WO2004007487A1 - Formes cristallines - Google Patents

Formes cristallines Download PDF

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Publication number
WO2004007487A1
WO2004007487A1 PCT/SE2003/001210 SE0301210W WO2004007487A1 WO 2004007487 A1 WO2004007487 A1 WO 2004007487A1 SE 0301210 W SE0301210 W SE 0301210W WO 2004007487 A1 WO2004007487 A1 WO 2004007487A1
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WO
WIPO (PCT)
Prior art keywords
compound
disorders
mixture
crystalline form
crystalline
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PCT/SE2003/001210
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English (en)
Inventor
Alan Kirschner
James Mccabe
Edward Pierson
Emyr Williams
Ingvar Ymén
Original Assignee
Astrazeneca Ab
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Publication date
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Priority to AU2003281053A priority Critical patent/AU2003281053A1/en
Publication of WO2004007487A1 publication Critical patent/WO2004007487A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • the present invention relates to novel crystalline forms of 6-fluoro-8-(4-methyl- piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]- amide, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.
  • Serotonin (5-HT) is implicated in many psychiatric disorders including, but not limited to, depression, generalized anxiety, eating disorders, dementia, panic disorder, and sleep disorders. Serotonin is also implicated in gastrointestinal disorders, cardiovascular regulation, motor disorders, endocrine disorders, vasospasm and sexual dysfunction. Serotonin receptors are subdivided into at least 14 subtypes, see Barnes & Sharp, 1999, Neuropharmacology, 38:1083-1152, which is incorporated herein by reference. These various subtypes are responsible for serotonin's action in many pathophysiological conditions.
  • the 5-HT ⁇ family of receptors has high affinity for serotonin and consists of five related receptors, including the 5-HT JB and 5-HT J D receptor subtypes.
  • Compounds that interact with the 5-HT ⁇ family are known to have therapeutic potential in the above mentioned disorders and diseases.
  • compounds that are 5HT IB and 5HT ! D antagonist are known to be antidepressant and anxiolytic agents.
  • Compounds that are 5HTi B and 5HT J D agonists have been used in the treatment of migraine.
  • the active pharmaceutical ingredient in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g., oral dosage forms such as tablets) comprising the active pharmaceutical ingredient.
  • Amorphous materials are typically more difficult to handle and to formulate, provide unreliable dissolution, and are often unstable. Thus, in the manufacture of commercially viable and pharmaceutically-acceptable drug compositions, it is desirable to provide the active pharmaceutical ingredient in a substantially crystalline and stable form.
  • Figure 1 is an X-ray powder diffractogram of 6-f ⁇ uoro-8-(4-methyl-piperazin ⁇ l-yl)-4- oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-p hen yl] -amide form I.
  • Figure 2 is an X-ray powder diffractogram of 6-fluoro-8-(4-methyl-piperazin-l-yl) ⁇ 4- oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide form II.
  • Figure 3 is an X-ray powder diffractogram of 6-fluoro-8-(4-methyl-piperazin-l-yl)-4- oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide form LU.
  • the present invention provides crystalline forms of 6-fluoro-8-(4-methyl-piperazin-l-yl)- 4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide, referred to herein as Compound I, having the following structure:
  • Compound I is a 5-HT]B ligand, capable of acting as an antagonist at 5-HTi B receptors.
  • crystalline forms of Compound I exhibit properties such as convenient handling and chemical and solid-state stability. Crystalline forms of Compound I are referred to herein as "forms.” Numeric designations provided herein for crystalline forms of Compound I are arbitrary and do not refer to relative thermodynamic stability or any other characteristic.
  • One aspect of the present invention provides Compound I, in substantially crystalline form.
  • the term "substantially crystalline” means at least about 50% crystalline and ranging up to about 100% crystalline.
  • the present invention provides Compound I that is at least about 50% crystalline, at least about 60% crystalline, at least about 70% crystalline, at least about 80% crystalline, at least about 90% crystalline, at least about 95% crystalline, at least about 98% crystalline, or at least about 100% crystalline in form.
