neurons in the VTA in rodents is well-documented but their functionality is unknown (Saganich et al. 2001, J. Neurosci. 21(13)4609-4624; Cooperet al. 2001, J. Neurosci., 21(24)9529-9540). Consequently, it was studied in vivo whether the KCNQ opener of the présent invention could acutely inhibit spontaneous activity of DA neurons in the VTA.
Subjects. Male Wistar rats (Harlan, The Netherlands) weighing 270-340 g were used. The animais were housed under a 12-hr light/dark cycle under controlled conditions for regular indoor température (21±2°C) and humidity (55±5%) with food and tap water available ad libitum. Experimental procedure. The rats were anaesthetised with an intraperitoneal injection of chloral hydrate (400 mg/kg). A fémoral vein cathéter was then inserted for supplementary anaesthetic injections (100 mg/kg) and drug administration. Animais were then mounted in a stereotaxic frame, the skull was exposed, and a hole (0.5 x 0.5 cm) was drilled above the ventral tegmental area. Extracellular single-cell recordings were performed using électrodes pulled from glass capillaries and filled with 2% Pontamine Sky Blue in 2 M NaCI. The tip of the electrode was broken under microscopie control, yielding an impédance of 2.0 - 8.0 ΜΩ at 135 Hz. The electrode was then lowered into the brain, using a hydraulic microdrive, aimed at the following coordinates: 5.5 - 5.0 mm posterior to Bregma; 0.5 - 0.9 mm latéral to the midline. Extracellular action potentiels were amplified, discriminated and monitored on an oscilloscope and an audiomonitor. Discriminated spikes were collected and analysed using Spike 2 software (Cambridge Electronic Design Ltd., Cambridge, UK) on a PC-based System connected to a CED 1401 interface unit (Cambridge Electronic Design Ltd.). Presumed dopaminergic neurons were typically found 7.0 - 8.5 mm beneath the brain surface and were characterised by (1) a slow and irregular firing pattern (0.5 - 10 Hz), and (2) triphasic action potentials with a prédominant positive component, a négative component followed by a minor positive component, with an overall duration > 2.5 ms (Bunney et al. 1973, J. Pharmacol. Exp. Ther., 185, 560-571.).
Administration of compounds. Once a stable basal firing rate was obtained, cumulated doses of N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide (dose range 0.03-0.5 mg/kg; volume range 0.12-1.0 ml/kg) were administered i.v., each injection being separated by at least 3 min. These i.v. doses match the s.c. dose range of 0-10 mg/kg.
Statistical analysis. Drug effects were assessed by statistical comparison of the mean firing rate calculated from the 2 - 3 min period immediately before the first drug administration (baseline) to the mean firing rate calculated from at least 60 s at the maximal drug effect. Data were analysed statistically by a one-way ANOVA followed by Student-Newman-Keuls posthoc test. A p-value less than 0.05 was considered significant. Results. As can be seen from
Table 1, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide significantly and dose-dependently inhibited the spontaneous DA cell firing in the VTA of anaesthetised rats following acute administration of compound. This data support the notion that this compound has a fast-onset antipsychotic potential.
Table 1. Effects on spontaneous DA cell firing in the VTA of anaesthetised rats.
| Cumulated dose (mg/kg) | N-(2,6-Dimethyl-4morpholin-4-yl-phenyl)3,3-dimethylbutyramide |
| 0 (Vehicle) | 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 | - |
Mean ± standard error of the mean. Spontaneous DA cell firing rates expressed as a percentage of baseline firing rate; n is indicated in brackets; * p<0.05, ** p<0.01, *** p<0.001 compared to baseline (pre-drug administration activity).
Example 5. Amphétamine challenge, rat.
D-amphetamine administration to rodents stimulâtes an increase in locomotor activity via mesolimbic dopamine receptors in the nucléus accumbens. While psychostimulant psychosis may not model ail forms of schizophrenia, it may hâve applicability to paranoid schizophrenia and non schizophrénie psychotic disorders (Krystal et al. pp. 214-224 in Neurobiology of Mental lllness, ISBN 0-19-511265-2). It is believed that inhibition ofthe amphetamine-induced increase in locomotor activity is a reliable method for the évaluation of compounds with an antipsychotic potential (Ôgren et al., European J. Pharmacol. 1984, 102, 459-464). In the following experiment, it was tested if the inhibition of spontaneous DA neurons in the mesolimbic circuit that was assessed above could be translated into behavioral antipsychotic endpoint.
