WO2011095579A1 - 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates - Google Patents
4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- 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
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
Definitions
- the present invention relates to polymorphs and solvates of the hydrochloride salt of 4- [2-[[5-methyl-1 -(2-naphthalenyl)-1 H-pyrazol-3-yl]oxy]ethyl]morpholine (P027), processes for their preparation, and to pharmaceutical compositions comprising them.
- sigma receptor a cell surface receptor of the central nervous system (CNS) which may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of opioids.
- CNS central nervous system
- sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355).
- the sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs.
- SKF 10047 has nanomolar affinity for the sigma 1 ( ⁇ -1 ) site, and has micromolar affinity for the sigma 2 ( ⁇ -2) site.
- Haloperidol has similar affinities for both subtypes.
- Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them.
- Possible sigma- site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci., 1992, 13:85-86).
- sigma binding sites are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective sigma ligands have been evaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93:8072-8077). The existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.
- 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H-pyrazol-3-yl]oxy]ethyl]morpholine is a highly selective sigma-1 ( ⁇ -1 ) receptor antagonist. It has displayed strong analgesic activity in the treatment and prevention of chronic and acute pain, and particularly, neuropathic pain.
- the compound has a molecular weight 337.42 uma.
- the structural formula of the compound is:
- the solid state physical properties of a pharmaceutical compound can be influenced by the conditions under which the compound is obtained in solid form.
- Solid state physical properties include, for example, the flowability of the milled solid which affects the ease with which the compound is handled during processing into a pharmaceutical product.
- Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences because it imposes an upper limit on the rate at which an orally administered active ingredient can reach the blood.
- the solid-state form of a compound may also affect its solubility, bioavailability, behavior on compaction, stability, or its electrostatic nature.
- Polymorphism is the property of some molecules and molecular complexes to assume more than one crystalline or amorphous form in the solid state.
- polymorphism is caused by the ability of the molecule of a substance to change its conformation or to form different inter molecular and intramolecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs.
- polymorphs are distinct solids shari ng the same molecu lar Form u la , h avi ng d isti nct advantageou s and/or disadvantageous physical properties compared to other forms in the polymorph family.
- solvate refers to any solid form of a given compound in which said compound is bonded by a non-covalent bond to molecule(s) of solvent (normally a polar solvent).
- P027 new solid forms of the hydrochloride salt of 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H- pyrazol-3-yl]oxy]ethyl]morpholine (P027) may achieve one or more of the above mentioned objectives.
- the novel polymorphic and solvated forms of P027 herein disclosed are fairly stable over the time and have good flow and dissolution characteristics.
- a novel and highly stable crystalline form of the P027 compound provides advantageous production, handling, storage and therapeutic properties.
- some of the new solid forms of P027 may be useful as intermediates for other useful forms such as the crystalline phase I form of P027.
- the present invention relates to polymorphic forms and solvates of P027, to their use and to several processes for their preparation.
- the hydrochloride salt of 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H-pyrazol-3- yl]oxy]ethyl]morpholine can be prepared by contacting a solution of the base with hydrochloric acid.
- the P027 compound has a molecular weight 373.88 uma, a pKa of 6.73 and a melting point of 194.2 °C.
- the compound is very soluble in water and freely soluble in methanol, 1 N hydrochloric acid and dimethyl sulphoxide. It is sparingly soluble in ethanol, slightly soluble in acetone and practically insoluble in ethyl acetate and in 1 N sodium hydroxide.
- the product exhibits a better dissolution and absorption profile in vivo than its related base.
- the present invention is directed to a solid polymorphic or solvated form of the hydrochloride salt of 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H-pyrazol-3- yl]oxy]ethyl]morpholine.
- said solid form is selected from the group consisting of:
- phase I form which can be characterized because it has a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2 ⁇ ] of about 5.9, 8.1 , 1 1 .3, 1 1 .7, 14.2, 15.1 , 15.8, 16.3, 16.8, 17.8, 18.1 , 18.6, 19.8, 20.9, 21 .9, 22.8, 23.0, 23.2, 23.6, 23.9, 24.3, 25.0, 25.1 , 28.0, 28.3, 28.6, 29.0, 29.2, 30.7, and 30.9, with the 2 ⁇ values being obtained using copper radiation (Cu K ai 1 .54060A).
- P027 phase II form which can be characterized because it has a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2 ⁇ ] of about the values indicated below in table 1 : Table 1
- P027 phase III form which can be characterized because it has a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2 ⁇ ] of about the values indicated below in table 2:
- P027 phase IV form which can be characterized because it has a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2 ⁇ ] of about the values indicated below in table 3:
- P027 dioxane solvate which can be characterized because it has a X-ray powder diffraction pattern showing characteristic peaks at a reflection angle [2 ⁇ ] of about the values indicated below in table 4:
- the P027 phase I form can be prepared by crystallizing the P027 compound in various solvents by means of various techniques such as: solvent evaporation at varying temperatures, crystallization from hot saturated solutions, crystallization by antisolvent addition, crystallization by antisolvent diffusion, crystallization from water and solvents mixtures and the preparation of suspensions.
