WO2016192831A1 - Compositions d'anions et de cations ayant une activité pharmacologique - Google Patents

Compositions d'anions et de cations ayant une activité pharmacologique Download PDF

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WO2016192831A1
WO2016192831A1 PCT/EP2016/000745 EP2016000745W WO2016192831A1 WO 2016192831 A1 WO2016192831 A1 WO 2016192831A1 EP 2016000745 W EP2016000745 W EP 2016000745W WO 2016192831 A1 WO2016192831 A1 WO 2016192831A1
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wca
organic compound
composition
composition according
group
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Inventor
Christoph Saal
Christian Weber
Klaus-Dieter Franz
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Merck Patent GmbH
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Merck Patent GmbH
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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
    • A61K31/69—Boron compounds

Definitions

  • the present invention relates to compositions comprising an organic compound (a) and a Weakly Coordinating Anion (WCA) (b), the use of these compositions as medicament as well as for the treatment of specific diseases and compounds of WCAs with suitable counter cations.
  • the compositions of the present invention exhibit improved solubility, dissolution, supersaturation and/or bioavailability when compared to the organic compounds (a) as such or to salts of the organic compounds (a) with usual counter anions, i.e., non- WCAs.
  • One of the goals of pharmaceutical research and development is to provide medicaments to patients in the need thereof that can be orally administered. (About 85% of the most sold medicaments in Europe and North America are orally administered.) This applies in particular to those medicaments that contain pharmacologically active ingredients (Active Pharmaceutical
  • API that are systemically active.
  • small chemical entities as API in contrast to large(r) biological entities such as peptides and proteins
  • the goal of providing orally applicable medicaments is hampered by several obstacles among which low solubility and dissolution rate and hence insufficient bioavailability of the API and pharmaceutical compositions comprising the API under physiological conditions are very prominent. If the API is poorly soluble or dissolves very slowly in
  • WCA Weakly Coordinating Anions
  • tetra(pentafluorophenyl)borate that exhibits low basicity and forms only weak coordination bond with a cation, like metal cations, in particular transition metal cations.
  • Its negative charge (preferably a -1 charge) is delocalized over a large area of non-nucleophilic and chemically robust (and preferably sterically demanding and bulky) moieties.
  • Typical WCAs are those discussed in S.H. Strauss, Chem. Rev. 1993 (93) 927-942, and, more recently, in I. Krossing and I. Raabe, Angew. Chem. Int. Ed.
  • WCAs are utilized in a wide variety of practical applications, for instance, as counter anions of cationic catalysts in olefin-polymerization reactions; in electrochemical applications, in particular in electrolyte salts of lithium-ion batteries; in so-called Ionic Liquids (IL); and in processes for the extraction of lanthanide cations; to mention only a few (see I. Krossing and I. Raabe, Angew. Chem. Int. Ed. 2004, 43, 2066-2090).
  • (a1) exhibits a pharmacological activity that is useful for the prevention and/or treatment and/or alleviation of a medical condition or disease; and (a2) is present in that composition in a protonated form.
  • the present invention provides a composition of a WCA with the protonated form of an API.
  • This composition shows improved solubility, dissolution rate, supersaturation and bioavailability when compared to the unprotonated API base as such or to salts of the API with conventional, non- WCA type anions like, e.g., chlorides, bromides, sulfates, mesylates and the like.
  • the composition of the present invention is in a solid state form, i.e., in an amorphous or crystalline form. It is even more preferred that the composition is in a crystalline form.
  • the improved solubility and/or dissolution rate and/or supersaturation and hence bioavailability of the composition according to the present invention are due to only weak Coulomb (ion-ion) interactions between the protonated API and the WCA in the solid state of the composition; those interactions are believed to be much weaker than the Coulomb interactions between the protonated API and a non-WCA type, i.e., "classical" anion in a classical API salt.
