HK1145148B - Solvate and crystalline forms of carbamoyl-cyclohexane derivatives - Google Patents

Description

Solvates and crystalline forms of carbamoyl-cyclohexane derivatives

Priority of U.S. provisional application No. 60/917,383, filed on 11/5/2007, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to solvates and crystalline forms of carbamoyl-cyclohexane derivatives, and more particularly to solvates and crystalline forms of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride. Methods of making these forms, compositions comprising these forms, and methods of using the same are also described.

Background

International publication No. WO 2005/012266 describes carbamoyl-cyclohexane derivatives which are D₃And D₂Preferred ligands for dopamine receptor subtypes. WO 2005/012266 describes trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-ethyl radical]-cyclohexyl } -3, 3-dimethyl-urea having para-dopamine D₃Binding affinity (IC) of receptors₅₀1-10nM) and para-dopamine D₂Binding affinity (IC) of receptors₅₀10-50 nM). Thus, trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl]-ethyl radical]-cyclohexyl } -3, 3-dimethyl-urea as mixed dopamine D₃/D₂Receptor ligands for use in the treatment of conditions requiring modulation of dopamine receptors.

A specific carbamoyl-cyclohexane derivative described in hungarian patent application No. P0700339 is trans-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -N, N-dimethylcarbamoyl-cyclohexylamine hydrochloride, also known as trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, the structural formula of which is shown in figure (I).

Hungarian patent application No. P0700339 describes a process for the preparation of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, a crystalline form of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, which is hereinafter referred to as "form I".

The present invention relates to the solid state physical properties of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride. These properties are adjusted by controlling the conditions under which the compound is formed into a solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. If the particles of the powdered compound do not flow readily with respect to each other, a formulation specialist must take this factor into account in developing a tablet or capsule formulation, which may require the use of glidants (glidants) such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound is its dissolution rate in aqueous fluids. The rate of dissolution of the active ingredient in the gastric juices of a patient may have a therapeutic effect, as it is the upper limit of the rate at which an orally administered active ingredient reaches the patient's bloodstream. Dissolution rates are also a consideration in syrups, elixirs and other liquid pharmaceutical preparations. The solid state form of a compound may also affect its compaction behavior and its storage stability.

These actual physical characteristics are influenced by the conformation and orientation of the molecules in the unit cell, defining a particular polymorphic form of a substance. Polymorphism may lead to thermal behavior different from that of amorphous materials or other polymorphs. Thermal behavior is measured in the laboratory by capillary melting point, thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) and can be used to distinguish some polymorphic forms. Particular polymorphic forms may also possess unique spectroscopic properties and may be detected by powder X-ray diffraction (XRPD), solid-state Nuclear Magnetic Resonance (NMR) spectrometry, raman spectrometry and Infrared (IR) spectrometry.

In determining the preferred polymorph, the various properties of the polymorph must be compared and the preferred polymorph selected based on the variables of the various physical properties. In some cases, where certain aspects, such as ease of preparation, stability, etc., are considered critical factors, it is entirely possible that a single polymorph may be preferred. In other cases, another polymorph is preferred for increased solubility and/or superior pharmacokinetics.

The discovery of polymorphs and solvates of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of pharmaceutical products. Which expands the types of materials available to formulation scientists for designing, for example, pharmaceutical dosage forms having a targeted release profile or other desired characteristics. Polymorphic forms or solvates of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride have now been found.

Disclosure of Invention

The present invention relates to solvates and crystalline forms of carbamoyl-cyclohexane derivatives, and more particularly to solvates and crystalline forms of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride. Methods of making these forms, compositions comprising these forms, and methods of using the same are also described.

Brief Description of Drawings

Figure 1 shows the X-ray powder diffraction pattern of crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 2 shows the FT raman spectrum of crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 3 shows the differential scanning calorimetry curve for crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 4 shows a thermogravimetric analysis of crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 5 shows an X-ray powder diffraction pattern of crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 6 shows the FT raman spectrum of crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 7 shows a differential scanning calorimetry curve for form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 8 shows a thermogravimetric analysis of crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 9 shows an X-ray powder diffraction pattern of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride carboxylic acid solvate.