- P027 phase II form may be obtained in polymer induced crystallizations by solvent evaporation.
- P027 phase III form may be obtained in polymer induced crystallizations either by solvent evaporation or by crystallization by antisolvent addition.
- P027 phase IV form may be obtained in polymer induced crystallizations by crystallization by antisolvent addition.
- P027 dioxane solvate may be obtained by solvent drop grinding in dioxane or by crystallization from a hot saturated solution of dioxane.
- P027 chloroform solvate may be obtained in polymer induced crystallizations either by solvent (chloroform) evaporation or by crystallization from hot saturated solutions of chloroform.
- Another embodiment of the present invention includes the transformation of crystalline forms phase II, phase III and phase IV above into a more stable polymorphic form such as P027 phase I form.
- Another embodiment of the present invention includes the transformation of a solvate of P027, preferably chloroform solvate, into a more stable polymorphic form such as phase I form.
- a further embodiment of the present invention includes pharmaceutical compositions comprising at least one of the forms of the hydrochloride salt of 4-[2-[[5-methyl-1 -(2- naphthalenyl)-1 H-pyrazol-3-yl]oxy]ethyl]morpholine above-mentioned, particularly P027 phase I, P027 phase II, P027 phase III, P027 phase IV, P027 chloroform solvate and P027 dioxane solvate.
- Fig. 1 Standard PXRD pattern of phase I.
- Fig. 2 1 H NMR spectrum of a P027 compound solution.
- Fig. 3 DSC and TGA analyses of phase I.
- Fig. 4 FTIR analysis of phase I.
- Fig. 5 Randomly selected PXRD patterns of different solids corresponding to phase I in which texture effects can be observed.
- Fig. 6 PXRD pattern of phase I samples before and after grinding. The standard PXRD pattern of phase I is shown for comparison purposes.
- Fig. 7 1 H-NMR spectra of the samples depicted in Figure 6.
- Fig. 8 DSC analysis of phase I at a heating rate of 5 °C/min.
- Fig. 9 DSC analysis of phase I at a heating rate of 20 °C/min.
- Fig. 10 Ortep-Plot (50 %) showing the organic cation and the two independent half chlorine anions contained in the unit cell.
- Fig. 11 Ortep-Plot (50 %) showing the structure of phase I. The hydrogen bonds are marked with discontinuous lines.
- Fig. 12 Simulated powder diffraction pattern generated from the single crystal data of phase I.
- Fig. 13 Comparison of the simulated powder diffraction pattern obtained from single crystal data and the experimentally measured powder diffraction pattern of phase I.
- Fig. 14 PXRD pattern of a phase I form obtained by the evaporation n-butanol at -21 °C.
- Fig. 15 PXRD pattern of a phase I form obtained by the slow crystallization of hot saturated P027 compound solution in methyl ethyl ketone.
- Fig. 16 PXRD pattern of a phase I form obtained by crystallization through the addition of a P027 solution in methanol to an n-heptane solution.
- Fig. 17 PXRD pattern of a phase I form obtained by crystallization through a liquid- liquid diffusion of a P027 solution in nitromethane and an isopropyl ether solution.
- Fig. 18 PXRD pattern obtained after grinding a sample of P027 phase I form together with dichloromethane. The pattern is consistent with the standard phase I PXRD pattern demonstrating the phase stability.
- Fig. 19 PXRD pattern of a sample of P027 phase I form after applying a pressure of 30 tons to the sample for 90 minutes. The pattern is consistent with the standard phase I PXRD pattern demonstrating the phase stability.
- Fig. 20 Comparison of the PXRD patterns obtained for Phase II and Phase III.
- Fig. 21 Comparison of the PXRD patterns obtained for Phase II and Phase IV.
- Fig. 22 Comparison of the PXRD patterns obtained for Phase III and Phase IV.
- Fig. 23 Comparison of the PXRD patterns obtained for Phase I and Phase II.
- Fig. 24 Standard PXRD pattern of Phase II.
- Fig. 25 1 H NMR spectrum of Phase II.
- Fig. 26 DSC and TGA analyses of Phase II.
- Fig. 27 Standard PXRD pattern of Phase III.
- Fig. 28 Comparison of the PXRD patterns obtained for poly(ethylene glycol) and Phase III.
- Fig. 29 1 H NMR spectrum of Phase III.
- Fig. 30 1 H NMR spectrum of poly(ethylene glycol).
- Fig. 31 DSC and TGA analyses of Phase III.
- Fig. 32 DSC and TGA analyses of poly(ethylene glycol).
- Fig. 33 DSC analyses of Phase III with a heating rate of 20 °C/min
- Fig. 34 DSC analyses of Phase III with a heating rate of 30 °C/min
- Fig. 35 Standard PXRD pattern of Phase IV.
- Fig. 36 1 H NMR spectrum of Phase IV.
- Fig. 37 DSC and TGA analyses of Phase IV.
- Fig. 38 Standard PXRD pattern of the dioxane solvate.
- Fig. 39 1 H NMR spectrum of the dioxane solvate.
- Fig. 40 DSC and TGA analyses of the dioxane solvate.
- Fig. 41 FTIR analysis of the dioxane solvate.
