WO2013087815A1 - Composition pharmaceutique liquide contenant un dérivé de pyrazolopyrimidine et utilisations pharmaceutiques de celle-ci - Google Patents

Composition pharmaceutique liquide contenant un dérivé de pyrazolopyrimidine et utilisations pharmaceutiques de celle-ci Download PDF

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Publication number
WO2013087815A1
WO2013087815A1 PCT/EP2012/075489 EP2012075489W WO2013087815A1 WO 2013087815 A1 WO2013087815 A1 WO 2013087815A1 EP 2012075489 W EP2012075489 W EP 2012075489W WO 2013087815 A1 WO2013087815 A1 WO 2013087815A1
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Prior art keywords
pyrazolo
pyrimidin
methanone
weight
methyl
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PCT/EP2012/075489
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English (en)
Inventor
Bernhard Hauptmeier
Kevin Kiehm
Alda Szlak-Freier
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2013087815A1 publication Critical patent/WO2013087815A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • Liquid pharmaceutical composition containing a pyrazolopyrimidine derivative and pharmaceutical uses thereof The present invention relates to liquid (or semi solid) pharmaceutical compositions containing at least one pyrazolopyrimidine derivative and at least one oily component.
  • the invention also deals with processes for the preparation and testing of such liquid pharmaceutical compositions, in particular emulsions, containing at least one pyrazolopyrimidine derivative, water and an oily component.
  • the invention also relates to different medical uses of these liquid pharmaceutical compositions.
  • heterocyclic drug compounds have lipophilic (hydrophobic) properties and are only sparingly or negligibly water-soluble.
  • the poor water-solubility of these compounds often result in major difficulties in pharmaceutical formulation of these drugs, particularly when stable emulsions for intravenous applications are needed.
  • These formulations however often have to be stable over long time and even at elevated temperatures.
  • compositions containing a pyrazolopyrimidine compound are heterogeneous systems consisting of at least two liquids which are normally not miscible or which have a limited miscibility with one another.
  • One phase can be described as hydrophilic phase, one phase can be described as lipophilic phase.
  • a pharmaceutical emulsion is a disperse system, where by applying certain levels of energy one of the two liquids is dispersed in the form of very fine droplets (dispersed phase) in the other liquid (continuous phase).
  • the main liquid component is water (hydrophilic phase) and the other liquid is an oily component (hydrophobic phase), then an oil-in-water (or water-in-oil emulsion) is formed.
  • an oil-in-water or water-in-oil emulsion
  • Emulsifiers normally have an amphiphilic molecular structure, consisting of a hydrophilic and a lipophilic molecular moiety, which are often separated from one and another by a spacer unit.
  • Emulsifiers In a classical emulsion, finely disperse droplets of the oily phase, surrounded by an emulsifier shell, are present in the aqueous phase. Emulsifiers lower the surface tension or surface energy between the two phases by positioning themselves at the interface between the two liquids. At the phase boundary, they form an oil/water interfacial film which prevents irreversible coalescence of the droplets. Pharmaceutical emulsions are frequently stabilized by natural or synthetic emulsifiers or mixtures thereof. Emulsifiers can traditionally be divided into ionic emulsifiers and non-ionic emulsifiers. One example of an anionic emulsifier is regular soap, examples of cationic emulsifiers are quaterny ammonium compounds.
  • the hydrophilic part of the molecule of non-ionic emulsifiers frequently consists of glycerol, polyglycerol, sorbitants, carbohydrates and/or polyoxyethylene glycols. In many cases, this hydrophilic moiety is linked to the lipophilic molecular moiety via an ester or ether group.
  • the lipophilic part of the molecule usually consists e.g. of fatty alcohols, fatty acids or iso fatty acids.
  • pyrazolopyrimidine derivatives have been described in recent literature. For example, different types of substituted pyrazolo[l,5-a]pyrimidines compounds and formulations containing these compounds have been disclosed in WO 2008/015269, WO 2008/015270, WO 2008/015271, WO 2009/095253, WO 2009/095254 and WO 2007/006530, wherein the pyrazolo[l,5-a]pyrimidines disclosed are negative modulators of the known receptor mGluR5.
  • pyrazolopyrimidines are described, which can act as small molecule immune potentiators (SMIP) and which can be used e.g. for cancer treatment.
  • JP- A 2002/212075 discloses oil- in- water lipid microspheres comprising a phenyl-group containing pyrazolopyrimidine compound.
  • WO 2004/089471 the use of substituted pyrazolo[l,5-a]pyrimidines for the treatment of diseases is described where it is desirable to inhibit the enzyme l lBHSDl .
  • WO 2003/037900 further specific pyrazolopyrimidine compounds are described as inhibitors of ion-channels in human cells.
  • WO 2003/101993 several types of pyrazolopyrimidine compounds and their use for the treatment of hepatitis infections are disclosed.
  • WO 2003/091256 pyrazolopyrimidine derivatives which have a NADPH-oxidase inhibitor activity are described.
  • pyrazolo[l,5-a]pyrimidine derivatives are disclosed, which are linked to a heterocyclic amine and which are potent modulators of the receptor mGluR5.
  • WO 2011/064237 describes crystalline forms of a specific pyrazolopyrimidine compound.
  • pyrazolo[l,5-a]pyrimidine derivatives have a low solubility in water, e. g. lower than 0.1 mg per ml of water (at 20°C). Furthermore, the wettability of many pyrazolo[l,5-a]- pyrimidine derivatives is very low (measured by contact angles theta » 90°), so that the preparation of aqueous compositions is difficult and time consuming.
  • the pyrazolo[l,5-a]pyrimidine derivatives of the invention often exhibit an octanol/water partition coefficient of log P greater than 1, in particular from 2 to 5, often from 3 to 4.
  • the lipophilicity of a compound can in general be expressed by the logP or logD value.
  • a high logP value describes lipophilic compounds and a low value describes hydrophilic compounds.
  • the octanol/water partition coefficient (logP) of the compounds tested according to this invention can e.g. be determined by accepted standard methods, such as OECD guideline (July 1995), "Test No.