Figure 10 shows the FT raman spectrum of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride carboxylic acid solvate.

Figure 11 shows the differential scanning calorimetry curve for trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride carboxylic acid solvate.

Figure 12 shows thermogravimetric analysis of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride carboxylic acid solvate.

Detailed Description

The present invention relates to solvates and crystalline forms of carbamoyl-cyclohexane derivatives, and more particularly to solvates and crystalline forms of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Hungarian patent application No. P0700339 describes a crystalline form of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, hereinafter referred to as polymorph "form I".

Figure 1 provides an X-ray powder diffraction pattern of form I. The X-ray powder diffraction pattern of form I has characteristic peaks at about 6.7, about 7.5, about 13.3, about 21.2 and about 23.1 ± 0.2 ° 2 Θ.

Figure 2 shows the FT raman spectrum of crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 3 shows a DSC curve for crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Figure 4 shows a thermogravimetric analysis of crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Crystalline form III

The present invention provides a crystalline form of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride (form III) which can be identified by one or more analytical methods. Figure 5 provides an X-ray powder diffraction pattern of form III.

In one embodiment, the present invention provides a crystalline form of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride (form III) characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 4.1, about 12.3, about 16.5 and about 17.4 ± 0.2 ° 2 Θ. In another embodiment, the X-ray diffraction pattern has at least one, such as at least two, at least three, or four, characteristic peaks selected from about 4.1, about 12.3, about 16.5, and about 17.4 ± 0.2 ° 2 Θ.

In another embodiment, form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride is characterized by an X-ray powder diffraction pattern substantially as shown in figure 5. With respect to the term "substantially", those skilled in the art will appreciate that the relative intensities of the peaks may vary depending on the sample preparation technique, the sample loading process, and the particular instrument employed. Also, instrument variables and other factors may affect the 2 θ value. Accordingly, the peak alignment of XRD may vary in the range of about ± 0.2 ° 2 θ.

Form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride can also be identified by its FT raman spectrum, as shown in figure 6.

In another embodiment, form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride can also be identified by its characteristic Differential Scanning Calorimetry (DSC) curve, as shown in figure 7. In another embodiment, form III is characterized by a DSC profile, exhibiting a melting endotherm at about 260 ℃.

Crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride thermogravimetric analysis (TGA) curve is shown in figure 8.

The present invention also provides a process for preparing crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

In one embodiment, form III is prepared by: trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride was dissolved in pyridine to form a solution (e.g., a supersaturated solution) from which crystalline form III was obtained.

In one embodiment, the pyridine mixture of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride is heated prior to recrystallization. Suitable temperatures are, for example, between about 30 ℃ and about 60 ℃, such as about 40 ℃ to 50 ℃, such as about 45 ℃.

In another embodiment, the starting material for the preparation of form III is form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Recrystallization may be carried out by any of a number of conventional methods in the art, such as by cooling or evaporation of the solvent to induce precipitation. In one embodiment, after dissolution, crystallization is induced by cooling the mixture. For example, the cooling may be performed at a temperature of about-10 ℃ to about 10 ℃. In another embodiment, the crystallization is obtained from a saturated solution at room temperature.

The crystalline form may be dried. For example, drying may be carried out at atmospheric pressure (e.g., allowing the solvent to evaporate), or at reduced pressure (less than 1 atmosphere), e.g., less than about 100mm Hg. For example, the drying may be performed at atmospheric pressure and room temperature.

In one embodiment, substantially pure crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride is isolated.

Formic acid solvate

In another embodiment, the present invention provides a formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride that can be identified by one or more analytical methods. Figure 9 provides an X-ray powder diffraction pattern of the formic acid solvate.

