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WO2010123441A1 - Forme cristalline de l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-n-propylcinnoline-3-carboxamide pour le traitement de troubles liés à l'anxiété - Google Patents

Forme cristalline de l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-n-propylcinnoline-3-carboxamide pour le traitement de troubles liés à l'anxiété Download PDF

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Publication number
WO2010123441A1
WO2010123441A1 PCT/SE2010/050425 SE2010050425W WO2010123441A1 WO 2010123441 A1 WO2010123441 A1 WO 2010123441A1 SE 2010050425 W SE2010050425 W SE 2010050425W WO 2010123441 A1 WO2010123441 A1 WO 2010123441A1
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Prior art keywords
amino
fluoro
methoxy
propylcinnoline
phenyl
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English (en)
Inventor
Simon Nicholas Black
Stephen David Cosgrove
Marc Mccormick
Jim Osborn
Julie Reid
Dedong Wu
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • 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

Definitions

  • the present invention relates to a new salt of 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide and polymorphs thereof.
  • the invention also concerns pharmaceutical compositions which include the salt, as well as processes for the manufacture of the salt.
  • the drug substance In the formulation of drug compositions, it is desirable for the drug substance to be 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 comprising the active compound. Further, in the manufacture of drug compositions, it is desirable that a reliable, reproducible and constant plasma concentration profile of drug is provided following administration to a patient.
  • the drug substance, and compositions containing it should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
  • FIG. 1 shows an X-ray powder diffractogram for the form A of 4-Amino-8-(2-fluoro-6- methoxy-pheny ⁇ -N-propylcinnoline-S-carboxamide hydrogen sulphate.
  • FIG. 2 shows an X-ray powder diffractogram for the form N of 4-Amino-8-(2-fluoro-6- methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate.
  • FIG. 3 shows an X-ray powder diffractogram for the form B of 4-Amino-8-(2-fluoro-6- methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate.
  • FIG. 4 shows an X-ray powder diffractogram for the amorphous form of 4-Amino-8-(2- fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate.
  • FIG. 5 shows the DSC trace of the amorphous 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide hydrogen sulphate.
  • FIG. 6 shows the dynamic vapor absorption/desorption isotherm for amorphous 4-Amino- 8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate.
  • the present invention provides a salt of 4-Amino-8-(2-fluoro-6- methoxy-phenyl)-N-propylcinnoline-3-carboxamide.
  • the present invention relates to a salt of the compound 4-Amino- 8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide, which is a sulphate of said compound.
  • the present invention provides 4-Amino-8-(2-fluoro-6-methoxy- phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate.
  • the present invention provides a 4-Amino-8-(2-fluoro-6- methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate, which is substantially crystalline.
  • Another embodiment of the invention relates to a hydrogen sulphate salt of 4-Amino-8-(2- fluoro- ⁇ -methoxy-phenyO-N-propylcinnoline-S-carboxamide having an X-ray powder diffraction pattern with specific peaks at 2 ⁇ values at about 9.37, about 14.57, about 22.08, about 27.61 and about 28.13 °, and/or essentially as defined in Table 1 and/or essentially as defined in Figure 1.
  • Another embodiment of the invention relates to a hydrogen sulphate salt of 4-Amino-8-(2- fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide having an X-ray powder diffraction pattern with specific peaks at 2 ⁇ values at about 14.22, about 21.07, about 23.47 and about 26.02 °, and/or essentially as defined in Table 2 and/or essentially as defined in Figure 2.
  • a further embodiment of the invention relates to a hydrogen sulphate salt of 4-Amino-8-(2- fluoro- ⁇ -methoxy-phenyO-N-propylcinnoline-S-carboxamide having an X-ray powder diffraction pattern with specific peaks at 2 ⁇ values at about 7.12, about 8.20, about 16.36 and about 22.89 °, and/or essentially as defined in Table 3 and/or essentially as defined in Figure 3.
  • a further embodiment of the invention relates to an amorphous hydrogen sulphate salt of 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide.
  • the X-ray powder diffraction patterns for typical samples of the salts of the present inven- tion are shown in the Figures hereinafter. It will be understood that the X-ray powder diffraction patterns may vary slightly from one machine to another or from one sample to another, and so the 2 ⁇ values quoted are not to be construed as absolute.