  • n-octanol/water Shake Flask Method
  • OECD Guidelines for the Testing of Chemicals Section 1 : Physical-Chemical properties, OECD Publishing.
  • the logP value may also be determined according to the Draft OECD guideline OECD (2000), see OECD Draft guideline for the Testing of Chemicals: 122 Partition Coefficient (n-Octanol/Water): pH-Metric Method for Ionisable Substances.
  • Liquid pharmaceutical compositions containing pyrazolo[l,5-a]pyrimidine derivatives often are difficult to prepare and/or are not stable during storage, in particular when formulated as aqueous preparations.
  • the stability of the liquid pharmaceutical composition containing the pyrazolo[l,5-a]pyrimidine should however be at least for 9 months (at 25°C), preferably for at least 12 months.
  • the amount of pyrazolo[l,5-a]pyrimidine derivative needed at the specific site of action is often higher than conventional pharmaceutical formulations can provide with.
  • the pyrazolo[l,5-a]pyrimidine derivatives substituted with an isoquinoline substituent are molecules with a very low aqueous solubility of e. g. only 2 to 50 microgram per milliliter.
  • the solubility in aqueous media often cannot be improved by the adjustment of pH- value, as many of these pyrazolo[l,5-a]pyrimidine derivatives have no relevant basic or acidic groups.
  • Solvents such as water
  • co-solvents such as DMSO or glycerol
  • liquid pharmaceutical compositions should provide with pharmacologically active and well tolerated concentrations of the pyrazo lo [ 1 , 5 -a] -pyrimidine compounds .
  • hydrophobic small molecules of substituted pyrazolo[l,5-a]pyrimidine derivatives (P) were found to be solubilised by the use of an oily component (C), which can consist of one or several lipophilic components.
  • the pharmaceutical compositions of this invention often comprise a pyrazolo[l,5-a]pyrimidine derivative which has a molecular weight between 200 and 800 g/mol.
  • the invention relates to a liquid (or semi solid) pharmaceutical composition
  • a liquid (or semi solid) pharmaceutical composition comprising water, at least one pyrazo lo-[l,5-a]pyrimidine compound (P) or a pharmaceutically acceptable salt or a stereoisomeric form thereof, and at least one pharmaceutically acceptable oily component (C), and optionally one or several further components (F).
  • the compositions are preferably liquid compositions. These compositions are preferably for parenteral applications, such as injections or infusions.
  • the further component(s) (F) can e.g. be a pharmaceutical additive from the group of emulsifiers (e.g. a lecithine or a phosphatidyl choline), pH-regulators and buffering agents (e.g. sodium hydroxide), emulsifiers (e.g. salt of oleic acid) and compounds for regulation of the tonicity (e.g. glycerol).
  • emulsifiers e.g. a lecithine or a phosphatidyl choline
  • pH-regulators and buffering agents e.g. sodium hydroxide
  • emulsifiers e.g. salt of oleic acid
  • compounds for regulation of the tonicity e.g. glycerol
  • the invention relates to a liquid (or semi solid) pharmaceutical composition
  • a liquid (or semi solid) pharmaceutical composition comprising water, at least one pyrazo lo-[l,5-a]pyrimidine compound (P) or a pharmaceutically acceptable salt or a stereoisomeric form thereof, and at least two different pharmaceutically acceptable oily components (C), and one or several further components (F).
  • the invention in particular relates to a liquid (or semi solid) pharmaceutical composition
  • a liquid (or semi solid) pharmaceutical composition comprising (or consisting of): at least one pyrazolo[l,5-a]pyrimidine compound (P) of formula (I)
  • Y 1 represents N or C-
  • Y 2 represents N or C-
  • Y 3 represents N or C-
  • Y 4 represents N or C-
  • R 1 represents chloro or bromo
  • R 2 and R 3 each independently represent hydrogen, Ci_ 3 alkyl,
  • R 4 and R 5 each independently represent hydrogen, Ci_ 3 alkyl,
  • R 6 and R 7 independently represent hydrogen, Ci_3-alkyl,
  • R 10 and R 11 independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Ci-C3alkyl, Ci-C3alkyloxy, cyclohexyl, phenyl, or a ring system radical from the group: furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benz
  • R 10 and R 11 together with the two carbon atoms carying them represent a heteroaryl having 5 or 6 ring members or a heterocyclyl group having 5 or 6 ring members, which can be substituted by one of the following groups: halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, Ci_3alkyl and Ci_3alkoxy; or a pharmaceutically acceptable salt or a stereoisomeric form thereof, and comprising at least one pharmaceutically acceptable oily component (C), and comprising water and optionally omprising one or several further components (F).
  • the groups R 10 and R 11 often denote hydrogen atoms.
  • composition often contains 0.01 to 0.5 % by weight of the pyrazolo[l,5-a]pyrimidine compound (P) of formula (I), from about 5 to about 30 % by weight of at least one pharmaceutically acceptable oily component (C), from about 70 to about 95 % by weight of water and optionally comprising 0.1 to 5 % by weight of one or several further components (F).
  • the liquid (or semi solid) pharmaceutical composition according to the invention often consists of the pyrazolo[l,5-a]pyrimidine compound of formula (I), water as the main component (more than 70 % by weight), at least one oily component (C) and one or several further components (F).
  • the liquid (or semi solid) pharmaceutical composition according to the invention often is consisting of the pyrazolo[l,5-a]pyrimidine compound of formula (I), water at the main component (70 % to 90 % by weight), at least two different oily components (C) and one or several further components (F).
  • the liquid (or semi solid) pharmaceutical composition often is comprising at least one pyrazolo[l,5-a]-pyrimidine compound of formula (I) in which the radicals denote:
  • R 10 and R 11 independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Ci-C3alkyl, Ci-C3alkyloxy, cyclohexyl, phenyl, or a ring system from the group: thiophene, pyrrole, furane, pyrazole, tetrazole, oxazole, isoxazole, thiazole, pyridine, pyrimidine and morpholino, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • R 10 and R 11 in formula (I) both represent hydrogen.