  • each weakly coordinating anion that forms a stabile composition with organic compound (a) may be suitable as the WCA (b) of the
  • Each WCA whether known from the prior art like those disclosed in US 2008/0033195 A1; S.H. Strauss, Chem. Rev. 1993 (93) 927-942; I. Krossing and I. Raabe, Angew. Chem. Int. Ed. 2004, 43, 2066-2090; or novel WCAs like those herein disclosed, may be suitable as Weakly Coordinating Anion (b) of the composition of the present invention.
  • the composition of the organic compound (a) and the WCA (b) is provided in a pharmaceutically acceptable form. That may be achieved by choosing a WCA (b) with properties that do not impair the desired pharmacological activity of the API compound (a) and/or do not exhibit undesired pharmacological effects (like, for instance, organ toxicity or genotoxicity) either on its own or in combination with the API (b).
  • the composition of the present invention comprises a WCA (b) that is selected from a boron (B) or phosphorous (P) containing WCA.
  • the WCA is a boron containing WCA, in particular a borate WCA. It is even more preferred that the borate WCAs (b) of the composition of the present invention do not contain any halogen substituents.
  • BTB W ith X OH, F, CI, Br, I, CN, SCN, OCN, NCO; especially OH ;
  • ThyCB with X OH, F, CI, Br, I, CN, SCN, OCN, NCO; especially OH.
  • Sodium and lithium salts of BMB, BHAcB and BOxB can be prepared as described in WO 2002/068433 A1 or in analogy thereto.
  • Sodium and lithium salts of BSalB are well known for a long time and can be obtained in analogy to the synthesis of the silver salt of BSalB that is disclosed in WO 2008/058490 A1.
  • the lithium salt of TEB can be prepared as described in WO 2011/032681 A1.
  • Novel WCAs B3B, B4B, B5B, B6B are readily available as their sodium salts according to the syntheses depicted in Scheme 1 ; alternatively, their silver, lithium and sodium salts may be available by applying the methodology described in WO 2002/068433 A1 and reacting 2 equivalents of the respective dicarboxylic acid with 1 equivalent of boronic acid or boronic oxide in the presence of about 0.4 to 0.6, preferably 0.51 to 0.52 equivalents of lithium or sodium carbonate, as the case may be.
  • Other alkali metal salts K, Rb, Cs
  • K, Rb, Cs alkali metal salts
  • Silver salts of these WCAs can be obtained, for instance, by reacting 1 equivalent of the respective dicarboxylic acid with 2 equivalents silver nitrate followed by reacting 1 equivalent of the resulting disilver dicarboxylic acid salt with about 0.4 to 0.5, preferably about 0.5 equivalents boron trichloride. cheme 1
  • ThyCB (with X being OH) is obtainable by the method described in J. Dale, J. Chem. Soc. 1961, 922-930.
  • the WCA salts may be obtained as solvates.
  • the WCA (b) is selected from B3B, B4B, B5B, B6B, BMB, BHAcB and BSalB.
  • the organic compound (a) of the composition according to the present invention can be any organic compound that (a1) exhibits a pharmacological activity that is useful for the prevention and/or treatment and/or alleviation of a medical condition or disease; and (a2) can be protonated, i.e., has at least one basic center.
  • the organic compound is a (small) chemical entity (in contrast to biological entities like peptides, proteins or nucleinic acids).
  • the organic compound (a) is selected from any kind of chemical API that has at least one basic centre and can therefore be protonated with protonic acids (Bronsted acids).
  • the focus of the present invention lies on the improvement of the solubility and/or supersaturation and/or bioavailability of otherwise poorly soluble API with low bioavailability, the present invention is not limited thereto but refers as well to compositions of WCA (b) with organic compounds (a) (APIs) that do not suffer from poor solubility and/or supersaturation and/or bioavailability.
  • compositions of the present invention are useful because they may further improve solubility, supersaturation, dissolution rate and bioavailability, thereby, for instance, improving the pharmacological effect of the API administered to a patient or allowing to lower the dosage of API administered without impairing the desired pharmacological effect.