  • a salt of the invention in substantially crystalline form.
  • salts of the invention in forms which are greater than 80% crystalline, by “substantially crystalline” we include greater than 20%, preferably greater than 30%, and more preferably greater than 40% (e.g. greater than any of 50, 60, 70, 80 or 90%) crystalline.
  • a salt of the invention in partially crystalline form.
  • partially crystalline we include 5% or between 5% and 20% crystalline.
  • the degree (%) of crystallinity may be determined by the skilled person using X-ray powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
  • XRPD X-ray powder diffraction
  • Other techniques such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
  • salts of the invention 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 a tablet, capsule etc.), under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
  • solid state stability we include that it may be possible to store salts of the invention 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 a tablet, capsule etc.), under normal storage conditions, with an insignificant degree of solid state transformation (e.g. crystallisation, recrystallisation, solid state phase transition, hydration, dehydration, solvation or desolvation).
  • pharmaceutically acceptable carriers diluents or adjuvants
  • normal storage conditions include temperatures of between minus 80 and plus 50 0 C (preferably between 0 and 40 0 C and more preferably room temperatures, such as 15 to 30°C), pressures of between 0.1 and 2 bars (preferably at atmospheric pressure), relative humidities of between 5 and 95% (preferably 10 to 60%), and/or exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months).
  • salts of the invention may be found to be less than 15%, more preferably less than 10%, and especially less than 5%, chemically degraded/decomposed, or solid state transformed, as appropriate.
  • a further aspect of the present invention comprises processes for the preparation of the salts.
  • the precise conditions under which the salts are formed may be empirically determined.
  • the salts may be obtained by crystallisation under controlled conditions.
  • One embodiment of the invention relates to a process for the preparation of a salt according to the present invention, which process comprises addition of the appropriate acid to a solution or slurry of 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3- carboxamide in suitable solvent or liquid.
  • the appropriate acid is added to 4-Amino-8- (2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide dissolved in a solvent selected from the group: DMSO, DMF, acetates, lower alkyl alcohols, aliphatic and aromatic hydrocarbons, dialkyl ethers, dialkyl ketones, acetonitrile, chlorinated alkanes, aqueous solvents, or mixtures thereof.
  • a solvent selected from the group: DMSO, DMF, acetates, lower alkyl alcohols, aliphatic and aromatic hydrocarbons, dialkyl ethers, dialkyl ketones, acetonitrile, chlorinated alkanes, aqueous solvents, or mixtures thereof.
  • the solvent is selected from the group: DMSO, DMF, C 1-6 -alkyl acetates, linear or branched C 1-6 -alkyl alcohols, C 6- i 2 -aliphatic hydrocarbons, C 6- io-aromatic hydrocarbons, di-C 1-6 -alkyl ethers, di-C 1-6 -alkyl ketones, chlorinated methanes or ethanes, acetonitrile, water, or mixtures thereof.
  • the solvent is selected from the group: DMSO, DMF, ethyl acetate, /so-propyl acetate, methanol, ethanol, /so-propanol, n- heptane, diethyl ether, acetone, dichloromethane, water, or mixtures thereof.
  • the solvent is selected from the group: water, DMSO, DMF, ethyl acetate, methyl /so-butyl ketone, and /so-propyl acetate.
  • the appropriate acid is added to 4-Amino- 8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide slurried in a liquid selected from the group: DMSO, DMF, acetates, lower alkyl alcohols, aliphatic and aromatic hydrocarbons, dialkyl ethers, dialkyl ketones, acetonitrile, chlorinated alkanes, aque- ous liquids, or mixtures thereof.
  • a liquid selected from the group: DMSO, DMF, acetates, lower alkyl alcohols, aliphatic and aromatic hydrocarbons, dialkyl ethers, dialkyl ketones, acetonitrile, chlorinated alkanes, aque- ous liquids, or mixtures thereof.
  • the liquid is selected from the group: DMSO, DMF, C 1-6 alkyl acetates, linear or branched C 1-6 alkyl alcohols, C 6- i 2 aliphatic hydrocarbons, C 6- ioaromatic hydrocarbons, di-Ci -6 alkyl ethers, di-Ci -6 alkyl ketones, chlorinated methanes or ethanes, acetonitrile, water, or mixtures thereof.