  • the liquid (or semi solid) pharmaceutical composition often is comprising at least one pyrazolo[l,5-a]pyrimidine compound of formula (I) in which R 2 , R 3 , R 4 and R 5 independently represent hydrogen, methyl, ethyl or trifluoromethyl; and R 6 and R 7 independently represent hydrogen or methyl, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • the liquid (or semi solid) pharmaceutical composition often is comprising at least one pyrazolo[l,5-a]pyrimidine compound of formula (I) in which one of R 2 and R 3 represents methyl, ethyl or trifluoromethyl and the remaining of R 2 and R 3 represents hydrogen, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • the liquid (or semi solid) pharmaceutical composition often is comprising a pyrazolo[l,5- ajpyrimidine compound of formula (I) in which R 1 denotes bromo, and one o f R 2 and R 3 represents methyl, ethyl or trifluoromethyl and the remaining of R 2 and R 3 represents hydrogen, or a pharmaceutically acceptable salt or a stereoisomeric form thereof.
  • the liquid (or semi solid) pharmaceutical composition often is comprising at least one pyrazolo[l,5-a]pyrimidine compound of formula (I), wherein R 1 denotes bromo, and R 2 represents methyl or ethyl and R 3 , R 4 , R 5 , R 6 , R 7 , R 10 and R 11 all represent hydrogen and which has at least one chiral carbon atom in the R-configuration, or a pharmaceutically acceptable salt thereof.
  • R 1 denotes bromo
  • R 2 represents methyl or ethyl
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 10 and R 11 all represent hydrogen and which has at least one chiral carbon atom in the R-configuration, or a pharmaceutically acceptable salt thereof.
  • the liquid (or semi solid) pharmaceutical composition often is comprising from 0.01 to 0.5 % be weight of a pyrazolo[l,5-a]pyrimidine compound of formula (I), wherein wherein at least three groups Y 1 to Y 4 denote a carbon atom, R 1 denotes bromo, R 2 denotes methyl, R 3 , R 4 , R 5 , R 6 , R 7 , R 10 and R 11 all represent hydrogen.
  • the liquid (or semi solid) pharmaceutical composition often is comprising at least one pyrazolo[l,5-a]pyrimidine compound of formula (I), which has an octanol/water partition coefficient of log P value from 2 to 5, often from 3 to 4.
  • the liquid (or semi solid) pharmaceutical composition often comprises from 0.01 to 0.5 % by weight of the compound of formula (A)
  • liquid (or semi solid) pharmaceutical composition often comprises:
  • oily component (C) 15 to 25 % by weight of a pharmaceutically acceptable oily component (C), which oily component (C) comprises at least 80 % by weight of at least two different types of triglycerides,
  • the oily component (C) often comprises:
  • R 1 wherein at least 98 % by weight of R 1 , R 2 and R 3 are saturated or unsaturated fatty acid with 14-24 carbon atoms, and
  • R 4 wherein at least 97 % by weight of R 4 , R 5 and R 6 are saturated or unsaturated fatty acid with 8-12 carbon atoms.
  • the liquid (or semi solid) pharmaceutical composition often comprises:
  • component (CI) contains the following amounts of fatty acids
  • the liquid (or semi solid) pharmaceutical composition often comprises an oily component, where: the oily component (C) comprises as component CI at least 45 % by weight (of component C) soybean oil and as component C2 at least 45 % by weight (of component C) triglycerides of formula (III) wherein:
  • oily component (III) contains the following amounts of fatty acids
  • component (II) soybean oil is used.
  • oily component of formula (III) middle chain triglycerides are used.
  • the liquid pharmaceutical composition often comprises:
  • oily component (C) comprises:
  • the liquid (or semi solid) pharmaceutical composition often comprises from 2 to 6 % by weight of one or several further components (F), in particular an emulsifier and a component for regulating the tonicity (such as glycerol or sodium chloride).
  • the liquid (or semi solid) pharmaceutical composition often is an aqueous emulsion composition comprising an amount of the pyrazolo[l,5-a]pyrimidine compound (P) is in the range from 0.1 to 5 mg/ml.
  • the liquid pharmaceutical composition often is an aqueous emulsion composition, comprising at least 75 % by weight of water and comprising at least 10 % by weight of the oily component (C) and comprising a concentration of the pyrazolo[l,5-a]pyrimidine compound (P) in the range from 0.1 to 5 mg/ml, and which further may comprise as further component (F) a tonicity adjusting agent (such as glycerol or sodium chloride), a pH- regulator and/or a phosphatidyl-choline component as emulsifier.
  • a tonicity adjusting agent such as glycerol or sodium chloride
  • the liquid (or semi solid) pharmaceutical composition often is an aqueous emulsion composition which comprises as further component (F) a pH-regulator (e.g. sodium hydroxide) or a buffering system.
  • a pH-regulator e.g. sodium hydroxide
  • the stability of the aqueous emulsion composition can be improved by choosing a pH value higher than 7, often in the range of 7.1 to 8.5, in particular from 7.1 to 8.0.
  • the liquid (or semi solid) pharmaceutical compositions can be used for the treatment of a disorder or a disease of the central nervous system.
  • the invention also relates to a process for the preparation of a liquid (or semi solid) pharmaceutical composition as described above, comprising the steps of mixing together at least one pyrazolo[l,5-a]pyrimidine compound (P) or a pharmaceutically acceptable salt or a stereo-isomeric form thereof, and at least one pharmaceutically acceptable oily component (C) and optionally one or several further components (F), where the mixing of the components is made by applying high shear and/or high pressure homogenization steps.
  • P pyrazolo[l,5-a]pyrimidine compound
  • C pharmaceutically acceptable salt or a stereo-isomeric form thereof
  • F optionally one or several further components
  • liquid pharmaceutical compositions as described above normally contain water as main component and, together with the active compound (P), an oily component (C).
  • active compound P
  • oily component C
  • Typical examples of oily components are vegetable or synthetic fats and oils.