Subjects. Male Wistar rats (Taconic, Denmark) weighing 170-240 g are used. The animais were housed under a 12-hr light/dark cycle under controlled conditions for regular in-door température (21+2°C) and humidity (55±5%) with food and tap water available ad libitum. Eight rats were used at each dose level and in the parallel control group receiving the vehicle to the test compound plus d-amphetamine and the group receiving vehicle injections only.
Experimental procedure. The experiment was made in normal light conditions in an undisturbed room. The test substance was injected 30 min before s.c. before the injection of d-amphetamine sulphate (0.5 mg/kg). Immediately after injection of d-amphetamine, the rats were placed individually in the test cages that were placed in a U-frame, equipped with 4 infrared light sources and photocells. The light beams crossed the cage 4 cm above the cage floor. Recording of a motility count required interruption of adjacent light beams, thus avoiding counts induced by stationary movements ofthe rat. Motility (counts) was recorded for a period of 2 hours. The mean motility induced by vehicle (saline) treatment in the absence of d-amphetamine was used as baseline. The 100 per cent effect of d-amphetamine was accordingly calculated to be total motility counts minus baseline. The response in groups receiving test compound was thus determined by the total motility counts minus baseline, expressed in per cent ofthe similar resuit recorded in the parallel amphétamine control group. The per cent responses were converted to per cent inhibition from which ED50 values were calculated by means of log-probit analyses. In a parallel set of data, the potential sédative properties (motility inhibition) ofthe test compounds were evaluated using essentially the same procedure with the exception of not administering d-amphetamine-sulphate at the initiation of locomotor assessment.
Results. As can be seen from Table 2, N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethylbutyramide produced an inhibition ofthe d-amphetamine induced hyperactivity in rats. The potency with which the effect was exerted was stronger than the potency to inhibit locomotor activity; that is, the inhibition of amphetamine-induced hyperactivity could not be explained by sédative properties ofthe compound. Rather, the efficacy reflects an antipsychotic potential N-(2,6Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide. Since lithium is well accepted as efficacious for the treatment of acute mania and the prophylaxis of bipolar disorders (Goldberg 2000, J. Clin. Psychiatry 61 (Suppl. 13), 12-18), while olanzapine is accepted for its efficacy for the treatment of schizophrenia, and both lithium and olanzapine were efficacious in this model, these data support a potential N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide to treat mania and bipolar disorder as well as schizophrenia.
Table 2. Effects of compounds on amphetamine-induced hyperactivity in the rat.
| Compound | Amphétamine antagonism ED50 (mg/kg) ± std.dev. | Motility inhibition ED50 (mg/kg) ± std.dev. |
| N-(2,6-Dimethyl-4morpholin-4-yl-phenyl)3,3-dimethylbutyramide | 2,1 (1,5) | 7,6 (4,8) |
| Lithium-chloride | 12 (1,7) | >40 |
| Olanzapine | 0,21 (1,7) | 0,72 (2,4) |
Example 6. Microdialysis, rat.
It is well-known that psychostimulants increase locomotor activity via an increase in extracellular DA levels in the nucléus accumbens, which is the terminal area of the mesolimbic DA projections (Guix et al., 1992, Neurosci. Lett., 138(1), 137-140; Moghaddam et al., 1989, Synapse, 4(2), 156-161). It is also known, that the antagonistic effect of antipsychotics on stimulant-induced hyperlocomotion is related to the effect of antipsychotics to inhibit the stimulated DA levels in the nucléus accumbens (Broderick et al., 2004, Prog.
Neuropsychopharmacology and Biol. Psych., 28, 157-171). Thus, the nucléus accumbens is an accepted neuroanatomical site for testing reversai of positive symptoms of psychosis.
Consequently, the following experiments were conducted to investigate the effect of N-(2,6Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide on baseline and amphetamineevoked levels of DA in the nucléus accumbens of freely moving rats. The experiments were conducted such that the data may be associated with the behavioural data obtained above. Subjects. Male Sprague-Dawley rats (Charles River), initially weighing 275-300 g, were used. The animais were housed under a 12-hr light/dark cycle under controlled conditions for regular in-door température (21+2°C) and humidity (55±5%) with food and tap water available ad libitum.