  • the liquid is selected from the group: DMSO, DMF, ethyl acetate, /so-propyl acetate, methanol, ethanol, 1-propanol, iso- propanol, n-heptane, diethyl ether, acetone, dichloromethane, water, or mixtures thereof.
  • the liquid is 1-propanol, isopropyl acetate, DMSO, water or a mixture thereof.
  • Crystallisation temperatures and crystallisation times depend upon the salt that is to be crystallised, the concentration of that salt in solution, and the solvent system which is used.
  • Crystallisation may also be initiated and/or effected by way of standard techniques, for example with or without seeding with crystals of the appropriate crystalline salt of the invention.
  • certain polymorph of the present invention shows an improved solid state stability under normal storage conditions.
  • form A of 4-Amino-8-(2- fluoro- ⁇ -methoxy-phenyO-N-propylcinnoline-S-carboxamide hydrogen sulphate may show an improved solid state stability.
  • One embodiment of the invention relates to a pharmaceutical formulation including a salt according to the present invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Another embodiment of the invention relates to a salt according to the present invention for use as a medicament.
  • a yet further embodiment of the invention relates to the use of a salt according to the pre- sent invention in the manufacture of a medicament for the therapy of pain.
  • One embodiment of the invention relates to the use of a salt according to any the present invention in the manufacture of a medicament for the treatment of anxiety disorders.
  • Another embodiment of the invention relates to the use of a salt according to the present invention in the manufacture of a medicament for the treatment of dementia, Alzheimer's disease, cognition deficiency, cognition deficiency associated with schizophrenia.
  • a further embodiment of the invention relates to a method for the therapy of anxiety disorders in a warm-blooded animal, comprising the step of administering to the animal in need of such therapy a therapeutically effective amount of a salt according to the present invention.
  • a yet further embodiment of the invention relates to a method for the treatment of anxiety disorders, whereby a pharmaceutically and pharmacologically effective amount of a salt according to the present invention is administered to a subject in need of such treatment.
  • One embodiment of the invention relates to a method for the treatment of pain, whereby a pharmaceutically and pharmacologically effective amount of a salt according to the present invention is administered to a subject in need of such treatment.
  • the quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 pg/kg to 10 mg/kg per day.
  • dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art.
  • the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the invention.
  • the salts and polymorphs thereof described herein are central nervous system depressants and may be used as tranquilizers or ataractic agents for the relief of anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species such as humans, in the same manner as chlordiazepoxide.
  • salts may be administered orally or parenterally in a conventional dosage form such as tablet, pill, capsule, injectable or the like.
  • the dosage in mg/kg of body weight of salts of the present invention in mammals will vary according to the size of the animal and particularly with respect to the brain/body weight ratio.
  • a minimum effective dosage for the salts will be at least about 0.1 mg/kg of body weight per day for mammals with a maximum dosage for a small mammal such as a dog, of about 100 mg/kg per day.
  • a dosage of about 0.1 to 12 mg/kg per day will be effective, for example, about 5 to 600 mg/day for an average man.
  • the dosage can be given once daily or in divided doses, for example, 2 to 4 doses daily, and such dosage will depend on the duration and maximum level of activity of the salt.
  • the dose may be conventionally formulated in an oral or parenteral dosage form by compounding about 5 to 250 mg per unit of dosage of conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice, for example, as described in U.S. Pat. No. 3,755,340.
  • the salts of this invention may be used in pharmaceutical compositions comprising a salt described herein or can be contained in the same formulation with or co-administered with one or more known drugs.
  • Some example tests that can be conducted to demonstrate the anxiolytic activity of the present compounds include binding tests of GABAA receptors.
  • the binding test was directed to a subtype of GABAA receptors, such as GABAA1 receptors (i.e., those containing the O 1 subunit), GABAA2 receptors (i.e., those containing the ⁇ 2 subunit), GABAA3 receptors (i.e., those containing the ⁇ 3 subunit) and GABAA5 receptors (i.e., those containing the ⁇ 5 subunit).