  • soybean oil e.g. Soiae oleum raffinatum
  • olive oil e.g. Olivae oleum raffinatum
  • castor oil e.g. Ricini oleum raffinatum
  • thistle oil e.g. Carthami oleum raffinatum
  • safflower oil cotton oil (e.g. Gossypii oleum hydrogenatum)
  • wheat germ oil e.g. Tritici aestivi oleum raffinatum
  • avocado oil evening primrose oil and sesame oil.
  • sesame oil e.g. Tritici aestivi oleum raffinatum
  • animal fats and oils for example, DHA, EPA, liver oil, yolk oil, seal oil, porcine oil and bovine oil have be used for various purposes.
  • oils and fats include medium chain fatty acid triglycerides, such as the commercial product Miglyol 812.
  • oily components (C) for the purpose of this invention, also mixtures of two or more types of oily components (C) may also be used. It is advantageous to choose one or preferably two appropriate oily components (C) depending on the type of substituted pyrazolo[l,5-a]pyrimidine active ingredient, in order to improve the solubility of the active ingredient.
  • liquid compositions are prepared, e. g. in form of solutions or emulsions, by solving the substituted pyrazolo[l,5-a]pyrimidine in one or more oily components (C), one or two or more additional components (F) can be used.
  • additional components (F) are in particular pharmaceutical excipients selected from the group of pH-regulators (such as NaOH) and buffering agents, emulsifiers (such as phosphatidyl cholines and derivatives), additional emulsifiers (such as sodium-oleat), suspending agents, stabilizers, antioxidants, colorants, wetting agents, aggregation inhibitors, co-solvents and compounds for regulating the isotonic character of the composition (such as glycerol).
  • pH-regulators such as NaOH
  • buffering agents such as emulsifiers (such as phosphatidyl cholines and derivatives), additional emulsifiers (such as sodium-oleat), suspending agents, stabilizers, antioxidants, colorants, wetting agents, aggregation inhibitors, co-solvents and compounds for regulating the isotonic character of the composition (such as glycerol).
  • emulsifiers such as phosphatidyl cholines and
  • Examples of the alternative dissolving agents include glycerin fatty acid esters, sucrose fatty acid esters, white beeswax and hardened oil.
  • each may generally be added in an amount within the range of about 0.1 to 5 % by weight, preferably 0.2 to 4 % by weight (of the total composition).
  • the amount of glycerol in the composition often is in the range of 2 to 3 % by weight.
  • the amount of emulsifier (e.g. phosphatidyl choline) in the composition often is in the range of 1 to 4 % by weight.
  • the amount of additional emulsifier (e.g. oleic acid salts) in the composition often is in the range of 0.1 to 1.5 % by weight.
  • Wetting agents or surfactants or tensides or emulsifying agents are chemical substances that increase the spreading and penetrating properties of a liquid by lowering its surface tension, which means the tendency of its molecules to adhere to each other.
  • the extent of wetting of a compound by water is dependent on the hydrophilicity of the compound. The more hydrophobic the compound, the more difficult to get it wet by water. Inability of wetting reflects the higher interfacial tension between the compound and the liquid.
  • interfacial tension can be reduced so that air is displaced from the solid surface of the compound by the liquid.
  • non-ionic and anionic surfactants are used as wetting agents in pharmaceutical practice, such as non- ionic surfactants having a HLB value from 7 to 10.
  • Typical examples are polysorbates, Docusate sodium, Poloxamer and Sodium lauryl sulfate.
  • Typical emulsifiers are phosphatidyl cholines, lecithines and others.
  • Typical lecithines and phosphatidyl cholines to be used in the compositions according to the invention are lecithins or lecithin based derivatives such as Lipoid 75 S and Lipoid 90G, (commercially available, e.g. via Lipoid GmbH, Germany, Ludwigshafen) and Phospholipom 90G (commercially available, e.g. via Phospholipid GmbH, Germany, Koln).
  • an amount of the pyrazolopyrimidine contained in the pharmaceutical compositions of the present invention is not particularly limited, the amount may be from 0.01 to 2 %, in particular 0.05 to 1%, often from 0.1 to 0.5% by weight, based on the total weight of the liquid composition (e.g. emulsion).
  • an amount of the oily component (C) in the composition is not particularly limited, the amount may be from 10 to 30 %, often from 15 to 25% by weight, based on the total mass of the pharmaceutical composition. Furthermore, it is possible to add one or two or more types of other further components (F).
  • the liquid pharmaceutical compositions containing at least one pyrazolopyrimidine derivative (P) can be prepared, which increase the solubility of a pyrazolopyrimidine derivative (P) into the milligram/ml range.
  • the formation of stable liquid compositions of the pyrazolo[l,5-a]pyrimidine derivative (P) and an oily component (C) can occur by applying high shear and/or high pressure homogenization steps, either with or without heating. This can be achieved by preparing a pre-emulsion e.g. by using a homogenizer (Ultra-Turrax®) e.g. with 8000 U/min, and then applying a step of high- pressure homogenization, e.g. by using a Micro fluidizer (e.g. MHOS from Microfluidics)
  • a homogenizer Ultra-Turrax®
  • Micro fluidizer e.g. MHOS from Microfluidics
  • the invention in particular relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one hydrophobic pyrazolo[l,5-a]pyrimidine compound of formula (I), which has an octanol/water partition coefficient (log P) greater than 1, in particular from 2 to 5 and often from 2.1 to 4.5.
  • log P octanol/water partition coefficient
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pyrazolo[l,5-a]- pyrimidine compound (P) with the following formula (A)
  • the invention also relates to a pharmaceutical composition wherein the oily component or components (C) is selected from the group consisting of:
  • MCT e.g. from Fagron or Caelo
  • the oily component (C) is a mixture of soybean oil and synthetic triglyceride of formula (III).
  • the invention also relates to a liquid pharmaceutical composition wherein the ratio of water and the oily component (C) is in the range from 10 : 1 to 3 : 1 ; in particular from 6 : 1 to 3: 1; often from 5: 1 to 4:1.