- Fig. 42 Standard PXRD pattern of the chloroform solvate.
- Fig. 43 DSC and TGA analyses of the chloroform solvate.
- novel solid forms of the hydrochloride salt of 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H-pyrazol-3- yl]oxy]ethyl]morpholine (P027) which provide advantageous production, handling, storage and therapeutic properties.
- These compounds have advantages due to the fact that they are solids, what simplifies isolation, purification and handling.
- the phase I form of this compound is highly stable and can be formulated and administered providing stable compositions and good pharmacological properties.
- the new forms of P027 may be used for obtaining other forms, such as crystalline phase I form of P027.
- the term "about” means a slight variation of the value specified, preferably within 10 percent of the value specified. Nevertheless, the term “about” can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention. Further, to provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about”.
- room temperature or its abbreviation “rt” is taken to mean 20 to 25 °C.
- the new forms of P027 herein disclosed were characterized by powder X-ray diffraction (PXRD), proton nuclear magnetic resonance ( 1 H-NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier-transformed infrared spectroscopy.
- PXRD powder X-ray diffraction
- 1 H-NMR proton nuclear magnetic resonance
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- Fourier-transformed infrared spectroscopy The present invention is directed in one aspect to the new solid forms of P027 in themselves, regardless of the technique used for their characterization. Therefore, the techniques and results provided herein are not intended to limit the present invention, but to serve as characterization of the same.
- solubility of P027 was determined at room temperature in the set of solvents of table 6 using the following methodology (table 7): 10 mg of the delivered sample were suspended at room temperature in 0.2 mL of the corresponding solvent and successive additions (initially 0.2 mL and finally 0.5 mL) of solvent until the solid was completely dissolved or up to a maximum of 8 mL were performed. After each solvent addition the suspension was vigorously stirred for 10-15 minutes and visually inspected to determine if the solid was completely dissolved. Solubility ranges are listed in table 7.
- the solid was dissolved at 60 °C. The solution was left at room temperature and no solid was observed 2The solid was dissolved at 80 °C. The solution was left at room temperature and no solid was observed
- the solvents in which P027 was insoluble were used as antisolvents (e.g. those solvents providing a solubility ⁇ 1 .2 mg/mL).
- n-Heptane (HEP) Methyl tert-butyl ether (MTE) and diisopropyl ether (DIE) were used as antisolvents.
- the other solvents were used as dissolving solvents in the different crystallization strategies assayed.
- several crystallization methodologies were employed using the solvents described in table 6. Procedures oriented to obtain the thermodynamically stable phase as well as procedures directed to obtain kinetically favoured phases were used.
- solvent mediated as well as solvent free crystallization procedures were assayed.
- a list of the crystallization procedures used in this invention is following:
- catalytic amounts represent a substoichiometric amount of polymer with respect to the compound P027; preferably below a 25% wt of the amount (wt) of compound P027: In a particular embodiment, “catalytic amounts” represent below a 20% wt of the compound P027. In a more particular embodiment, “catalytic amounts” represent below a 10% wt of the compound P027.
- P027 phase I form P027 phase II form
- P027 phase III form P027 phase IV form
- P027 dioxane solvate P027 chloroform solvate.
- the P027 phase I form is obtained by dissolving the P027 compound in a suitable solvent and then evaporating the solvent to obtain the phase I crystalline form.
- the P027 compound is dissolved at a temperature ranging from about room temperature to about 120 °C.
- the solvent is evaporated at a temperature ranging from about -21 °C to about 60 °C.
- the P027 solution is allowed to cool down slowly.
- the P027 solution is cooled down rapidly.
- the P027 phase I form is obtained by mixing a P027 solution and an antisolvent.
- the P027 solution is added to the antisolvent.
- the antisolvent is added to the P027 solution.
- the P027 solution and the antisolvent are mixed at a temperature ranging from about room temperature to about 90 °C.
- the P027 phase I form is obtained by combining a P027 solution and an antisolvent through diffusion.
- the diffusion is a liquid-liquid diffusion.
- the diffusion is a gas-liquid diffusion.
- the P027 phase I form is collected from mixtures of P027, water and solvents.
- the P027 phase I form is obtained from suspensions containing the P027 compound.
- the suspension is maintained at a temperature ranging from about room temperature to about 80 °C.
- an hydrochloric acid solution and 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H-pyrazol-3-yl]oxy]ethyl]morpholine are mixed to obtain the P027 compound.
- an antisolvent is added to the mixture to induce the crystallization of the P027 compound.
- phase II form, phase III form and phase IV form may be obtained in polymer induced crystallizations either by solvent evaporation or by crystallization by antisolvent addition.
- another embodiment of the present invention refers to a process for the preparation of polymorphic forms of the hydrochloride salt of 4-[2-[[5-methyl-1 -(2- naphthalenyl)-1 H-pyrazol-3-yl]oxy]ethyl]morpholine, comprising: a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H- pyrazol-3-yl]oxy]ethyl]morpholine in a suitable solvent or mixture of solvents in the presence of catalytic amounts of a polymer, and
- P027 phase II form is prepared by evaporation of a solution of P027 in water with the presence of catalytic amounts of polyvinyl alcohol).