Surgery, Animais were anaesthetized with hypnorm/dormicum (2 ml/kg s.c.) and intracérébral guide cannulas (CMA/12) were stereotaxically implanted, positioning the dialysis probe tip in the nucléus accumbens (co-ordinates: 1.7 mm anterior to bregma, -1,2 mm latéral to bregma, 8.0 mm ventral to the dura). Anchor screws and acrylic cernent was applied for fixation of the guide cannula. The body température ofthe animais was maintained at 37°C by means of a rectal probe and a heating plate. The rats were allowed to recover from surgery for 2 days, housed singly in cages.
Experimental procedure. On the day ofthe experiment, a microdialysis probe (CMA/12, 0,5 mm diameter, 2 mm length) was inserted through the guide cannula ofthe conscious animal. The probes were connected to a microinjection pump via a dual channel swivel which allowed the animais unrestricted movements. Perfusion of the microdialysis probe with filtered Ringer solution (145 mM NaCI, 3 mM KCI, 1 mM MgCI2, 1,2 mM CaCI2) was maintained for the duration of the experiment at a constant flow rate of 1 pL/min. After 180 min of stabilisation, the experiments were initiated. Dialysates were collected every 20 min. After the experiments the rats were sacrificed by décapitation, their brains removed, frozen and sliced for probe placement vérification.
Administration of compounds. N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethylbutyramide (5 mg/kg) or vehicle (10% 2-hydroxy-propyl-beta-cyclodextrin, isotonie, pH 5-7) was administered subcutaneously in a volume of 2.5 ml/kg. Thirty min after the first administration dex-amphetamine sulphate (0.5 mg/kg s.c.) was administered.
Analysis of dialysate. The concentration of dopamine (DA) in the dialysates was assessed by means of HPLC with electrochemical détection. The dialysate constitutents were separated by reverse phase liquid chromatography (ODS 150 x 3 mm, 3 μΜ). Mobile phase consisted of 90 mM NaH2PO4, 50 mM sodium citrate, 367 mg/l sodium 1-octanesulfonic acid, 50 μΜ EDTA and 8% acetonitrile (pH 4.0) at a flow rate of 0.5 ml/min. Electrochemical détection of DA was accomplished using a coulometric detector; potential set at E1 = -75 mV and E2 = 300 mV (guard cell at 350 mV) (Coulochem II, ESA). The dialysate levels of DA in the three dialyse samples preceding the administration of compound were averaged and used as baseline level of DA (100%).
Statistical analysis. The dialysate levels of DA in the three dialyse samples preceding the administration of compound were averaged and used as baseline level of DA (100%). Data were analysed using repeated measure analyses of variance followed by post hoc tests (Tukey test), when appropriate. *p < 0.05 were considered significant.
Results. As can be seen in Table 3, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethylbutyramide significantly (p = 0.002) dampened the amphetamine-induced increase in extracellular levels of DA in the nucléus accumbens of freely moving rats. N-(2-6-dimethyl-4morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide did not significantly affected the basal extracellular DA level in this région (data not shown). These data suggest that the antagonistic effect of and N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide on amphetamine-induced activity in rats seen above, i.e. antipsychotic activity, is indeed associated with a dampening of provoked DA levels in the nucléus accumbens which further strengthens the antipsychotic potential of these compounds. The observation that merely provoked levels of DA were affected, but not basal levels of DA, suggests a low risk of causing anhedonia, a trait that is transiently, but frequently, observed with clinically used antipsychotics.
Table 3. Effects of compounds on the amphetamine-evoked increase in DA levels in the nucléus accumbens of freely moving rats.
| Time (min) | Amphétamine + vehicle % of baseline | Amphétamine + N-(2,6dimethyl-4-morpholin-4-ylphenyl)-3,3-dimethylbutyramide (5 mg/kg) % of baseline |
| -40 | 91 ±6 | 108 ±5 |
| -20 | 96 ±5 | 100 ±3 |
| 0 | 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 | 129 ±27 | 129 ±35 |
Normalised DA levels in the nucléus accumbens of freely moving rats are shown. * P < 0.05 compared to amphetamine-vehicle group, same time.