  • the present invention may in particular be useful for compositions comprising organic compounds (a) that are APIs classified as BCS (Biopharmaceutics Classification System) Class II or IV compounds.
  • a Class II compound (or drug substance or API) is defined to exhibit low solubility and high permeability, while a Class IV compound is defined to exhibit both low solubility and permeability.
  • a compound (or drug substance or API) is considered to be “poorly soluble”, if it is not “highly soluble”, while a compound is considered “highly soluble”, when the highest dose strength of that substance is soluble in less than 250 ml water over a pH range of 1 to 7.5.)
  • the present invention is particularly useful for compositions comprising an organic compound (a) having a dose number (Do) larger than 1 (>1), more preferably larger than 3 (>3), and/or a bioavailability upon administration of an immediate release oral dosage form of 40% or less, more preferably of 20% or less, if present in unprotonated form or in protonated form in a salt together with a salt former or anion other than a WCA (b).
  • Dose number Do is defined as the ratio of drug concentration in 250 ml water to the saturation solubility of that drug in water (see A. Dahan, et al., The AAPS Journal, Vol. 11 , No. 4, December 2009, 740-746).
  • API of poor solubility and/or bioavailability that may constitute the organic compound (a) in the composition of the present invention are selected from the group listed below, however, without being limited to it:
  • Sorafenib piracetam; levetiracetam; acetazolamide; carbamazepine;
  • norfloxacin haloperidol; indapamide; diazepam; tamoxifen; triamterene; nitrendipine; nifedipine; phenytoin; dipyridamole; ketoconazol; fexofenadine; gefitinib; rosuvastatin;; efavirenz; danazol; amiodarone; pimozide;
  • indomethacin glibenclamide
  • hydrochlorothiazide iopanoic acid
  • polythiazide polythiazide; atovaquone; diltiazem; metformin, metoprolol; paracetamol; propranolol; verapamil; theophylline; carbamazepine; felodipine; nicardipine; nifedipine; nisoldipine; troglitrazone; acyclovir; alendronate; atenolol;
  • captopril cimetidine; enalaprilate; neomycin; ranitidine; cefuroxime, chlorothiazine; ciclosporin; furosemide; itraconazole, tobramycin; donepezil; galanthamine, clomipramine; ondansetron; domperidone; pramipexole;
  • ropinirole olanzapine; clozapine; quetiapine; risperidone; abacavir;
  • albendazole albuterol; adriamycin; oxcarbazepine; amiodarone;
  • amphetamine amphotericin B; atovastartin; atovaquone; azithromycin; baclofen; bicalutamide; busulfan; butenafine;camptothecin; capsaicin;
  • carotenes cerivastatin; chlorpheniramine; cimetidine; ciprofloxacin; cisapride; cetirizine; clarithromycin; clemastine; codeine; dantrolene;
  • etoposide famotidine
  • fentanyl finasteride
  • fluconazole fluvastatin
  • miglitol miglitol; mitoxantrone; nabumetone; nalbuphine; naratriptan; nefinavir;
  • nilutamide nizatidine; paclitaxel; docetaxel; pentazocine; naloxone;
  • pioglitazone pizotifin; pyridostigmine; raloxifene; repaglinidine; rifapentine; rimexolone; rizatriptan; rosiglitazone; saquinavir; sibutramine; sildenafil;
  • teniposide terbinafine; tiagabine; tizanidine; topotecan; toremifene, troglitazone; moxifloxacin; verteporfin; vigatriptan; zafirlukast; zileuton;
  • amoxicillin atenolol; benserazide; camostat; losartan; methotrexate;
  • metoclopramide nizatidine; nystatin; ondansetron; oseltamivir; primaquine; procaterol; propylthiouracil; ranitidine; ribaverin; stavudine; sulfadiazine;
  • the API being the organic compound (a) of the composition according to the present invention is selected from the group consisting of: sorafenib (4- ⁇ 4-[3-(4-Chlor-3- trifluormethylphenyl)
  • 3-(1- ⁇ 3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl ⁇ -6-oxo-1 ,6- dihydro-pyridazin-3-yl)-benzonitrile is described in WO 2009/007074 A1 and WO 2010/078897 A1 and may be useful for the treatment of diseases and conditions, such as angiogenesis, cancer, tumor formation, - growth and proliferation, atherosclerosis, eye diseases such as age-related macular degeneration, choroidal neovascularization, diabetic retinopathy,
  • any of these compounds (a) can be combined with any suitable WCA (b) to form a composition of the present invention.