In one embodiment, the present invention provides a formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride characterized by an X-ray powder diffraction pattern having one or more characteristic peaks, in terms of ° 2 Θ, at about 3.8, about 7.4, about 18.3, about 24.2 and about 29.3 ± 0.2 °. In another embodiment, the X-ray diffraction pattern has at least one, such as at least two, at least three, at least four, or five characteristic peaks selected from the group consisting of at about 3.8, about 7.4, about 18.3, about 24.2, and about 29.3 ± 0.2 ° 2 Θ. In another embodiment, the formic acid solvate is characterized by an X-ray powder diffraction pattern substantially as shown in figure 9.

The formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride can also be identified by its FT raman spectrum, as shown in figure 10.

In another embodiment, the formic acid solvate can also be identified by its characteristic Differential Scanning Calorimetry (DSC) curve, as shown in figure 11. In another embodiment, the formic acid solvate can be characterized by a DSC curve that exhibits an endotherm at about 77 ℃ and a melting endotherm at about 262 ℃.

The thermogravimetric analysis (TGA) curve of the formic acid solvate is shown in figure 12.

At elevated temperatures, e.g., 90 ℃, such as upon heating in the solid state, the formic acid solvate may undergo desolvation (e.g., conversion to form I).

The present invention also provides a process for the preparation of a formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

In one embodiment, a formic acid solvate may be prepared by crystallizing a formic acid solvate from trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride in a slurry of formic acid.

In another embodiment, the starting material for preparing the formic acid solvate is crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

Recrystallization may be carried out by any of a number of conventional methods in the art, such as by cooling or evaporation of the solvent to induce precipitation. In one embodiment, after dissolution, crystallization is induced by cooling the mixture. For example, the cooling may be performed at a temperature of about-10 ℃ to about 10 ℃. In another embodiment, crystallization is obtained from a supersaturated solution at room temperature.

The crystalline form may be dried. For example, drying may be performed at atmospheric pressure (e.g., allowing the solvent to evaporate), or at reduced pressure (less than 1 atmosphere), such as below about 100mm Hg. For example, the drying may be performed at atmospheric pressure and room temperature.

Those skilled in the art will appreciate that the relative intensities and positions of the peaks obtained by X-ray powder diffraction and the bands obtained by infrared or raman spectroscopy may vary depending on such factors as the sample preparation technique, the sample loading process, and the particular instrument employed.

Composition comprising a metal oxide and a metal oxide

The polymorphs and/or solvates of the present invention may be administered alone or as the active ingredient of a formulation. Accordingly, the invention also includes pharmaceutical compositions of the polymorphic forms and solvates of the invention comprising, for example, one or more pharmaceutically acceptable carriers.

There are a number of standard documents describing methods for preparing various formulations suitable for administration of the compounds of the present invention. Examples of possible formulations and preparations include, for example, those described in Handbook of pharmaceutical Excipients (Handbook of pharmaceutical Excipients), american pharmaceutical association (latest edition); the dosage form of the medicine is as follows: the latest version of the tablet (compiled by Lieberman, Lachman and Schwartz), published by Markelike Dekker, Inc., and described in Remington's pharmaceutical sciences (compiled by Arthur Osol), 1553-.

Administration of the polymorphs and solvates of the present invention can be accomplished, for example, orally, intranasally, parenterally (subcutaneous, intravenous, intramuscular, intrasternal, and infusion), by inhalation, rectally, vaginally, topically, and by intraocular administration, as desired by the patient.

The polymorphs and solvates of the present invention can be administered using a variety of solid oral dosage forms including tablets, gel capsules, caplets, granules, lozenges, and bulk powders. The polymorphs and solvates of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and excipients known in the art, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, and the like. Time-release capsules, tablets and gels are also suitable for administration of the compounds of the invention.

The polymorphs and solvates of the present invention can also be administered using a variety of liquid oral dosage forms, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms may also contain suitable inert diluents (e.g., water) as are known in the art, and suitable excipients as are known in the art, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsifying and/or suspending the compounds of the present invention. The polymorphs and solvates of the present invention can be administered by injection in the form of an isotonic sterile solution, for example, intravenous injection. Other formulations are also possible.