- P027 phase III form is prepared by evaporation of a solution of P027 in water or acetone with the presence of catalytic amounts of poly(ethylene glycol).
- P027 phase III form may also be conveniently prepared by addition of diisopropyl ether as antisolvent to a solution of P027 in water with the presence of catalytic amounts of poly(ethylene glycol).
- P027 phase IV form is prepared by using chloroform as solvent, diisopropyl ether as antisolvent and the following polymers: polyvinyl pyrrolidone (PVP), poly(acrylic acid) (PAA), polypropylene (PPL), poly(styrene-co- divinylbenzene) (PSV), poly(tetrafluoroethylene) (PTF), polyvinyl alcohol) (PVH), polyacrylamide (PAD) and poly(methyl methacrilate) (PMM).
- PVP polyvinyl pyrrolidone
- PAA poly(acrylic acid)
- PPL polypropylene
- PSV poly(styrene-co- divinylbenzene)
- PTF poly(tetrafluoroethylene)
- PVH polyvinyl alcohol
- PAD polyacrylamide
- PMM poly(methyl methacrilate)
- P027 dioxane solvate may be obtained in a solvent drop grinding experiment in dioxane or by crystallization from a hot saturated solution of dioxane.
- P027 chloroform solvate may be obtained in polymer induced crystallizations either by solvent (chloroform) evaporation or by crystallization of hot saturated solutions of chloroform.
- another embodiment of the present invention refers to a process for the preparation of solvated forms of the hydrochloride salt of 4-[2-[[5-methyl-1 -(2- naphthalenyl)-1 H-pyrazol-3-yl]oxy]ethyl]morpholine, comprising at least one of the 3 alternatives i) to iii):
- a polymer induced crystallization comprising: a) dissolving the hydrochloride salt of 4-[2-[[5-methyl-1 -(2-naphthalenyl)-1 H- pyrazol-3-yl]oxy]ethyl]morpholine in a suitable solvent in the presence of catalytic amounts of a polymer, and
- P027 dioxane solvate is prepared by:
- P027 chloroform solvate is prepared by:
- Another embodiment of the present invention includes the use of crystalline forms phase II, phase III and phase IV of P027 in the obtention of the more stable polymorphic phase I form of P027.
- the transformation is by heating of crystalline forms phase II, phase III and phase IV into the polymorphic phase I form.
- phase II In the DSC analysis of phases II, III and IV broad exothermic peaks were observed which correspond to a solid-solid transition.
- Th e sol i d-solid transition (recrystallization) of phase III into phase I was observed in the range 150-170 °C.
- the solid-solid transition (recrystallization) of phase IV into phase I was observed at 147 °C. Therefore, in another embodiment the invention is directed to the preparation of phase I form of P027 comprising the step of heating crystalline forms phase II, phase III and phase IV of P027 at a temperature between about 140 °C and about 170 °C.
- Another embodiment of the present invention includes the transformation of a solvate of P027, preferably chloroform solvate, into a more stable polymorphic form such as phase I form. After drying the dioxane solvate for 4 hours at 60 °C, 80 °C and 100 °C the transformation to Phase I was observed. The solids obtained were characterized by PXRD.
- a further embodiment of the present invention includes pharmaceutical compositions comprising at least one of the forms of the hydrochloride salt of 4-[2-[[5-methyl-1 -(2- naphthalenyl)-1 H-pyrazol-3-yl]oxy]ethyl]morpholine above-mentioned, particularly P027 phase I, P027 phase II, P027 phase III, P027 phase IV, P027 chloroform solvate and P027 dioxane solvate.
- Powder diffraction patterns were acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using Cu Ka -radiation in transmission geometry (Wavelength: 1 .54060).
- the system was equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller.
- Standard DSC analyses were recorded in a Mettler Toledo DSC822e. Samples of 1 -2 mg were weighted into 40 ⁇ _ aluminium crucibles with a pinhole lid, and were heated, under nitrogen (50 mL/min), from 30 to 300 °C at 1 0 °C/min . Data collection and evaluation was done with software STARe.
- Thermogravimetric analyses were recorded in a Mettler Toledo SDTA851 e. Samples of 3-4 mg were weighted (using a microscale MX5, Mettler) into open 40 ⁇ _ aluminium crucibles with a pinhole lid, and heated at 10 °C/min between 30 and 500 °C, under nitrogen (80 mL/min). Data collection and evaluation was done with software STARe. e) Fourier Transform Infrared analysis (FTIR)
- the FTIR spectra were recorded using a Bruker Tensor 27, equipped with a MKI I golden gate single reflection ATR system, a mid-infrared source as the excitation source and a DTGS detector.
- the spectra were acquired in 32 scans at a resolution of 4 cm "1 . No sample preparation was required to perform the analysis.
- Crystal structure solution was achieved using direct methods as implemented in SH ELXTL Version 6.10 (Sheldrick, Universtitat Gottingen (Germany), 2000) and visualized using XP program. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F 0 2 using all measured intensities was carried out using the program SHELXTL Version 6.10 (Sheldrick, Universtitat Gottingen (Germany), 2000). All non hydrogen atoms were refined including anisotropic displacement parameters.