  • X-ray powder diffraction X-ray powder diffraction
  • Other techniques such as solid-state nuclear magnetic resonance (NMR), FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
  • Crystalline forms of Compound I may be in the form of a solvate, including but not limited to a hydrate (e.g., a monohydrate), or otherwise (e.g., in the form of an anhydrate).
  • a hydrate e.g., a monohydrate
  • otherwise e.g., in the form of an anhydrate.
  • Compound I is in the form of an anhydrate.
  • the crystalline form of Compound I is in the form of a hydrate.
  • the compounds of the invention have improved stability over 6- fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl- piperazin-l-yl)-phenyl]-amide prepared as described in U.S. Patent Application No. 10/051,776.
  • stable or “stability” include chemical stability and solid-state stability.
  • chemical stability means that the compound can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g., in an oral dosage form, such as tablet, capsule, etc.), under normal storage conditions, with little or no chemical degradation or decomposition.
  • Solid-state stability means that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g., in an oral dosage form, such as tablet, capsule, etc.), under normal storage conditions, with little or no solid-state transformation (e.g., crystallization, recrystallization, solid-state phase transition, hydration, dehydration, solvatization or desolvatization).
  • pharmaceutically acceptable carriers, diluents or adjuvants e.g., in an oral dosage form, such as tablet, capsule, etc.
  • Examples of "normal storage conditions” include temperatures ranging from about minus 80 °C to about plus 50 °C, from about 0 °C to about plus 40 °C, and from 15 °C to about 30 °C; pressures ranging from about 0.1 bars to about 2 bars, more particularly at about atmospheric pressure; relative humidities ranging from about 5% to about 95%, more particularly from about 10% to about 75%; and/or exposure to 460 lux of UV/visible light for prolonged periods, for example, at least about 6 months.
  • Compound I form I is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 1, and exhibiting substantially the following 2-theta values and relative intensities:
  • Compound I form I is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.
  • Compound I form II is anhydrous and is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 2, and exhibiting substantially the following 2-theta values and relative intensities:
  • Compound I form II is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.
  • Compound I form III is a monohydrate and is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 3, and exhibiting substantially the following 2-theta values and relative intensities:
  • Compound I form III is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.
  • the compounds of the present invention may be obtained by crystallizing Compound I.
  • a suitable solvent system may be heterogeneous or homogeneous and may thus comprise one or more solvents.
  • appropriate solvents include, but are not limited to alkyl acetates (e.g., linear or branched C ⁇ -6 alkyl acetates, such as ethyl acetate, isopropyl acetate, butyl acetate and n-butyl acetate), lower
  • alkyl alcohols e.g., methanol, ethanol, iso-propanol
  • aliphatic hydrocarbons e.g., iso-octane, n-heptane
  • aromatic hydrocarbons e.g., toluene
  • dialkyl ketones e.g., acetone, methyl iso-butyl ketone
  • acetonitrile dichloromethane (methylene chloride), dimethylsulfoxide, tetrahydrofuran, dialkyl ethers (e.g., di-isopropyl ether), amides
  • Crystallization of compounds of the present invention from a suitable solvent system, containing at least one solvent may be achieved by attaining supersaturation in a solvent system, by solvent evaporation, by temperature decrease, and/or via the addition of anti-solvent (i.e., a solvent in which the compounds of the invention are poorly soluble).
  • anti-solvent i.e., a solvent in which the compounds of the invention are poorly soluble.
  • Crystallization temperatures and crystallization times will depend upon the concentration of the compound in solution, and upon the solvent system used.
  • LUU4ZJ Crystallization may also be initiated and/or effected with or without seeding with crystals of the appropriate crystalline compound of the invention, and/or by adjustment of pH.
  • Compounds of the invention may be prepared in the form of solvates, hydrates, and anhydrates, and salts.
  • anhydrate or a solvate crystallizes is related to the kinetics and equilibrium conditions of the respective forms at the specific conditions.