Suppositories for rectal administration of the polymorphic forms and solvates of the invention are prepared by: the compounds are mixed with suitable excipients such as cocoa butter, salicylates, and polyethylene glycols. Formulations for vaginal administration may be in the form of pessaries, tampons, creams, gels, paste foams, or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For topical administration, the pharmaceutical composition may be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear, or nose. Topical administration may also involve transdermal administration by means such as transdermal patches.

Aerosols suitable for administration by inhalation may also be prepared. For example, for the treatment of respiratory diseases, the compounds of the invention may be administered by inhalation in the form of a powder (e.g. micronised) or in the form of an aerosolized solution or suspension. The aerosol formulation may be placed in a pressurized acceptable propellant.

In one embodiment, the present invention provides a composition comprising crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

In another embodiment, the present invention provides a composition comprising form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride and form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

In another embodiment, the present invention provides a composition comprising a formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

In another embodiment, the present invention provides a composition comprising a formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride and trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride of form I and/or form III.

The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a condition requiring modulation of a dopamine receptor, e.g. dopamine D₃And/or D₂The use in medicine for the treatment of a disorder of a receptor.

The invention further provides methods for treating a need for modulation of a dopamine receptor, e.g., dopamine D₃And/or D₂A method of treating a disease of a receptor. In another embodiment, the invention provides methods of using one or more compounds of the invention to treat a condition requiring modulation of dopamine D₃And/or D₂A method of treating a disease of a receptor.

Dysfunction of the dopaminergic neurotransmitter system is involved in the pathological processes of some neuropsychiatric and neurodegenerative diseases, such as schizophrenia, drug abuse and parkinson's disease. Dopamine action is mediated by at least 5 specific dopamine receptors, and belongs to D₁-(D₁，D₅) Or D₂-(D₂，D₃，D₄) A family. D₃Receptors have been shown to have a characteristic distribution in the brain dopaminergic system. That is, at certain edge structures, such as the nucleus and Carliger islandHigh density occurs. Thus, preferentially targeting D₃Receptors may be a promising approach for selectively modulating dopaminergic function, thereby achieving successful therapeutic intervention in certain abnormalities, such as schizophrenia, emotional and cognitive dysfunctions, as well as addiction ((see, e.g., Sokoloff, P. et al: Nature, 1990, 347, 146; Schwartz, J.C., et al: Clin. Neuropharmacol.1993, 16, 295; Levant, B.: Pharmacol. Rev.1997, 49, 231), addiction (see, e.g., Pilla, C. et al: Nature 1999, 400, 371) and Parkinson's disease (see, e.g., Levant, B. et al: CNS Drugs 1999, 12, 391) or pain (see, e.g., Levant, B. et al: Neurosci. Lett.2001, 303, 9)).

Dopamine D₂Receptors are widely distributed in the brain and are known to be involved in many physiological functions and pathological states. For example, D₂Antagonists are widely used as antipsychotics. However, as is well known, D₂Widespread antagonism of receptors can lead to undesirable side effects such as extrapyramidal motor symptoms, psychomotor sedation, or cognitive impairment. These side effects severely limit D₂Therapeutic use of antagonist compounds. (Wong A.H.C. et al: neurosci.Biobehav.Rev.2003, 27, 269.)

In another aspect, the invention provides methods for preferential modulation of dopamine D in need of treatment₃And/or D₂A method of treating a disease of a receptor, such as psychosis (e.g. schizophrenia, schizoaffective disorder), cognitive deficits associated with schizophrenia, mild to moderate cognitive impairment, dementia, psychotic states associated with dementia, psychotic depression, mania, acute mania, bipolar disorder, paranoid and delusional disorders, movement disorders such as parkinson's disease, psychotic depression induced parkinsonism, tardive dyskinesia, eating disorders (e.g. bulimia nervosa), attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, sexual dysfunction, sleep disorders, emesis, aggression, autism and drug abuse, which method comprises administering to a patient in need thereof an effective amount of a polymorph or solvate of the invention, or a combination thereof.