  • GABAA1 receptors i.e., those containing the O 1 subunit
  • GABAA2 receptors i.e., those containing the ⁇ 2 subunit
  • GABAA3 receptors i.e., those containing the ⁇ 3 subunit
  • GABAA5 receptors i.e., those containing the ⁇ 5 subunit
  • anxiolytics lack GABAA receptor subtype-selectivity.
  • the subtype-selective GABAA receptor modulators may offer more advantages. For example, a growing body of work suggests that desirable anxiolytic activity is driven primarily by interactions with GABAA receptors containing the ⁇ 2 subunit. Sedation, a side-effect common to all marketed benzodiazepines, is believed to be mediated by interactions at GABAARs containing the ⁇ ⁇ subunit. To develop anxiolytics with minimal liabilities due to interactions with other subunits, an electrophysiological assay was developed to screen modulatory effects of various compounds on different GABA subunit combinations heterologously expressed in Xenopus oocytes.
  • GABAA receptors are heterologously expressed in Xenopus oocytes by injecting cRNA corresponding to human ⁇ i, ⁇ 2 , ⁇ 3 , ⁇ 5 , ⁇ 2 , ⁇ 3 and ⁇ 2 subunits of the GABAA receptor genes.
  • the specific subunit combinations (subtypes) are as follows: ⁇ D ⁇ 2 ⁇ 2 , ⁇ 2 ⁇ 3 ⁇ 2 , ⁇ 3 ⁇ 3 ⁇ 2 , and ⁇ 5 ⁇ 3 ⁇ 2 .
  • the EC10 of GABA is approximated for each cell. Stability of GABA-mediated (EC10) current is established. Modulatory effect of test compound is determined and compared across subtypes.
  • the assay developed has reproducibility which allows discrimination of modulatory activity down to minimal effect of about 25% potentiation (prior to normalization to standard) for all four subtypes.
  • the assay can characterize modulatory effects and determine subtype selectivity of test compounds on major subtypes of GABAA receptors.
  • a salt can selectively bind to one subtype of GABAA receptor (by showing about 25% or more of binding comparing to another subtype of GABAA receptor).
  • Anxiolytic activity is indicated in the GABAA binding test by a displacement of the flunitrazepam such as is exhibited by benzodiazepines or by enhancement of the binding such as is shown by cartazolate and tracazolate.
  • the salts of the invention can bind to GABAA receptors. In some embodiments, the salts of the invention can bind to GABAA receptors by displacement of benzodiazepines. Accordingly, the salts of the invention can be used to modulate activities of GABAA receptors.
  • the salts of the invention can selectively bind to a subtype of GABAA receptors, such as such as GABAA1 receptors (i.e., those containing the ⁇ i subunit), GABAA2 receptors (i.e., those containing the 0 2 subunit), GABAA3 receptors (i.e., those containing the ⁇ 3 subunit) or GABAA5 receptors (i.e., those containing the ⁇ 5 subunit).
  • the salts of the invention can selectively bind to a subtype of GABAA receptors by displacement of benzodiazepines. Accordingly, the salts of the invention can be used to selectively modulate activities of a subtype of GABAA receptors, such as GABAA1 receptors, GABAA2 receptors, GABAA3 receptors or GABAA5 receptors.
  • certain salts of the invention are GABAA1 receptor antagonists and GABAA2 receptor agonists.
  • the salts of the invention can be used to modulate activities of GABAA receptors, or to selectively modulate activities of a subtype of GABAA receptors, the salts of the invention are envisioned to be useful for treating or preventing diseases mediated by GABAA receptors or a subtype of GABAA receptors.
  • Such disease include, but is not limited to, stroke, head trauma, epilepsy, pain, migraine, mood disorders, anxiety, post traumatic stress disorder, obsessive compulsive disorders, schizophrenia, seizures, convulsions, tinnitus, neurodegenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's Chorea, Parkinson's disease, depression, bipolar disorders, mania, trigeminal and other neuralgia, neuropathic pain, hypertension, cerebral ischemia, cardiac arrhythmia, myotonia, substance abuse, myoclonus, essential tremor, dyskinesia and other movement disorders, neonatal cerebral hemorrhage, spasticity, cognitive disorder, and sleeping disorder.
  • X-ray powder diffraction analysis is performed using variable slits on samples prepared according to standard methods, for example those described in Giacovazzo, C. et a/ (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.