  • the invention also relates to a pharmaceutical composition wherein the composition is a liquid composition, comprising an amount of the pyrazolo[l,5-a]pyrimidine compound (P) in the range from 0.1 to 20 mg/ml, preferably from 0.5 to 10 mg/ml, often from 1 to 5 mg/ml.
  • the invention also relates to a pharmaceutical composition wherein the composition is an aqueous liquid composition, comprising at least 70 % by weight of water and comprising at least 10 % by weight of an oily component.
  • the composition may comprise as further component (F) one or several excipients, in particular one or several emulsifiers and one or several compounds for regulating the isotonic character of the composition (such as glycerol).
  • excipients such as glycerol
  • emulsifiers are phosphatidyl cholines, lecithines and others.
  • the emulsifier often is used in an amount of less than 5 percent by weight, in particular less than 4 percent by weight of the total liquid composition.
  • the invention also relates to a pharmaceutical composition for the treatment of a disorder or a disease of the central nervous system, in particular of those CNS-diseases described below (such as Alzheimer or Parkinson disease).
  • a further aspect of the invention deals with a process for preparation of a pharmaceutical composition as described above, comprising the steps of mixing together at least one pyrazolo[l,5-a]pyrimidine compound (P) or a pharmaceutically acceptable salt or a stereoisomeric form thereof, and at least one pharmaceutically acceptable oily component (C) and optionally one or several further components (F), where the process encompasses the step of preparing a solution of compound (P) in the oily component (C),then preparing a pre-emulsion which is further homogenized by applying high pressure homogenization steps.
  • One preferred process for preparation of a pharmaceutical composition as described above encompasses the steps of: a) Heat the oily mixture to a temperature of 30 to 70°C, potentially add the emulsifier (such as Phospholipon 90 G or Lipoid S75) while mixing;
  • soybean oil e. g. soybean oil, using heat and/or ultrasonification
  • the process can also encompass the step of introducing the oily phase into the aqueous phase (e.g. as described in the experimental part).
  • Certain triglycerides of formulae (II) and (III) are well tolerated on many human application routes like the oral or parenteral routes, such as refined soybean oil. Certain triglycerides of formulae (II) and (III) are also toxicologically well characterized.
  • the new liquid pharmaceutical compositions can easily be prepared, based on water, low- cost oily components (C) and small amounts of additional excipientes (F), which compositions are easily applicable to humans and animals, and are well tolerated and have an acceptable long-term stability.
  • the compositions described above can be e. g. in the form of a semi-solid composition (e.g. gel or cream) or a liquid composition (e.g. solution or emulsion).
  • a semi-solid composition e.g. gel or cream
  • a liquid composition e.g. solution or emulsion.
  • Stable liquid formulations of the pyrazolo[l,5-a]pyrimidine derivatives (P) can be provided, which can be stored for many months, even at elevated temperature.
  • composition is an aqueous liquid composition comprising at least 70 % by weight of water and wherein the concentration of the compound of formula (I), in particular of formula (A), is in the range from 1 mg/ml to 50 mg/ml.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a hydrophobic pyrazolopyrimidine compound (P).
  • P hydrophobic pyrazolopyrimidine compound
  • the hydrophilicity and lipophilicity can be determined by the octanol/water partition coefficient (logP), for example according to the standard methods mentioned herein.
  • a compound having an octanol/water partition coefficient of logP ⁇ l will be considered hydrophilic.
  • a compound having an octanol/water partition coefficient of logP>l will be considered lipophilic.
  • the invention also relates to a pharmaceutical composition, such as an aqueous composition, comprising as further component (F) a co-solvent and/or a preservative and/or an emulsifier.
  • the invention also relates in general to a composition
  • a composition comprising a phosphatidyl choline as emulsifier, e. g. in a concentration from 0.5 to 3 % by weight, often from 1 to 2% by weight (of the total formulation).
  • the invention also relates to a pharmaceutical composition as described above for the treatment of a disorder or a disease of the central nervous system, such as the following diseases: Alzheimer's disease, Creutzfeld- Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE), diseases involving ⁇ -amyloid and/or tauopathy, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic clerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, ma
  • ADHD attention deficit syndrome
  • ADS attention deficit syndrome
  • RLS restless leg syndrome
  • hyperactivity in children autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, major depressive disorder, depression, bipolar manic-depressive disorder, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, schizophrenia, spasticity, Tourette's syndrome, sleep disorders, anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders and schizophreniform disorder.
  • Parkinson's disease and dyskinesias can be treated by the composition comprising a compound (P) and an oily component (C).
  • the invention also relates to a process for preparation of a liquid pharmaceutical composition comprising the steps of mixing together at least one pharmaceutically acceptable compound of formula (I) and at least one pharmaceutically acceptable oily component (C) and if necessary further pharmaceutically acceptable components (F).
  • the invention also relates to the use of a combination of two oily components (CI) and (C2), for the preparation of a pharmaceutical composition comprising a pyrazolopyrimidine compound (P) for the treatment of a disease, in particular a CNS- disease
  • CI oily components
  • C2 pyrazolopyrimidine compound
  • the invention further relates to such a use, wherein the composition is an aqueous liquid composition comprising as further component (F) a co-solvent, a pH-regulator and/or an emulsifier.
  • the compounds of the invention are usually named according to the IUPAC or CAS nomenclature system.
  • the term "derivative" is used herein in the conventional pharmaceutical sense referring to a molecule that structurally resembles a reference molecule, but has been modified in a controlled manner to replace one or more specific substituent(s) of the molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
  • composition according to the invention may comprise the compound of formula (I) and/or a "pharmaceutically acceptable salt” and/or a “derivative” and/or a “polymorphic form” and/or one or several "stereoisomeric forms” of a compound of formula (I).
  • pharmaceutically acceptable refers to ingredients of the compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (such as a human).
  • pharmaceutically acceptable means approved by a European or US-regulatory agency or listed in a recognized pharmacopeia for use in mammals.
  • the compounds of the present invention may be in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • the compounds of the invention having at least one chiral center may exist in and be isolated in optically active (such as R- or S-isomers) and racemic forms.