Example 7. Amphétamine sensitisation, mouse.
Clinical data imply that amphetamine-naïve schizophrénie and bipolar patients display an exaggerated response to a first dose of amphétamine implying that these patients may show a dopaminergic sensitisation (Strakowski et al. 1996, Biol. Psychiatry 40, 872-880, Lieberman et al. 1987, Psychopharmacology, 91,415-433, Strakowski et al., 2001, CNS Drugs 15, 701-708). This phenomenon is modeled in rodents when repeated intermittent administration of amphétamine leads to a progressive increase in the behavioral response to an amphétamine challenge, a phenomenon known as behavioral sensitisation (Robinson and Berridge, Brain Research Rev. 1993, 18(3):247-91). The mesolimbic dopamine pathway is believed to be the major neural circuit involved in this behavioral sensitisation (Robinson and Becker, Brain Research 1986, 396(2):157-98). Inhibition ofthe behavioral response to an acute amphétamine challenge in sensitised animais is proposed as a model for evaluating the antipsychotic or antimanic potential of compounds.
Subjects. Male NMRI mice (Charles River) weighing approx. 35 g were used. The animais were housed 6 mice pr cage in a 12-hr light/dark cycle under controlled conditions for regular in-door température (21+2°C) and humidity (55±5%) with food and tap water available ad libitum. 12 mice were used pr experimental group.
Experimental procedure. Ail mice were pre-treated once daily for five days with either damphetamine sulphate (2.5 mg/kg s.c.) or saline (10 ml/kg). For the 17 days between the last day of pre-treatment and the test day, the animais were kept in their home cage receiving the standard care as described above. The experiment was performed under normal light conditions in an undisturbed room. The mice were treated with test substance or vehicie and placed individually in the test cages for 30 min. The mice were then challenged with Damphetamine sulphate (1.25 mg/kg s.c.) or saline (5 ml/kg) and replaced in the test-cage and data acquisition began. 5x8 infrared light sources and photocells interspaced by 4 cm monitor the locomotor activity. The light beams crossed the cage 1.8 cm above the bottom of the cage. The recording of a motility counted requires interruption of adjacent light beams, thereby avoiding counts induced by stationary movements of the mice.
Administration of compounds. Amphetamine-pretreated mice and vehicle-pretreated mice were s.c. treated with N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide (0-5 mg/kg) or vehicie (10% 2-hydroxy-propyl-beta-cyclodextrin, isotonie, pH 5-7, 5 ml/kg) 30 min priorto the data acquisition.
Data analyses. The total counts obtained in the 30 min test were averaged pr animal group and used for calculation of drug effects in the following manner: The average motility induced by an amphétamine challenge in amphetamine-pretreated animais was used as the sensitised response. The average motility induced by a vehicie challenge to vehicle-pretreated animais was used as a baseline motility response. The baseline value was subtracted from the sensitized amphétamine response value and set as 100% i.e. the sensitised response. This calculation was repeated for each dose group and the value for each dose-group is subsequently expressed relative to the 100% value. That is, the response in amphetamine-sensitized groups receiving test compound was thus determined as the sensitised response minus the baseline motility, expressed in per cent of the similar resuit recorded in the sensitized amphétamine response group. The percent responses were converted to percent inhibition and exposed to log-probit analysis thus producing an ED50 for inhibiting the sensitised response. Similarly, an ED50 for inhibiting baseline motility was calculated by expressed the motility response in vehicle-pretreated, vehiclechallenged, drug-treated animais relative to the baseline motility response. A therapeutic index value can subsequently be calculated by dividing the first ED50 by the second.
Results. As can be seen in
Table 4, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide as well as the antimanic compound lithium and the antipsychotic olanzapine ail inhibit the hyperactivity induced by an amphétamine challenge in sensitised mice. The potency with which these compounds exert this effect is stronger than the potency with which these compounds inhibit baseline motility. That is, the compounds posses a calming effect, i.e. antipsychotic/antimanic effect, that is separable from its sédative effects (i.e. therapeutic index > 1). This séparation is characteristic for neuroleptics (Kapur and Mamo 2003, Biol. Psych. 27(7), 1081-1090) and thus support an antipsychotic/antimanic potential for N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3dimethyl-butyramide.