  • X-ray analyses are performed using Bruker D5000 diffracto meter.
  • the testing sample is mounted on to a zero background silicon wafer.
  • the radiation is Cu K 0 , with a wavelength of 1.54A.
  • the scan start angle is 2°2 ⁇ and the scan finish angle is 40°2 ⁇ with increments at 0.03°2 ⁇ .
  • the scan time is 30 minutes.
  • crystalline forms of compounds of the invention may be prepared by analogy with processes described herein and/or in accordance with the Examples below, and may show essentially the same XRPD diffraction patterns as those disclosed herein.
  • essentially the same XRPD diffraction patterns we include those instances when it is clear from the relevant patterns (allowing for experimental error) that essentially the same crystalline form has been formed.
  • XRPD 2 ⁇ values may vary in the range ⁇ 0.1 °
  • XRPD intensities may vary when measured for essentially the same crystalline form for a variety of reasons including, for example, preferred orientation.
  • Tetrahydrofuran (515 mL, anhydrous) and isopropanol (147 mL, anhydrous) were added and the resulting red suspension was stirred at room temperature for 15 minutes.
  • a solution of sodium carbonate (57.0 g, 537.7 mmol) in water (220 mL) was added rapidly through the addition funnel and the resulting mixture immediately placed into a pre-heated 8O 0 C oil bath. After 90 minutes at reflux (observed internal temperature 65°C), the reaction mixture was cooled to room temperature and filtered though a bed of Celite supported on a sintered glass funnel topped with Norite decolorizing carbon (30 g). The residua!
  • Example 2 4-Amino-8-bromo-N-propyl-cinnoline-3-carboxamide 4-Amino-8-bromo-N-propyI-cinnoline-3-carboxamide may be prepared according to the method described in the U.S. Patent No. 4,886,800 example 35a.
  • a 1 litre jacketed vessel equipped with an overhead stirrer was charged with 2[(2- bromophenyl)hydrazono]-2-cyano-N-propylethanamide (14Og, 0.453 mol) and chlorobenzene (840 ml, 6 rel vols) and the mixture was stirred for at least 15 minutes before charging aluminium trichloride (181.14g, 1.358 mol).
  • the reaction mixture was heated to 100 0 C 1 causing it to quickly turn dark green / black, and was held at 100 0 C for at least five hours.
  • a 3 litre jacketed vessel was charged with 2M aqueous hydrogen chloride solution (700 ml, 5 rel vols) and methanol (980 ml, 7 rel vols) which were heated to 55 0 C.
  • the reaction mixture was cooled to 55 0 C and added to the methanol and aqueous hydrochloric acid mixture, at such a rate that the temperature of the exothermic addition was maintained between 50 and 60 0 C, followed by two line washes of methanol (140ml, 1 rel vol). Stirring was stopped and the mixture separated into two phases. The lower organic phase was separated off and methanol (280 ml, 2 rel vols) was added to the remaining aqueous phase, which was then cooled to 40 0 C.
  • 4-Amino-8-bromo-N-propyl-cinnoline-3-carboxarnide hydrogen chloride form 1 seed (0.35g, 0.0025 rel weight) was charged and the mixture was held at 40 0 C for 30 minutes then cooled to 0 0 C over at least 4 hours and held at O 0 C for at least another 2 hours. If the seed dissolved on addition at 40°C the mixture was cooled to 35 0 C before charging further 4-Amino-8-bromo-N-propyl-cinnoline-3-carboxamide hydrogen chloride form 1 seed (0.35g, 0.0025 rel weight).
  • Fine white solid precipitated during the addition The mixture was then cooled to between -5°C and 5°C before charging a solution of sodium nitrite (60.16g, 1 mol equivalent) in water (225 ml, 1.5 rel vol) at such a rate that the temperature was maintained between 0 and 2.5 0 C followed by water (75 ml, 0.5 rel vol) as a line wash. During addition the solid dissolved to form an orange solution.
  • a 3-litre jacketed vessel was charged with sodium acetate (143.1 g, 2 mol eq), 2-cyano-N- propylacetamide (121g, 1.1 mol eq), ethanol (750 ml, 5 rel vol) and water (300ml, 2 rei vol) and the mixture was heated to 5O 0 C to form a clear colourless solution.