- Example 1.1 Solvent evaporation at two rates at room temperature
- FIG. 15 illustrates the PXRD pattern of a phase I form obtained by the slow crystallization of hot saturated P027 compound solution in methyl ethyl ketone.
- Example 1.4 Small scale crystallization by addition of an antisolvent
- DIE Diisopropyl ether
- HEP n-heptane
- the solids obtained after mixing the dissolving agent and antisolvent were separated from the solution by filtration or centrifugation. If no solids were formed, the solution was kept at 4 °C for a few days in first step. Any solids formed during this step were separated from the solution. If no solids were formed during the first step, the solution was kept at -21 °C for a few additional days. Any solids formed during this second step were separated from the solution. The solutions that did not crystallize during the second step were left to evaporate to dryness at room temperature. The solid was filtered off in some experiments when crystallization occurred before complete evaporation.
- FIG. 16 illustrates the PXRD pattern of a phase I form obtained by crystallization through the addition of a P027 solution in methanol to an n-heptane solution.
- Example 1.5 Large scale crystallization by addition of an antisolvent
- Example 1.6 Crystallization by diffusion of an antisolvent
- FIG. 17 illustrates the PXRD pattern of a phase I form obtained by crystallization through a liquid-liquid diffusion of isopropyl ether into a P027 solution in nitromethane.
- the solutions were allowed to crystallize at room temperature in a closed tube for two weeks. If no solids were formed, the solution was kept at 4 °C for a few days. Any solids formed during this step were separated from the solution. If no solids were formed during the first step, the solution was left to evaporate to dryness at room temperature.
- the solid samples obtained were analyzed by PXRD.
- the samples showed a pattern consistent with the standard PXRD phase I pattern.
- P027 phase I Approximately 40 mg of P027 phase I were transferred to a ball mill container together with catalytic quantities of the relevant solvent (three drops). The P027 phase I and the solvent were grinded at a maximum frequency of 30 s "1 for 30 minutes (see Table 23).
- Tablets of P027 phase I were prepared in a hydraulic press at three different pressures (5, 7.5 and 10 tons) for three different times (5, 30 and 90 minutes) [see Table 24].
- the solid samples obtained were analyzed by PXRD.
- the samples showed a pattern consistent with the standard PXRD phase I pattern, thus demonstrating that P027 phase I is stable under pressure.
- Figure 19 illustrates the PXRD pattern of a phase I form obtained by applying a pressure of 30 tons to P027 for 90 minutes.
- the P027 phase I form shows a PXRD pattern having characteristic peaks at a reflection angle [2 ⁇ ] of about 5.9, 8.1 , 1 1 .3, 1 1 .7, 14.2, 15.1 , 15.8, 16.3, 16.8, 17.8, 18.1 , 18.6, 19.8, 20.9, 21 .9, 22.8, 23.0, 23.2, 23.6, 23.9, 24.3, 25.0, 25.1 , 28.0, 28.3, 28.6, 29.0, 29.2, 30.7, and 30.9 with the 2 ⁇ values being obtained using copper radiation (Cu Ka i 1 .54060A).
- Differences in the PXRD patterns peak intensities could be observed depending of the crystallization procedure or crystallization solvent used (see Figure 5). Strong differences in the peak intensities could be due to preferred orientations, texture effects, of the crystals and are not indicative of the presence of different crystalline phases. Non ideal crystalline phases are defined by the peak positions and not by the peak intensities. Differences in the peak intensities could be due to different configurations of the measurement devices (transmission vs. reflection) or to texture effects related to the preferred orientations of the crystals.
- a DSC analysis of phase I samples was performed with a heating rate of 10 °C/min.
- the analysis presented a sharp endothermic peak, which does not recover the base line, with an onset at 194 °C and an enthalpy of 103 J/g corresponding to melting followed by decomposition of the product (see Figure 3).
- additional DSC analyses of the same sample performed with a heating rate of 5 °C/min and 20 °C/min, it was observed that the onset temperature of the endothermic peak does not vary with the heating rate (see Figures 8 and 9).
- the FTIR spectrum of P027 phase I presented intense peaks at about 2965, 2609, 1632, 1600, 1559, 1508, 1490, 1439, 1376, 1301 , 1257, 1242, 1 169, 1 129, 1 103, 1042, 1010, 932, 914, 862, 828 and 753 cm "1 (see Figure 4).
- the identity and crystal structure of the P027 compound phase I was assayed by a single crystal X-ray structure determination. Suitable crystals were obtained by slow diffusion of n-heptane into a concentrated solution of the product in acetone. Since the selected crystals were mostly twinned, a small fragment of a plate (0.30 x 0.30 x 0.07 mm 3 ) was separated with a micro scalpel and used for single crystal X-ray structure determination. Table 26 shows the measurement conditions utilized, cell constants and results obtained in a single crystal X-ray structure diffraction analysis. Table 27 depicts phase I selected bond distances and angles for an X-ray structure determination performed at 100 K.