Table 4. Effects of compounds on a sensitised behavioural response to amphétamine in mice.
| Compound | Inhibition of amphétamine sensitised response. ED50 (± S.D.) (mg/kg) | Inhibition of baseline motility. ED50 (± S.D.) (mg/kg) | Therapeutic index |
| N-(2,6-Dimethyl-4morpholin-4-ylphenyl)-3,3dimethyl-butyramide | 1,6 (1,2) | >2,5 | >1 |
| Lithium-chloride | 34 (7,2) | »40 | »1 |
| Olanzapine | 0,11 (1,4) | >0,31 | >3 |
Example 8. Conditioned avoidance, rat.
In the conditioned avoidance response (CAR) model, rats are trained to respond to a stimulus within a fixed time by moving from one place to another in order to avoid a footshock.
Antipsychotics selectively suppress the avoidance response within a certain dose-range without suppressing escape behavior elicited by the appearance ofthe footshock. The CAR model is considered to be a prédictive and reliable animal model that is sensitive to compounds with an antipsychotic potential. Ail clinically effective antipsychotics hâve been shown to inhibit CAR (Wadenberg and Hicks, Neuroscience and Biobehav Rev 23, 851-862, 1999).
Subjects. Male Wistar rats (Taconic, Denmark) weighing 150 g at the beginning of the study were used. The rats were housed in pairs and maintained on a 12 h light/dark cycle (lights on 06:00). The animais were fed once daily (approx. 6 pellets/rat) in order to keep the rats at 80% of their free-feeding weight. Water was available ad libitum. Température (21 + 1°C) and relative humidity (55 + 5%) were automatically controlled.
Experimental procedure. Conditioned avoidance testing was conducted using four automated shuttle-boxes (ENV-010M, MED-Associates) each placed in a sound-attenuated chamber. Each box was divided into two compartments by a partition with an opening. The position ofthe animal and crossings from one compartment to the other were detected by two photocells placed on either side ofthe dividing wall. Upon présentation ofthe conditioned stimuli (CS), tone and light, the animais hâve 10s to cross to the other compartment of the shuttle-box in order to turn the CS off (end the trial) and avoid the appearance of the unconditioned stimulus (UCS). If the rat remained in the same compartment for more than 10s, the UCS is presented as 0.5 mA scrambled foot-shocks until escape was performed or 10s in maximal duration. The following behavioural variables were evaluated: avoidance (response to CS within 10s); escape (réponse to CS + UCS); escape failures (failure to respond); intertrial crosses and locomotor activity. The rats were habituated to the shuttle-box 3 min before each test session. During training each test session consists of 30 trials with intertrial intervals varying randomly between 20s and 30s. Training was carried until the rats display an avoidance of 80% or more, on 3 consecutive days. A test was preceded by a pre-test the day before giving rise to a baseline value for each animal, thus the animais served as their own control. Seven to eight rats were used at each dose level. A parallel control group receiving the vehicle ofthe test compound was also included.
Administration of compound. N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide (2,5 and 5 mg/kg) was administered s.c. 30 min before the test, in a volume of 5 ml/kg. The compound was dissolved in a vehicle of 10% 2-hydroxy-propyl-beta-cyclodextrin (isotonie with glucose, pH 5-7).
Statistical analyses. The effects of compounds on avoidance and escape failure behaviours were statistically evaluated by means of a two-way repeated measures ANOVA followed by post hoc comparisons (Student-Newman-Keuls Method) when appropriate. P-levels < 0.05 were considered statistically significant.
Results. As can be seen in Table 5, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethylbutyramide significantly reduced the number of avoidances. None of the tested doses caused any incidences of escape failures, corresponding to a lack of effect on motor performance (data not shown). In conclusion, these data support an antipsychotic potential of N-(2,6-dimethyl-4morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide.
Table 5. Effects of compounds on the conditioned avoidance response in rats.
| T reatment | % inhibition of avoidance (Std.dev.) Relative to baseline. |
| Vehicle (10%Hpbeta) | -2 (4,2) |
| N-(2,6-dimethyl-4morpholin-4-yl-phenyl)3,3-dimethyl-butyramide, 2,5 mg/kg | 1 (14) |
| N-(2,6-dimethyl-4morpholin-4-yl-phenyl)3,3-dimethyl-butyramide, 5 mg/kg | 71 (26) *** P < 0.001 |
Example 9. Forced swim test, mouse.