  • the diazonium solution was added to the 3 litre vessel via a peristaltic pump over at least 30 minutes, maintaining the batch temperature between 45 and 52 0 C, followed by a line wash of ethanol (75 mi, 0.5 re! vol). Solid crystallised out early in the addition.
  • the mixture was held at 50°C for 30 minutes before charging 2[ ⁇ 2-bromophenyl)hydrazono] ⁇ 2 ⁇ cyano-N- propylethanamide seed (0.75g, 0.5% rel weight) and heating to reflux (77°C) for at least 1 hour, during which time 2[(2-bromophenyl)hydrazono]-2-cyano-N-propylethanamide will convert from form 1 to form 2.
  • the mixture was cooled to 2O 0 C over at least 1 hour and held at 20 0 C for at least 1 hour before isolating the solid by filtration.
  • a 2 litre jacketed vessel fitted with a temperature probe and a retreat curve agitator was inerted with nitrogen and charged with n-propylamine (196.86g, 274.25 ml, 3.33 mols) and t- butylacetate (540 ml, 1.8 rel vol). The mixture was cooled to 15 0 C. Methylcyanoacetate (30Og 1 267.62ml, 302.76 mol) was charged via a dropping funnel over at least 30 minutes, maintaining the batch temperature between 20 and 25°C, followed by t-butylacetate (60 ml) as a line wash.
  • the reaction mixture was stirred at 20 0 C for between 10 and 17 hours until the level of methylcyanoacetate remaining was below 0.5 mol%.
  • the vessel was set for vacuum distillation with a vacuum of 160 mbar and the mixture was heated to between 46 and 61 "C until 3.43 relative volumes of distillate had been collected.
  • t-Butylacetate (549 ml, 1.83 rel vol) was then charged and the mixture was cooled to between 22 and 2O 0 C before charging 2-cyano-N-propylacetamide seed (3g, 1% rel weight).
  • the batch was cooled to 15 0 C over at least 1 hour and held at 15°C for at least 30 minutes before charging heptane (900 ml, 3 rel vol) over at least 3 hours, cooling further to 5 0 C over at least 4 hours and holding at 5°C for at least 30 minutes.
  • the solid was isolated by filtration, washed with premixed heptane (199.8 ml, 0.666 rel vol) and t-butylacetate (100.2 ml, 0.334 rel vol) then heptane (300 ml, 1 rel vol) and dried under vacuum at ambient temperature to yield 2-cyano-N-propylacetamide (354.7g).
  • 4-Amino-8-bromo-N-propyl-cinnoline-3-carboxamide hydrochloride (175.0 g) is charged to a vessel.
  • 2-fluoro-6-methoxy-phenylboronic acid (120.5 g, 1.40 mol eq) is charged to the vessel.
  • (1,1 l -bis(ditertbutylphosphine)ferrocene)palladium(ll) chloride (8.25 g, 0.025 mol eq) is charged to the vessel.
  • the content of the vessel is heated to 70 0 C with agitation.
  • Triethylamine (247.0 ml_, 3.5 mol eq) is charged to the vessel while maintaining the temperature at 65 to 75°C followed by addition of water (262.5 ml_, 1.5 rel vol). The mixture was allowed to react for at least 6 hours at 70 0 C. The contents of the vessel are cooled to 50 0 C and the aqueous layer is separated and removed. The organic layer is washed with 10% w/v aqueous citric acid solution (525 ml_, 3.0 rel vol) and 10% w/v aqueous sodium chloride solution (437.5 ml_, 2.5 rel vol). The residual water in the organic layer is distilled off.
  • Dimethyl sulfoxide (87ml_) is added to the organic layer (approximately 1825ml anisole solution) to which is then added a solution of sulfuric acid (1.0 mol eq) in Dimethyl sulfoxide (87ml_) in a controlled manner at 70 0 C together with crude 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate seed.
  • Example 7 The solid is dried in a vacuum oven at 4O 0 C and 700 mbar to yield 33 g of 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate.
  • the crystals of Example 7 are analyzed by XRPD and the results are tabulated below (Table 1 ) and are shown in Figure 1. Further water analysis is performed according to USP 921 on this material to show that Form A is anhydrous.