  • optically active such as R- or S-isomers
  • the present invention encompasses any racemic, optically active, polymorphic, tautomeric or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.
  • the pharmaceutically acceptable salts of the compound (I) can be prepared by known methods. These salts include e. g. acid addition salts, such as salts made with hydrochloric, methylsulfonic, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic, methanesulfonic, ethane-sulfonic, hydroxyl- ethanesulfonic, benezenesulfonic, p-toluenesulfonic, cyclohexane-sulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic or 2-acetoxybenzoic acid. Pharmaceutically acceptable salts also include base addition salts, e.g. using rations such as Na,
  • All of these salts may be prepared by conventional means.
  • the nature of the salt is not particularly critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • the invention in particular relates to aqueous liquid compositions containing a compound (A).
  • aqueous liquid compositions containing a compound (A).
  • These are liquid preparations wherein the major liquid component is water.
  • the compositions normally contain at least 70% by weight, often about 80 % by weight (w/w of the total composition) of water, but these aqueous liquid compositions further comprise other liquid components, such as one or several oily components (C) and pharmaceutically acceptable further components (F).
  • the invention also relates to semi-solid compositions.
  • This term means a composition with low viscosity whose major liquid component is water.
  • the semi-solid composition may comprise further components (F), such as pharmaceutically acceptable organic co- solvents, viscosity regulation polymers, pH-regulators, preservatives and emulsifiers.
  • liquid components are ethanol, propylene glycol, and polyethylene glycol, and in particular glycerol.
  • water-miscible organic solvents may be incorporated for example in order to solubilise an insufficiently water-soluble ingredient, such as a lipophilic substance.
  • the term semi-solid composition includes in particular gels, but also creams and ointments.
  • compositions In comparison to a liquid composition these formulations have an increased viscosity, compared to aqueous solutions.
  • the viscosity of semi-solid compositions can be controlled by using one or several polymeric components or a combination of polymers.
  • the term "stereoisomeric form" of compound (I) is used herein in the conventional chemical sense to refer to a molecule that has the same summarizing chemical formula but differs in the structure. Typical examples are enantiomers, diastereoisomers and racemates.
  • heteroaryl means an aromatic heterocyclic system, in particular having 5 or 6 membered ring systems, which contain at least one atom which is not a carbon atom, such as e.g. N, S, O.
  • heterocyclyl means a non-aromatic heterocyclic system, in particular having 5 or 6 membered ring systems, which contain at least one atom which is not a carbon atom, such as e.g. N, S, O.
  • Typical examples are piperidine, pyrolidine, etc.
  • the amount of the compound of formula (I) in the liquid pharmaceutical composition may be decided taking into account the desired pharmaceutical use (e.g. oral or parenteral CNS- formulations), the type of the active ingredient of formula (I) and the concentrations of the other ingredients.
  • the concentration of the active ingredient of formula (I) may be e. g. at least 0.5 mg/ml. If the active ingredient is a compound of formula (I), in particular of formula (A), the concentration in the liquid formulation often is in the range from 0.01 to 100 mg/ml, for example 0.1 to 50 mg/ml, and often from 1 to 10 mg/ml.
  • the compound of formula (I) is rapidly absorbed from the composition and becomes bioavailable.
  • composition of the invention may further comprise, besides the pyrazolopyrimidine derivative (P) at least one further active ingredient (B), such as a further drug compound useful for the treatment of CNS-diseases.
  • a further drug compound useful for the treatment of CNS-diseases such as a further drug compound useful for the treatment of CNS-diseases.
  • Typical examples are drug compounds commercialized for the treatment of Alzheimers or Parkinson disease.
  • the preservation of the active compound of formula (I) can be important. It is possible to formulate the composition without any additional preservative.
  • the composition of the invention is substantially free of preservatives.
  • the term "substantially” means that preservatives are not detectable in the composition, or only in concentrations which are generally considered irrelevant with regard to any preservation effects.
  • the liquid pharmaceutical composition may optionally comprise as further component (F) at least one preservative. Whether a composition is effectively preserved may be determined according to tests known in the art.
  • the pharmaceutical composition can also contain as further component (F) a preservative such as benzalkonium chloride, cetylpyridium chloride, cetrimide, cetyl trimethyl- ammonium bromide, benzethonium chloride, chlorhexidine gluconate, ethanol, isopro- panol, propylen glycol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid, benzoic acid, thiomersal, organomercury components, chlorobutanol and/or benzyl alcohol.
  • a preservative such as benzalkonium chloride, cetylpyridium chloride, cetrimide, cetyl trimethyl- ammonium bromide, benzethonium chloride, chlorhexidine gluconate, ethanol, isopro- panol, propylen glycol, butylparaben, ethylparaben, methylpara
  • the pharmaceutical composition can as further component (F) also contain a pH-regulator, e. g. to improve the stability.
  • a pH-regulator e. g. to improve the stability.
  • Typical examples are selected from the group consisting of physiologically acceptable acids, bases, and acidic and alkaline salts.
  • the preparation of the composition comprising the pyrazolopyrimidine (P) according to the invention is technically easy, quick and cost-efficient.
  • the components are e. g. weighed and the compound of formula (I) is combined (mixed) with measured amounts of the oily component (C) and optionally further components (F), optionally followed by intensiv stirring until dissolution occurs.
  • the mixture may be agitated and/or heated for some time, e. g. from 2 minutes to 64 hours.
  • the solution may be further processed by filtration or centrifugation to remove residual particles.
  • the oily phase is then combined with water to form a stable pre-emulsion. Then an emulsion is prepared by further high pressure mixing. If a solid formulation is desired, the solution described may be dried, such as by spray drying or freeze drying.
  • compositions were prepared by using as pyrazolopyrimidine- component the compound (A), which has the chemical name:
  • Compound (A) can be formulated together with various oily components (C) as aqueous based, liquid compositions with higher concentration of the drug substance. These formulations can be easily applied to different animal species and human beings via application routes like the parenteral route.
  • the compound (A) is a lipophilic compound with limited wettability and solubility in aqueous media. The lipophilicity can be expressed by the logP value, which is approximately 3 for compound (A).