- the powder diffraction pattern simulated from the single crystal data shows a good correspondence to the experimentally measured standard powder diffraction pattern of phase I.
- the overlay confirms the phase purity. Small variations in peak positions are due to the temperature difference at which the compared powder diffractograms were measured (simulated at -173 °C and experimentally measured at room temperature).
- Figures 12 and 13 show the phase I simulated powder diffraction pattern and its comparison to the experimentally measured pattern, respectively.
- phase I a mixture of phase I and a phase I I was obtained by solvent evaporation in several solvents (methanol, water, diisopropyl ether-water, nitromethane dioxane-water and heptane-water).
- solvents methanol, water, diisopropyl ether-water, nitromethane dioxane-water and heptane-water.
- This new phase II could be reproduced pure in the screening performed using polymers by evaporation of a solution of P027 in water and with the presence of catalytic amounts of polyvinyl alcohol).
- phase II obtained using polyvinyl alcohol
- a standard PXRD pattern for phase II form is shown in figure 24. Characterization by 1 H NMR, DSC and TGA is shown in figures 25 and 26.
- phase II is not a decomposition product.
- the spectra obtained for phase I and phase II are compared in figure 25. No differences in the shifts of relevant hydrogen atoms can be observed.
- the DSC analysis of phase II shows a weak broad exothermic peak with an onset at 145 °C and an enthalpy of 4 J/g and a sharp endotherm ic peak with an onset at 1 94 °C and an enthal py of 92 J/g , corresponding to melting followed by decomposition of the product ( Figure 26).
- the small exothermic peak at 145 °C suggests that phase II should be a metastable phase monotropically related to phase I.
- the DSC actually shows a solid-solid transition of phase II to I, followed by fusion of phase I.
- Phase III form was generated by polymer induced crystallization. This solid was obtained in four experiments always in the presence of poly(ethylene glycol). In three cases it was obtained by evaporation of water or acetone and in one case it was obtained by addition of diisopropyl ether as antisolvent to a solution in water.
- Phase I I I was characterized by PXRD, 1 H NMR, DSC and TGA.
- a representative PXRD pattern for phase III is shown in figure 27.
- the peak at 19.1 ° in 2 ⁇ can be observed as a weak signal and the broad peak at 23.2° in 2 ⁇ can be also observed slightly shifted to 23.6° in 2 ⁇ in the pattern of phase III.
- the DSC analysis of Phase III presents a first sharp endothermic peak with an onset at 56 °C and an enthalpy of 46 J/g corresponding to melting of poly(ethylene glycol).
- the DSC of pu re poly(ethylene glycol) is shown in figure 32. In the range from 150 to 170 °C the DSC shows a double peak, first endothermic and then exothermic, corresponding probably to melting of phase I I I overlapped with recrystallization to phase I . Finally, an endothermic peak with an onset at 190 °C and an enthalpy of 47 J/g, corresponding to melting followed by decomposition of phase I can be observed.
- Phase IV form was only generated by polymer induced crystallization. This phase was formed in experiments performed using chloroform as solvent and diisopropyl ether as antisolvent.
- Phase IV solid was obtained with the following polymers: polyvinyl pyrrolidone (PVP), poly(acrylic acid) (PAA), polypropylene (PPL), poly(styrene-co- divinylbenzene) (PSV), poly(tetrafluoroethylene) (PTF), polyvinyl alcohol) (PVH), polyacrylamide (PAD) and poly(methyl methacrilate) (PMM).
- Polymers PVP, PAA, PSV, PVH, PAD and PMM are amorphous and polymers PPL and PTF are crystalline. Only in the sample of phase IV obtained with crystalline PTF, a weak peak of the polymer could be detected in the PXRD pattern.
- Phase IV form was characterized by PXRD, 1 H NMR, DSC and TGA.
- a representative PXRD pattern for Phase IV is shown in figure 35.
- the dioxane solvate crystallizes in form of small sticky crystallites.
- a representative PXRD pattern of the solvate is shown in figure 38. Characterization by 1 H NMR, DSC, TGA and FTIR is shown in figures 39 to 41.
- the FTIR spectrum characteristic for the dioxane solvate is represented in figure 41 and presents intense peaks at 3138, 3055, 2959, 2857, 2660, 2572, 2540, 2444, 1633, 1600, 1556, 1509, 1488, 1446, 1372, 1304, 1289, 1255, 1168, 1118, 1099, 1083, 1039, 933, 872, 861, 819, 771 and 748 cm "1 .
- the chloroform solvate of P027 was obtained by evaporation of a chloroform solution or by crystallization of hot saturated chloroform solutions using the following polymers: poly(ethylene glycol) (PGY), polyvinyl pyrrolidone (PVP), poly(acrylic acid) (PAA), nylon 6/6 (NYL), polypropylene (PPL), poly(tetrafluoroethylene) (PTF), polyvinyl acetate) (PVA), polyvinyl alcohol) (PVH), polyacrylamide (PAD) and polysulfone (PLS).