  • the crystalline form that is obtained depends upon both the kinetics and the thermodynamics of the crystallization process. Under certain thermodynamic conditions (e.g., solvent system, temperature, pressure and concentration of compound of the invention), one crystalline form may be more stable than another (or indeed any other).
  • Crystalline forms that have a relatively low thermodynamic stability may be kinetfcally favored. Therefore, kinetic factors such as time, impurity profile, agitation, the presence or absence of seeds, etc., may influence which form crystallizes.
  • kinetic factors such as time, impurity profile, agitation, the presence or absence of seeds, etc.
  • One of skill in the art may, therefore, adapt the procedures discussed herein in order to obtain different crystalline forms.
  • a further aspect of the present invention is to provide processes for the preparation of 6- fluoro-8-(4-methyl-piperazin- l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl- piperazin-l-yl)-phenyl] -amide (Compound I) crystalline forms I, II, and III.
  • Compound I form I can be obtained upon crystallization from a mixture of dichloromethane and ethanol.
  • Compound I form II can be obtained upon crystallization from a mixture of dimethylsulf oxide, water and ethanol.
  • Compound I form III can be obtained upon crystallization from a mixture of dimethylsulfoxide and water.
  • Each of crystalline forms I, II, and III of 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H- chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide, obtained according to the present invention, are substantially free from other crystal and non-crystal forms of 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl- piperazin-l-yl)-phenyl]-amide.
  • substantially free from other crystal and non-crystal forms means that the desired crystal form of 6-fluoro-8-(4-methyl-piperazin-l- yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]-amide, prepared according to the present invention, contains less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5% or about 0% of any other crystal and non- crystal forms of 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4- (4-propionyl-piperazin- 1 -yl)-phenyl] -amide.
  • One method to ensure that a particular crystalline form is prepared in the absence of other crystalline forms is to carry out crystallization by seeding with nuclei and/or seed crystals of the desired crystalline form in the complete absence of nuclei and/or seed crystals of other crystalline forms.
  • Compounds of the invention may be isolated using any of a variety of techniques well known to those of skill in the art, including, but not limited to, decanting, filtering, or centrifuging.
  • compositions comprising the compounds of the invention.
  • a pharmaceutical composition of the invention may comprise a compound of the invention in admixture with at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, and optionally other therapeutic ingredients.
  • the compounds of the invention may be further processed before formulation into a suitable pharmaceutical composition.
  • the crystalline form may be milled or ground into smaller particles.
  • any of the compounds of the invention in the manufacture of a medicament for use in the treatment of depression, generalized anxiety, eating disorders, dementia, panic disorders, sleep disorders, gastrointestinal disorders, motor disorders, endocrine disorders, vasospasm, or sexual dysfunction.
  • a method of treatment of a human or animal suffering from depression, generalized anxiety, eating disorders, dementia, panic disorder, sleep disorders, gastrointestinal disorders, motor disorders, endocrine disorders, vasospasm, or sexual dysfunction comprising administering to the human or animal an effective amount of any of the compounds of the invention.
  • treating includes therapeutic treatment, as well as prophylaxis of a disease or condition. Additionally, “treating” or “treatment” refers to the amelioration and/or elimination of a disease or condition.
  • the compounds of the present invention may be administered and used as described in U.S. Patent Application 10/051,776.
  • the compounds of the invention have the advantage that they are in a form that provides for improved ease of handling. Further, the compounds of the invention have the advantage that they may be produced in forms that have improved chemical and solid-state stability as well as lower hygroscopicity. Thus, the compounds may be stable when stored over prolonged periods.
  • the invention is further illustrated by way of the following examples, which are intended to elaborate several embodiments of the invention. These examples are not intended to, nor are they to be construed to, limit the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the present invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.
  • Example 1 Experimental procedures. Standard X-ray diffraction measurement conditions
  • X-ray powder diffraction analyses were performed on samples prepared according to standard methods (see for example Giacovazzo et al., eds., Fundamentals of Crystallography, Oxford University Press (1992); Jenkins & Snyder, eds., Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York (1996); Bunn, ed., Chemical Crystallography, Clarendon Press, London (1948); and Klug & Alexander eds., X-ray Diffraction Procedures, John Wiley & Sons, New York (1974), each of which is incorporated herein by reference).