Deviation of the invention from D₃D of (A)₃/D₂Preferred uses of the antagonists are in the treatment of schizophrenia, schizoaffective disorders, cognitive deficits associated with schizophrenia, mild to moderate cognitive impairment, dementia-related psychotic states, psychotic depression, mania, acute mania, bipolar disorder, paranoia and delusional disorders, movement disorders such as Parkinson's disease, psychotic-induced parkinsonism, depression, anxiety and drug abuse (e.g. cocaine abuse).

In one embodiment, the disease treated is schizophrenia. In one embodiment, the condition treated is acute mania. In another embodiment, the condition treated is acute mania associated with bipolar disorder.

A particular combination of the actions of the two receptors mentioned above is capable of having D at the same time₃Antagonism (e.g. cognitive improvement, inhibition of extrapyramidal motor symptoms, inhibition of drug abuse) and D₂Antagonism (e.g., antipsychotic effect) of the beneficial effects. Moreover, the same combination surprisingly compensates for D₂Antagonism (e.g., extrapyramidal symptoms, psychomotor sedation, cognitive impairment).

In some embodiments, the compounds of the present invention may be administered as a monotherapy. In other embodiments, the compounds of the present invention are administered as part of a combination therapy. For example, the compounds of the present invention may be used in combination with other drugs or therapies that are useful in the treatment/prevention/inhibition or amelioration of the diseases or conditions that can be treated with the compounds of the present invention.

These other drugs may be administered simultaneously or sequentially with the compounds of the present invention, in their particular routes of administration and in the usual dosages. When a compound of the present invention is used in combination with one or more other drugs, a pharmaceutical unit dosage form containing such other drugs in addition to the compound of the present invention may be employed. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more additional active ingredients in addition to a compound of the present invention.

Typically, the compounds of the invention are administered in a daily dosage regimen (for adult patients), for example an oral dosage of the compounds of the invention is between 1 mg and 500 mg, for example 10-400 mg, for example 10-250 mg, or an intravenous, subcutaneous, or intramuscular dosage is between 0.1 mg and 100 mg, for example 0.1-50 mg, for example 1-25 mg.

In some embodiments, the amount of active ingredient administered is about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, or about 15 mg. For example, the active ingredient may be administered in an amount of about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, or about 6 mg. In physiological embodiments, the active ingredient is administered in an amount of about 1.5 mg, about 3 mg, or about 4.5 mg. In other embodiments, the amount of active ingredient administered is in a range between any two of these dosage ranges. For example, the active ingredient may be administered in an amount of about 0.5-12 mg, about 0.5-6 mg, about 1-6 mg. In an exemplary embodiment, the active ingredient is administered in an amount of about 1.5 mg to about 4.5 mg.

The compounds of the invention may be administered 1-4 times per day, for example once per day, twice per day. The compounds of the invention may suitably be administered for a sustained period of treatment, for example for a week or more.

Subjects suffering from, for example, schizophrenia, acute mania and other such conditions, and in need of treatment, may be treated by administering a therapeutically effective amount of the crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride (optionally in combination with one or more other crystalline forms of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, such as crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride together).

Subjects suffering from, for example, schizophrenia, acute mania and other such conditions, and in need of treatment, can be treated by administering a therapeutically effective amount of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride (optionally in combination with one or more other crystalline forms of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, such as form I and/or form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride together).

The terms "about" or "approximately" as used herein mean within an acceptable error range for the particular value determined by one of ordinary skill in the art, depending in part on the manner in which the value is measured or determined, i.e., the limits of the measurement system. For example, "about" can mean within 1 or a standard deviation of more than 1, in accordance with practice in the art. Alternatively, "about" may represent a range of up to 20%, preferably up to 10%, more preferably up to 5%, even more preferably up to 1% of the given value.