- PY poly(ethylene glycol)
- PVP polyvinyl pyrrolidone
- PAA poly(acrylic acid)
- NYL nylon 6/6
- PPL polypropylene
- PPF poly(tetrafluoroethylene)
- PVH polyvinyl alcohol
- PAD polyacrylamide
- PLS polysulfone
- the polymers PGY, PPL and PTF are crystalline and the rest amorphous. No signals of the crystalline polymers could be observed in the PXRD patterns.
- the chloroform solvate crystallizes in the majority of the cases in form of large crystals which are probably stabilized by the presence of the polymers.
- a representative PXRD pattern of the solvate is shown in figure 42. Characterization by DSC and TGA is shown in figure 43.
- the DSC analysis of the chloroform solvate measured with a heating rate of 10 °C/min presents a broad endothermic peak with an onset at 67 °C and an enthalpy of 42 J/g, due to the loss of chloroform, and a second sharp endothermic peak with an onset at 194 °C and an enthalpy of 73 J/g, corresponding to melting followed by decomposition of phase I ( Figure 43).
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Priority Applications (26)
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US15/616,347 USRE47214E1 (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
ES11702056.0T ES2586212T3 (en) | 2010-02-04 | 2011-02-04 | Polymorphs and solvates of 4- [2 - [[5-methyl-1- (2-naphthalenyl) -1H-pyrazol-3-yl] oxy] ethyl] morpholine hydrochloride |
AU2011212476A AU2011212476B2 (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
KR1020127023081A KR20120123532A (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-2-naphtalenyl-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
RS20160612A RS55046B1 (en) | 2010-02-04 | 2011-02-04 | 4-[2-[[5-methyl-1-(2-naphthalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride and solvates |
BR112012018958A BR112012018958A8 (en) | 2010-02-04 | 2011-02-04 | polymorphic solid or solvated form of 4- [2 - [[5-methyl-1- (2-naphthalenyl) -1h-pyrazol-3-yl] oxy] ethyl] morpholine hydrochloride salt, solid form, process for preparation polymorphic phase form i, polymorphic phase form iii, polymorphic phase form ii, polymorphic phase form iv, dioxane solvate, chloroform solvate, use of polymorphic phase form ii, polymorphic phase form iii, polymorphic phase form iv, dioxane solvate or chloroform solvate, process for preparing phase 4- form of 4- [2 - [[5-methyl-1- (2-naphthalenyl) -1h hydrochloride salt -pyrazol-3-yl] oxy] ethyl] morpholine and pharmaceutical composition |
KR1020187015725A KR20180063379A (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
EP11702056.0A EP2531177B8 (en) | 2010-02-04 | 2011-02-04 | 4-[2-[[5-methyl-1-(2-naphthalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
SG2012053724A SG182628A1 (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
SI201130895A SI2531177T1 (en) | 2010-02-04 | 2011-02-04 | 4-(2-((5-methyl-1-(2-naphthalinyl)-1h-pyrazol-3-yl)oxy)ethyl)morpholin hydrochlorid polymorphe und solvate |
NZ601316A NZ601316A (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
RU2012137495/04A RU2560150C2 (en) | 2010-02-04 | 2011-02-04 | 4-[2-[[5-methyl-1-(2-naphthalinyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorph and solvates |
DK11702056.0T DK2531177T3 (en) | 2010-02-04 | 2011-02-04 | 4- [2 - [[5-methyl-1- (2-naphthalenyl) -1H-pyrazol-3-yl] oxy] ethyl] morpholine hydrochloride and solvates |
US13/577,078 US9051275B2 (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1H-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
MEP-2016-154A ME02483B (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
MA35183A MA34047B1 (en) | 2010-02-04 | 2011-02-04 | POLYMORPHS AND SOLVATES OF 4 - [- 2 - [[5-METHYL-1- (2-NAPHTHALENYL) -1H-PYRAZOL-3-YL] OXY] ETHYL] MORPHOLINE HYDROCHLORIDE |
MX2012009018A MX339193B (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]mor pholine hydrochloride polymorphs and solvates. |
CN201180008354.5A CN102753155B (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl isophthalic acid-(2-naphthyl)-1H-pyrazole-3-yl] oxygen base] ethyl] morpholine hydrochloride polymorphs body and solvate |
JP2012551631A JP5894086B2 (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-Methyl-1- (2-naphthalenyl) -1H-pyrazol-3-yl] oxy] ethyl] morpholine hydrochloride polymorphs and solvates |
CA2788024A CA2788024C (en) | 2010-02-04 | 2011-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