  • Example 8 The crystals of Example 8 are analyzed by XRPD and the results are tabulated below (Table 2) and are shown in Figure 2. Further analysis is conducted on this sample to show that Form N is a sesquihydrate of 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide hydrogen sulphate.
  • Example 9 The crystals of Example 9 are analyzed by XRPD and the results are tabulated below (Table 3) and are shown in Figure 3. Further analysis is conducted on this sample to show that Form B is a heptahydrate of 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide hydrogen sulphate. Table 3: Form B main peaks
  • a water solution of 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3- carboxamide hydrogen sulphate is prepared, filtered through a 0.2- ⁇ m filter, and frozen in liquid nitrogen.
  • the frozen sample is lyophilized using an FTS system Flexi-Dry to result in an amorphous 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate.
  • the lyophilization temperature is not controlled.
  • the amorphous form may be obtained by drying 4-Amino-8-(2-fluoro-6- methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate Form N at 40 0 C, under 500mBar vacuum for 5 days. A weight loss of 48% occurs and the sample changes colour from off white to distinctly yellow.
  • amorphous 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide hydrogen sulphate is analyzed by XRPD and the results are shown in Figure 4.
  • XRPD pattern exhibits a broad halo indicative of amorphous material.
  • Cyclic DSC of the sample (as shown in FIG. 5) shows a step transition at 52 0 C (inflection) followed by a recrystallization exotherm at 207 0 C and a broad endotherm at 249 0 C, presumably a melt.
  • DVS analysis of the sample shows 19% weight gain between 5 - 85% relative humidity indicating hygroscopicity.
  • Form A When the amorphous 4-Amino-8-(2-fluoro-6-methoxy-phenyl)-N- propylcinnoline-3-carboxamide hydrogen sulphate is dissolved and reprecipitated from an ethanol water mixture, Form A is generally formed. When the amorphous sample is exposed to ethanol vapor, the amorphous sample is also converted to Form A.
  • UV ultraviolet
  • n-, s-, /-, t- and ten- have their usual meanings: normal, secondary, iso, and tertiary.

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Abstract

L'invention porte sur l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-N-propylcinnoline-3-carboxamide, sur des polymorphes de celui-ci, sur des compositions pharmaceutiques les contenant et sur des procédés de fabrication de ceux-ci. Ils sont utiles dans le traitement des troubles liés à l'anxiété.
PCT/SE2010/050425 2009-04-21 2010-04-20 Forme cristalline de l'hydrogénosulfate de 4-amino-8-(2-fluoro-6-méthoxy-phényl)-n-propylcinnoline-3-carboxamide pour le traitement de troubles liés à l'anxiété Ceased WO2010123441A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US17112109P 2009-04-21 2009-04-21
US61/171,121 2009-04-21
US17584409P 2009-05-06 2009-05-06
US61/175,844 2009-05-06

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WO2010123441A1 true WO2010123441A1 (fr) 2010-10-28

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0205272A2 (fr) * 1985-05-30 1986-12-17 Ici Americas Inc. Dérivés de cinnoline
EP0328282A2 (fr) * 1988-02-09 1989-08-16 Ici Americas Inc. Produit pharmaceutique
WO2007073283A1 (fr) * 2005-12-20 2007-06-28 Astrazeneca Ab Derives substitues de la cinnoline en tant que modulateurs du recepteur du gabaa et leur procede de synthese
WO2008155573A1 (fr) * 2007-06-19 2008-12-24 Astrazeneca Ab Composés cinnoline utilisés dans le traitement de la schizophrénie

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0205272A2 (fr) * 1985-05-30 1986-12-17 Ici Americas Inc. Dérivés de cinnoline
EP0328282A2 (fr) * 1988-02-09 1989-08-16 Ici Americas Inc. Produit pharmaceutique
WO2007073283A1 (fr) * 2005-12-20 2007-06-28 Astrazeneca Ab Derives substitues de la cinnoline en tant que modulateurs du recepteur du gabaa et leur procede de synthese
WO2008155573A1 (fr) * 2007-06-19 2008-12-24 Astrazeneca Ab Composés cinnoline utilisés dans le traitement de la schizophrénie

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