  • X-ray analyses were performed using a Siemens D5000 diffractometer.
  • Sample preparation for D5000 -30 mg material, silicon wafers. Samples were spun at 30 rpm to improve counting statistics. X-rays were generated by a: 'copper long-fine focus tube' operated at 40 kV and 40 mA, wavelength of X-rays - 1.54 A. The data for each sample were obtained using the standard scintillation detector. The collimated X-ray source was passed through an Automatic Variable Divergence Slit set at V20 (20mm path-length) and the reflected radiation directed through a 2 mm anti-scatter slit and a 0.2mm detector slit. Each sample was exposed for 1 second per 0.02° 28 increment (continuous scan mode) over the range 2° to 40° 28 in theta-theta mode. The running time for each sample was thus 31 minutes 41 seconds. The secondary soller slit was left in position.
  • a Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac+ version was used for control and data capture. The following definitions were used to compare relative intensities:
  • DSC showed onset of melting at 246.4 °C with peak at 247.2 °C
  • Example 4 Compound I Free Base Form III (Monohydrate). [0074] A mixture of Compound I free base (20.0 g) and dimethylsulfoxide (240 ml) was heated to 95 °C. The solution was screened through filter aid, which was washed with dimethylsulfoxide (40 ml). The combined filtrate plus wash was cooled to 85 °C and water (180 ml) was added over 20 minutes whereupon the temperature rose to 87 °C. The mixture was cooled and stirred at 23 °C for 16 hours and then at 4 °C for a further one hour. The solid was filtered off, washed with a mixture of water (40 ml) and ethanol (40 ml) and dried overnight in vacuo at 60 °C. The yield of Compound I free base Form III was 18.7 g.
  • DSC showed loss of water (hydrate) (onset 53.3 °C, peak 78.4 °C) followed by onset of melting at 232.7 °C with a peak at 236.9 °C.
  • Asymmetric unit C 28 H 32 F N 5 0 * H 2 0 Cell parameters: from 1
  • Triclinic M 0.10 mm "1
  • V 1347.5(2) A 3 Brownish yellow prism
  • Atomic scattering factors from D. Waasmaier & A.Kirfel
  • the overall conformation of the molecule is bent with two 'arms' of different lengths stretching outwards and forming a cavity. These 'arms' are the substituted pyrazinyl rings, deviating from the fluorine substituted ten-member chromene plane.
  • the substance crystallizes from wet methanol as a monohydrate.
  • the water molecule is H-bonded in the cavity.
  • the space group is triclinic P-l.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Endocrinology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
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Abstract

L'invention concerne de nouvelles formes cristallines de [4-(4-propionyl-pipérazine-1-yl)-phényl]-amide de l'acide 6-fluoro-8-(4-méthyl-pipérazine-1-yl)-4-oxo-4H-chromène-2-carboxylique. L'invention concerne également l'utilisation desdits composés pour le traitement de la dépression, d'états d'anxiété généralisée, de troubles de l'alimentation, d'états démentiels, de troubles paniques, de troubles du sommeil, de troubles gastrointestinaux, de troubles moteurs, de troubles endocriniens, de spasmes vasculaires, ou de dysfonctionnement sexuel. L'invention concerne en outre des compositions pharmaceutiques renfermant les composés précités et des procédés permettant leur obtention.
PCT/SE2003/001210 2002-07-15 2003-07-14 Formes cristallines WO2004007487A1 (fr)

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US39626202P 2002-07-15 2002-07-15
US60/396,262 2002-07-15

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055013A2 (fr) * 2001-01-16 2002-07-18 Astrazeneca Ab Composes de chromone therapeutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002055013A2 (fr) * 2001-01-16 2002-07-18 Astrazeneca Ab Composes de chromone therapeutiques

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