UAA201210429A UA112629C2 (en) | 2010-02-04 | 2011-04-02 | POLYMORPHS AND SOLVATES OF HYDROCHLORIDE 4- [2 - [[5-METHYL-1- (2-NAPHTHALINYL) -1H-PYRAZOL-3-yl] OXY] ETHYL] MORPHOLINE |
TNP2012000347A TN2012000347A1 (en) | 2010-02-04 | 2012-07-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
IL221277A IL221277A (en) | 2010-02-04 | 2012-08-02 | 4 -[2-[[5-methyl-1-(2- naphthalenyl)-1h -pyrazol -3 -yl] oxy] ethyl] morpholine hydrochloride polymorphs and solvates |
HRP20160937TT HRP20160937T1 (en) | 2010-02-04 | 2016-07-25 | 4-[2-[[5-methyl-1-(2-naphthalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine-hydrochloride polymorphs and solvates |
SM201600264T SMT201600264B (en) | 2010-02-04 | 2016-08-04 | POLYMORPHOES AND SOLVATES OF 4 - [- 2 - [[5-METLL-1- (2-NAFTALENlL) -1H-PIRAZOL-3-IL] OSSL] ETlL] MORPHOLINE CHLORIDRATE |
CY20161100779T CY1117886T1 (en) | 2010-02-04 | 2016-08-08 | HYDROCHLORIDE 4- [2 - [[5-Methyl-1- (2-naphthalenyl) -1H-pyrazol-3-yl] oxy] ethyl] morpholine and resins |
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EP10382025A EP2361904A1 (en) | 2010-02-04 | 2010-02-04 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride and crystalline forms thereof |
EP10382025.4 | 2010-02-04 | ||
EP10382226A EP2426112A1 (en) | 2010-08-09 | 2010-08-09 | 4-[-2-[[5-methyl-1-(2-naphtalenyl)-1h-pyrazol-3-yl]oxy]ethyl]morpholine hydrochloride polymorphs and solvates |
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US (2) | US9051275B2 (en) |
EP (1) | EP2531177B8 (en) |
JP (1) | JP5894086B2 (en) |
KR (2) | KR20120123532A (en) |
CN (1) | CN102753155B (en) |
AR (1) | AR080133A1 (en) |
AU (1) | AU2011212476B2 (en) |
BR (1) | BR112012018958A8 (en) |
CA (1) | CA2788024C (en) |
CO (1) | CO6592093A2 (en) |
CY (1) | CY1117886T1 (en) |
DK (1) | DK2531177T3 (en) |
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RS (1) | RS55046B1 (en) |
RU (1) | RU2560150C2 (en) |
SG (2) | SG10201500832PA (en) |
SI (1) | SI2531177T1 (en) |
SM (1) | SMT201600264B (en) |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006021462A1 (en) | 2004-08-27 | 2006-03-02 | Laboratorios Del Dr. Esteve, S.A. | Sigma receptor inhibitors |
EP2113501A1 (en) * | 2008-04-25 | 2009-11-04 | Laboratorios Del. Dr. Esteve, S.A. | 5-Methyl-1-(naphthalen-2-YL)-1H-Pyrazoles useful as sigma receptor inhibitors |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ243065A (en) * | 1991-06-13 | 1995-07-26 | Lundbeck & Co As H | Piperidine derivatives and pharmaceutical compositions |
US8202872B2 (en) * | 2006-03-01 | 2012-06-19 | Laboratorios Del Dr. Esteve, S.A. | Pyrazole derivatives as sigma receptor inhibitors |
US7695199B2 (en) | 2006-07-20 | 2010-04-13 | Finisar Corporation | Optical subassembly having insertable cylindrical sleeve |
CN101328155B (en) * | 2007-06-20 | 2010-11-03 | 上海医药工业研究院 | Oxazolidine derivates, preparation and application thereof |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006021462A1 (en) | 2004-08-27 | 2006-03-02 | Laboratorios Del Dr. Esteve, S.A. | Sigma receptor inhibitors |
EP2113501A1 (en) * | 2008-04-25 | 2009-11-04 | Laboratorios Del. Dr. Esteve, S.A. | 5-Methyl-1-(naphthalen-2-YL)-1H-Pyrazoles useful as sigma receptor inhibitors |
Non-Patent Citations (8)
Title |
---|
BERGE S M ET AL: "PHARMACEUTICAL SALTS", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 66, no. 1, 1 January 1977 (1977-01-01), pages 1 - 19, XP002552191, ISSN: 0022-3549, DOI: DOI:10.1002/JPS.2600660104 * |
C. PRICE ET AL., J. AM. CHEM. SOC., vol. 127, 2005, pages 5512 |
HANNER, M. ET AL., PROC. NATL. ACAD. SCI., vol. 93, 1996, pages 8072 - 8077 |
LEE S ET AL: "Handbook of Pharmaceutical Salts: Properties, Selection , and Use, Chapter 8 (Large-Scale Aspects of Salt Formation: Processing of Intermediates and Final Products, Chapter 12 (Monographs on Acids and Bases)", 1 January 2002, HANDBOOK OF PHARMACEUTICAL SALTS : PROPERTIES, SELECTION, AND USE, ZÜRICH : VERL. HELVETICA CHIMICA ACTA ; WEINHEIM [U.A.] : WILEY-VCH, DE, PAGE(S) 191 - 192,211, ISBN: 978-3-906390-26-0, XP002548973 * |
M. LANG ET AL., J. AM. CHEM. SOC., vol. 124, 2002, pages 14834 |
QUIRION, R. ET AL., TRENDS PHARMACOL. SCI., vol. 13, 1992, pages 85 - 86 |
SNYDER, S.H., LARGENT, B.L. J. NEUROPSYCHIATRY, vol. 1, 1989, pages 7 |
WALKER, J.M. ET AL., PHARMACOLOGICAL REVIEWS, vol. 42, 1990, pages 355 |
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