The term "substantially pure" means that the compound has a purity of greater than about 90% by weight, such as greater than about 91% by weight, greater than about 92% by weight, greater than about 93% by weight, greater than about 94% by weight, greater than about 95% by weight, greater than about 96% by weight, greater than about 97% by weight, greater than about 97.5% by weight, greater than about 98% by weight, greater than about 99% by weight, greater than about 99.5% by weight, or greater than about 99.9% by weight.

The term "treating" means alleviating, delaying, reducing, reversing, ameliorating, or preventing at least one symptom of a disease in a subject. The term "treating" may also mean terminating, delaying the onset of a disease (i.e., the stage prior to clinical manifestation of a disease) and/or reducing the risk of developing or worsening a disease.

By "effective amount" is meant an amount of a solvate or polymorph of the invention sufficient to effect treatment of a disorder, or an amount of a compound sufficient to modulate a dopamine receptor (e.g., dopamine D) when administered to a patient (e.g., a mammal) for treatment of such disorder₂And/or dopamine D₃Receptor) to achieve the object of the invention. The "effective amount" will vary depending on the compound, the disease and its severity, as well as the age, weight, etc., of the patient in need of treatment.

The subject or patient to whom a therapeutic compound is administered is preferably a human being, but can be any animal, including laboratory animals during clinical trials or screening or activity trials. Thus, it will be readily appreciated by those of ordinary skill in the art that the methods, compounds and compositions of the present invention are particularly suitable for administration to any animal, particularly mammals, including, but not limited to, humans, domestic animals such as cat or canine subjects, farm animals, such as, but not limited to, bovine, equine, caprine, ovine and porcine subjects, wild animals (whether wild or zoo animals), research animals, such as mice, rats, goats, sheep, pigs, dogs, cats and the like, birds, such as chickens, turkeys, singing birds and the like, i.e., for veterinary use.

The following examples are intended only to illustrate the invention and should not be construed as limiting the scope of the invention in any way, many variations and equivalents within the scope of the invention will be apparent to those skilled in the art upon reading the specification.

Examples

X-ray powder diffraction (XRD) analysis

A small amount of sample (approximately 12 mg) was loaded onto a zero background holder and exposed to CuK α radiation (30kV X15 mA) in a wide angle desktop X-ray diffractometer (model MiniFlex, Rigaku/MSC ltd, Woodlands, TX, texas, usa). The instrument was run in a step scan mode at 0.05 ° 2 θ increments. The angle range is 2-40 degrees 2 theta, and the scanning speed is 1.0-3.0 degrees 2 theta/min. Data collection and analysis was performed using commercially available software (JADE, version 7.1, Materials Data inc., Livermore, CA) from philips, california.

Fourier transform Raman Spectroscopy (FT-Raman)

A small amount of sample (approximately 5 mg) was loaded onto a glass slide and exposed to a raman laser in a raman spectrophotometer using Nicolet EZ omni 5.1 software (Thermo Nicolet Nexus 670 FT-IR/FT-raman spectrophotometer, Thermo Electron, Waltham MA, Waltham). All spectra were at 3600-100cm^-1Stokes shift, 100 scans and 2cm^-1At the resolution.

Differential Scanning Calorimetry (DSC):

a differential scanning calorimeter with a cryo-cooling attachment (MDSC Q1000, TA Instruments, New Castle, DE) was used. The instrument was calibrated with a pure indium sample. About 3-5 mg of sample was weighed into an open aluminum pan and heated at 10 deg.C/min under a dry nitrogen purge (flow rate 50 ml/min). Data analysis was performed using general analysis software 2000 (TA instruments, new sai, tera, usa).

Thermogravimetric analysis (TGA)

An air-cooled thermogravimetric analyzer (Pyris 1, PE corporation of welsley, MA) (Perkin Elmer, Wellesley, MA) was used. About 3-7 mg of sample was weighed into a TGA platinum pan and heated at 10 ℃/min under a dry nitrogen purge (flow rate 70 ml/min). Data analysis was performed with Pyris software (version 5.00.02, PE corporation of welsley, MA, Perkin Elmer, Wellesley).

Trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride crystalline form I was prepared as described in hungarian patent application No. P0700339.

General Experimental procedures

Trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride was crystallized with various solvents under the following three conditions:

(i) recrystallization from a saturated solution at room temperature,

(ii) recrystallization from saturated solutions at about 45-50 ℃, or

(iii) Recrystallisation from a slurry, i.e. from a supersaturated solution containing undissolved trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride.

To obtain different samples from a series of sample preparations, the following preparation methods were employed.

A weighed amount of crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride was dispersed in a glass test tube at 25 ℃ into a constant volume of the specified solvent, then capped and sonicated for 2 hours. One third of the sample was removed, filtered through a non-syringe (syringeless) filter and transferred to a well plate for recrystallization (condition (i)). The remaining sample was further sonicated/shaken in a water bath at about 45 ℃ for 2 hours. Half of the remaining sample was filtered and transferred to a well plate for recrystallization (condition (ii)). The remaining slurry remained unchanged in the test tube (condition (iii)). During the process, if at any point all of the starting material is dissolved in the solvent, more crystalline form I trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride is added to maintain saturation.

Recrystallization was performed at room temperature and the recrystallized sample was dried at ambient conditions.

Example 1: preparation of crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride

Using the general procedure described above, crystalline form III trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride was prepared using pyridine as the solvent and the product was isolated from the sample according to condition (ii).

Example 2: preparation of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride

Using the general procedure described above, a formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride was prepared using formic acid as the solvent and the product was isolated from the sample according to condition (iii).

Table 1 provides the peak positions of the XRPD patterns in fig. 5 (form III) and fig. 9 (formic acid solvate).

TABLE 1

While the invention has been depicted and described with reference to exemplary embodiments thereof, such references do not imply a limitation on the invention, and no such limitation is to be inferred. The invention is capable of considerable modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts and having the benefit of this description.

The depicted and described embodiments of this disclosure are exemplary only, and are not exhaustive of the scope of the disclosure. The invention, therefore, is not to be restricted except in the spirit and scope of the appended claims, giving full cognizance to equivalents in all respects.

All documents cited herein are incorporated by reference in their entirety.

Claims (14)

1. A crystalline form of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride, form III, having an X-ray powder diffraction pattern comprising characteristic peaks, in degrees 2 Θ, at 4.1, 12.3, 16.5 and 17.4 ± 0.2, as shown in figure 5.

2. The crystalline form of claim 1, which has an endotherm of melting at 260 ℃ as determined by DSC.

3. A method of preparing the crystalline form of claim 1, comprising:

(i) adding trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride to pyridine; and

(ii) precipitating said crystalline form from the solution.

4. The method of claim 3, wherein the mixture of step (i) is heated to 30-50 ℃.

5. The method of claim 3, wherein step (i) comprises forming a saturated solution.

6. The process of claim 3, further comprising step (iii) recovering the crystalline form.

7. The method of claim 6, wherein step (iii) comprises: (a) (iii) filtering the precipitate formed in step (ii) and (b) drying said crystalline form.

8. A formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride having an X-ray powder diffraction pattern comprising characteristic peaks, in degrees 2 Θ, at 3.8, 7.4, 18.3, 24.2 and 29.3 ± 0.2, as shown in figure 9.

9. A process for preparing the formic acid solvate of trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride of claim 8 comprising:

(i) mixing trans-1 {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea hydrochloride with formic acid to form a solvate, and

(ii) (ii) precipitating the solvate formed in step (i).

10. The method of claim 9, wherein step (i) comprises forming a slurry.

11. The process of claim 9, further comprising step (iii) recovering the formic acid solvate.

12. The method of claim 11, wherein step (iii) comprises: (a) (iii) filtering the precipitate formed in step (ii) and (b) drying said formic acid solvate.

13. A pharmaceutical composition comprising the crystalline form of claim 1 or 2.

14. A pharmaceutical composition comprising the formic acid solvate of claim 8.