  • pyrazolopyrimidine component (6-Bromo-pyrazolo[l,5-a]-pyrimidine-2-yl)-(l(R)- methyl-3,4-dihydro-lH-isoquinoline-2-yl)-methanone was formulated with various oily components with higher concentrations of the drug substance using specific amounts of oily components (C).
  • the following compositions were prepared by mixing the respective oily component (C) and the pyrazolopyrimidine compound, followed by filtration (PTFE- filter) and then analysis by High Performance Liquid Chromatography.
  • the compound (A) was found to be sufficiently solubilised by the use of soybean oil, castor oil and MCT as component (C).
  • a liquid mixture was prepared by using 100 g of soybean oil and 100 g of MCT.
  • the soybean oil is commercially available by Caelo (Caesar & Lorenz GmbH, Hilden, Germany).
  • the component MCT is also commercially available (e.g. by Caelo).
  • the solubility of compound (A) in this 50:50 (w/w) mixture of two oily components (CI) and (C2) was tested.
  • Three different compositions were prepared (containing 1 mg/ml, 1.5 mg/ml and 2.0 mg/ml) of compound (A).
  • the maximum solubility of compound (A) in this mixture of oily components was found to be 8 mg/ml.
  • the oily phase containing the compound (A) was then mixed with an emulsifier (l%-3% by weight) of e.g. Lipoid S 75 Lipoid GmbH Germany, and afterwards with the aqueous phase containing a small amount (2.5% by weight) of a tonicity adjusting agent (Glycerol).
  • emulsifier l%-3% by weight
  • a tonicity adjusting agent Glycerol
  • Different compositions were prepared containing about 10% to 20%of the oily component (C) and about 70 to 90%> of water. These compositions were mixed by using an Ultra- Turrax-homogenizer followed by one to 10 cycles of high pressure homogenisation.
  • These emulsions prepared are then characterized by microscopic analysis and by dynamic light- scattering methods (Horiba LB 500).
  • laser diffraction experiments were made with the emulsions (EMan Coulter LS) and electro-acoustic experiments were performed (Dispersion Technology DT 300; Malvern Ze
  • the average particle sizes of the oily components (comprising the active ingredient) were found to be less than 1.2 ⁇ , preferably with D90-values from 0.2 to 1.2 ⁇ .
  • the emulsions were found to be stable over a period of more than 12 months.
  • the viscosities of the various emulsions tested were measured (using a rotation viscosimeter MCR 101).
  • the emulsions tested had a viscosity (at room temperature) of about 2 to 3 mPas.
  • Emulsion with 0.5 mg/ml of Compound (A) for parenteral application in rats were prepared containing 10% soybean oil
  • the emulsion looks homogeneous, no sign of precipitation of drug substance, no sign of phase separation.
  • Emulsion osmolality 276 mmol/kg.
  • Emulsion with 5 mg/ml Compound (A) for oral application in rats were prepared containing 10% soybean oil and 10% MCT (middle chain triglycerides)
  • Phospholipon 90 G The mixture was mixed with the magnetic stirrer for app. 2 hours at temperature of 50°C. The Compound (A) could not be seen anymore, the yellowish solution was clear.
  • Glycerol was mixed with 9.5 g water and heated to app. 40°C. This mixture was added to the lipid blend stepwise and mixed with the Ultraturrax for 5 min. at 9500 rpm.
  • the emulsion looks homogeneous, no sign of precipitation of drug substance, no sign of phase separation.
  • Emulsion with 0.5 mg/ml Compound (A) for oral application in rats were prepared containing 10% soybean oil and 10% MCT
  • Phospholipon 90 G The mixture was mixed with the magnetic stirrer for 2 hours at 50°C. The Compound (A) could not be seen anymore, the yellowish solution was clear.
  • Glycerol was mixed with 14.9 g water and heated to app. 40°C. This mixture was added to the lipid blend stepwise and mixed with the Ultraturrax for 5 min. at 9500 rpm c) The emulsion was treated with the French Press for 5 cycles at 800 bar.
  • the emulsion looks homogeneous, no sign of precipitation of drug substance, no sign of phase separation.
  • Emulsion osmolality 347 mmol/kg.
  • Emulsion with 0.5 mg/ml Compound (A) for parenteral application in rats were prepared containing 10% soybean oil and 10% MCT
  • the emulsion looks homogeneous, no sign of precipitation of drug substance, no sign of phase separation.
  • Emulsion osmolality 318 mmol/kg.
  • Emulsion with 1 mg/ml Compound (A) for parenteral application in monkeys were prepared, containing 10%> soybean oil and 10%> MCT
  • the emulsion looks homogeneous, no sign of precipitation of drug substance, no sign of phase separation.
  • Compound (A) is added with continued heating and stirring;
  • composition B) is filtered and then introduced into Composition A),
  • the emulsion (pH about 7.5; particle size of the oily phase about 240 nm) obtained was stored at different temperatures in glass bottles and observed over a period of 12 months with analysis after 1, 3, 6, 9 and 12 months. Different humidities were tested, e.g. 60% r.h.
  • the emulsion was filled in 50mL clear glass bottles of hydro lytic class 2, which were closed with red brom-butyl stoppers and aluminum caps.
  • the samples were stored in a refrigerator at 5°C, under long term storage conditions at 25°C/ 60%> r.h., under accelerated storage conditions at 40°C/ 75% r.h. and at 60°C.
  • the main results are summarized as follows:
  • the emulsion was stable for 12 months. A slight decrease of PH and content was observed with increasing temperatures. - At 5°C nearly complete stability (93% content of active compound) of the emulsion of compound (A) was found after 12 month, the pH very slightly decreased.

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Abstract

L'invention concerne une composition pharmaceutique liquide comprenant au moins un composé pyrazolo[1,5-a]pyrimidine substitué (P) ou un sel pharmaceutiquement acceptable ou une forme stéréoisomérique de celui-ci, de l'eau et au moins un composant huileux pharmaceutiquement acceptable (C), et facultativement un ou plusieurs autres composants (F), tels qu'un émulsifiant. Cette composition est particulièrement stable pendant une longue durée.