The schizophrénie spectrum of symptoms involves a cluster of négative symptoms including anhedonia, social withdrawal and emotional flattening. Such symptoms are inadequately treated by currently available antipsychotics (Duncan et al. 2004, Schizoph. Res., 71(2-3), 239-248).
The forced swim is test is a widely and frequently used model for preclinical évaluation of antipressant activity (Porsolt et al. 1977, Arch. Int. Pharmacodyn. 229, 327-336). In order to test whether N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide has an antidepressant-like or mood elevating effect, the compound was tested in the mouse forced swim test.
Subjects. Male NMRI mice (Charles River) weighing 23-25 g were used. The mice were kept 8 mice pr cage in a 12-hr light/dark cycle under controlled conditions for regular in-door température (21+2°C) and humidity (55±5%) with food and tap water available ad libitum. 8 mice were used pr experimental group.
Experimental procedure. The mice were placed in 2000 ml beaker containing 1200 ml of tempered water (25°C) and left to swim for 6 min. The performance of the mice was video recorded, digitalized and analysed by means of a digital analysis system (Bioobserve). The time spent immobile for the last 3 min. of the test session was quantified for each mouse.
Treatment. 30 min. before the test, mice were treated s.c. with N-(2,6-dimethyl-4-morpholin-4yl-phenyl)-3,3-dimethyl-butyramide or vehicle (10-%-2-OH-propyl-cyclodextrin, 10 ml/kg). In addition as positive control, imipramine-HCI (40 mg/kg) and a saline control (10 ml/kg) was included.
Analyses. The time spent immobile was statistically compared across the experimental groups against the relevant control group by means of one-way analysis of variance. A post-hoc test (Student-Newman-Keuls) was employed when appropriate. P-levels < 0.05 were considered significant.
Results. As can be seen from Table 6, N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethylbutyramide significantly reduced the time spent immobile during the 3-6 min swim in mice. The efficacy was inferior to, yet comparable to, the effect of a relevant dose of imipramine-HCI. In contrast, the antipsychotic olanzapine had only a weak effect in this test which is in line with the observation that this compound has an inadéquate effect on négative symptoms in humans. These data support an antidepressant potential of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3dimethyl-butyramide which may translate into a potential to treat négative symptoms in schizophrénie patients.
Table 6. Effects of compounds on immobility in the mouse forced swim test.
| Dose: mg/kg | N-(2,6- Dimethyl-4morpholin-4-ylphenyl)-3,3dimethylbutyramide | Olanzapine Immobility in % (±S.D.) | Imipramine-HCI Immobility in % (±S.D.) |
| Immobility in % (± S.D.) | |||
| Vehicle | 100 (6,6) | 100 (6,61) | 100 (7,1) |
| 0,31 | - | 96 (14) | - |
| 1,3 | 102 (4,6) | 95 (11) | - |
| 2,5 | 96,7 (7,5) | - | - |
| 5,0 | 82,3 (20) * | - | - |
| 40 | - | - | 73,8 (22) * |
Claims (10)
- Claims1. The compound N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 10.36, 12.67, 28.64 and 29.98 (°2Θ).
- 2. The compound according to claim 1, wherein said compound exibits a XRPD pattern as shown in figure 1.
- 3. The compound N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.68, 18.09, 22.60 and 30.62 (°2Θ)
- 4. The compound according to claim 3, wherein said compound exhibits an XRPD pattern as shown in figure 2.
- 5. The compound N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.63, 22.26, 23.40 and 30.49 (°2Θ).
- 6. The compound according to claim 5, wherein said compound exhibits an XRPD pattern as shown in figure 3.
- 7. A compound according to any of claims 1-6 for use in therapy.
- 8. A compound according to any of claims 1-6 for use as a médicament.
- 9. A pharmaceutical composition comprising a compound according to any of claims 1-6.
- 10. The use of a compound according to any of claims 1-6 in the manufacture of a médicament for the treatment of a disease selected from seizure disorders, schizophrenia, dépressive disorders, and bipolar spectrum disorders.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200900597 | 2009-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA19696A true OA19696A (en) | 2021-02-26 |
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