PCT/EP2012/075489 2011-12-15 2012-12-14 Composition pharmaceutique liquide contenant un dérivé de pyrazolopyrimidine et utilisations pharmaceutiques de celle-ci WO2013087815A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9181249B2 (en) 2013-12-20 2015-11-10 Takeda Pharmaceutical Company Limited Substituted pyrido[3,4-b]pyrazines as GPR6 modulators
US10968217B2 (en) 2016-11-03 2021-04-06 Hoffmann-La Roche Inc. Tetrahydropyridopyrimidines for the treatment and prophylaxis of hepatitis B virus infection

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002212075A (ja) 2001-01-17 2002-07-31 Otsuka Pharmaceut Factory Inc 脂肪乳剤及び医薬製剤
WO2003037900A2 (fr) 2001-11-01 2003-05-08 Icagen, Inc. Pyrazolopyrimidines
WO2003091256A1 (fr) 2002-04-23 2003-11-06 Shionogi & Co., Ltd. Derive de pyrazolo[1,5-a]pyrimidine et inhibiteur de la nad(p)h oxydase contenant ledit derive
WO2003101993A1 (fr) 2002-06-04 2003-12-11 Neogenesis Pharmaceuticals, Inc. Composes de pyrazolo(1,5a)pyrimidine servant d'agents antiviraux
WO2004087153A2 (fr) 2003-03-28 2004-10-14 Chiron Corporation Utilisation de petites molecules de composes pour une immunopotentialisation
WO2004089471A2 (fr) 2003-04-11 2004-10-21 Novo Nordisk A/S Utilisation pharmaceutique de pyrazolo[1,5-a]pyrimidines substituees
WO2007006530A1 (fr) 2005-07-12 2007-01-18 Novartis Ag Emploi de mglur5 (en particulier afq056) dans le tractus gastro-intestinal (en particulier dans le cas de reflux gastro-oesophagien)
WO2008015271A1 (fr) 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, procédé permettant de les préparer et de les utiliser en tant que médicament
WO2009095253A1 (fr) 2008-02-01 2009-08-06 Merz Pharma Gmbh & Co. Kgaa 6-halo-pyrazolo[1,5-a]pyridines, leur méthode de préparation et leur utilisation comme modulateurs des récepteurs métabotropiques du glutamate (mglur)
WO2009095254A1 (fr) 2008-02-01 2009-08-06 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, leur méthode de préparation et leur utilisation comme médicaments
WO2011064237A1 (fr) 2009-11-25 2011-06-03 Merz Pharma Gmbh & Co. Kgaa Formes cristallines de pyrazolopyrimidines substituées

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002212075A (ja) 2001-01-17 2002-07-31 Otsuka Pharmaceut Factory Inc 脂肪乳剤及び医薬製剤
WO2003037900A2 (fr) 2001-11-01 2003-05-08 Icagen, Inc. Pyrazolopyrimidines
WO2003091256A1 (fr) 2002-04-23 2003-11-06 Shionogi & Co., Ltd. Derive de pyrazolo[1,5-a]pyrimidine et inhibiteur de la nad(p)h oxydase contenant ledit derive
WO2003101993A1 (fr) 2002-06-04 2003-12-11 Neogenesis Pharmaceuticals, Inc. Composes de pyrazolo(1,5a)pyrimidine servant d'agents antiviraux
WO2004087153A2 (fr) 2003-03-28 2004-10-14 Chiron Corporation Utilisation de petites molecules de composes pour une immunopotentialisation
WO2004089471A2 (fr) 2003-04-11 2004-10-21 Novo Nordisk A/S Utilisation pharmaceutique de pyrazolo[1,5-a]pyrimidines substituees
WO2007006530A1 (fr) 2005-07-12 2007-01-18 Novartis Ag Emploi de mglur5 (en particulier afq056) dans le tractus gastro-intestinal (en particulier dans le cas de reflux gastro-oesophagien)
WO2008015271A1 (fr) 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, procédé permettant de les préparer et de les utiliser en tant que médicament
WO2008015269A1 (fr) 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines substituées, procédé de préparation et d'utilisation de celles-ci en tant que médicaments
WO2008015270A1 (fr) 2006-08-04 2008-02-07 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, procédé permettant de les préparer et de les utiliser en tant que médicaments
WO2009095253A1 (fr) 2008-02-01 2009-08-06 Merz Pharma Gmbh & Co. Kgaa 6-halo-pyrazolo[1,5-a]pyridines, leur méthode de préparation et leur utilisation comme modulateurs des récepteurs métabotropiques du glutamate (mglur)
WO2009095254A1 (fr) 2008-02-01 2009-08-06 Merz Pharma Gmbh & Co. Kgaa Pyrazolopyrimidines, leur méthode de préparation et leur utilisation comme médicaments
WO2011064237A1 (fr) 2009-11-25 2011-06-03 Merz Pharma Gmbh & Co. Kgaa Formes cristallines de pyrazolopyrimidines substituées

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GRIMM ET AL., STABILITY TESTING, APV WORKSHOP, 2001

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9181249B2 (en) 2013-12-20 2015-11-10 Takeda Pharmaceutical Company Limited Substituted pyrido[3,4-b]pyrazines as GPR6 modulators
US9708313B2 (en) 2013-12-20 2017-07-18 Takeda Pharmaceutical Company Limited Substituted pyrido[3,4-b]pyrazines as GPR6 modulators
US10077266B2 (en) 2013-12-20 2018-09-18 Takeda Pharmaceutical Company Limited Substituted pyrido[3,4-b]pyrazines as GPR6 modulators
US10738046B2 (en) 2013-12-20 2020-08-11 Takeda Pharmaceutical Company Limited Substituted pyrido[3,4-b]pyrazines as GPR6 modulators
US10968217B2 (en) 2016-11-03 2021-04-06 Hoffmann-La Roche Inc. Tetrahydropyridopyrimidines for the treatment and prophylaxis of hepatitis B virus infection

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