  • the composition of the present invention comprises an organic compound (a) in its protonated form selected from sorafenib (4- ⁇ 4-[3-(4-Chlor-3- trifluormethylphenyl) ureido]phenoxy ⁇ pyridin- 2-carbonsauremethylamid) (API1); 3-(1- ⁇ 3-[5-(1- methyl-piperidin-4-yImethoxy)-pyrimidin-2-yl]-benzyl ⁇ -6-oxo-1 ,6-dihydro- pyridazin-3-yl)-benzonitrile (API2); (methyK3-[5-(2'-methyl-2-trifluoromethyl- biphenyl-4-yl)-[1 ,2,4]oxadiazol-3-yl]-benzyl ⁇ -amino)-acetic acid (API3); and a WCA (b) selected from the group consisting of B3B, B4B, B5B, B
  • Even more preferred compositions are: [API2H + ][BHAcB], [API2H + ][BMB], [API2H + ][BSalB], [API2H + ][B3B], [API2H + ][B4B],
  • composition of the present invention comprising an organic compound (a) and a WCA (b) can be readily prepared as follows: A suitable salt of the organic compound (a) in its protonated form with an anion not being a WCA is reacted with a salt of a WCA (b) with a suitable counter cation in a suitable solvent thereby forming the desired composition of the present invention which can be obtained in a solid form after usual work-up procedure.
  • the solid form may be an amorphous form or, preferably, a crystalline form of the composition of the present invention.
  • compounds (a) are, for instance, hydrochloride, hydrobromide, mesylate, sulfate salts that can be readily obtained by reacting the free base of organic compound (a) with the respective protonic (Bronsted) acid.
  • Suitable counter cations of WCA (b) are mono-valent cations like silver, sodium or lithium cations.
  • Suitable solvents are usually aprotic solvents sufficiently dissolving the reaction partners, e.g., DMSO.
  • composition of 3-(1- ⁇ 3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl ⁇ -6-oxo-1 ,6- dihydro-pyridazin-3-yl)-benzonitrile as organic compound (a) (API) with B3B as WCA (b) can be prepared by reacting the HCI salt of the API with the sodium salt of B3B in DMSO.
  • the API WCA compositions of the present invention may be obtained as solvates. It is another aspect of the present invention to use the composition of an API being the organic compound (a) and a WCA (b) as a medicament. This medicament may be used for the prevention, treatment and/or alleviation of any medical condition or disease that can be targeted by the organic compound (a) as an API being comprised in the medicament.
  • the specific condition(s) or disease(s) that can be targeted depends on the very nature of the API.
  • compositions of the present invention exhibit increased solubility, dissolution rate and/or bioavailability when compared to the respective classical API salt or the API free base, these compositions are useful for medical applications requiring sufficient solubility of the API.
  • applications are preferably, though not limited to, oral applications; however, they may also comprise, e.g., those parenteral or topical applications where sufficient solubility of the API is needed.
  • composition or the medicament of the present invention is comprised by a pharmaceutical composition that further comprises at least one pharmaceutical acceptable carrier.
  • that pharmaceutical composition is selected to be suitable for oral administration.
  • That acceptable carrier may be one or more organic or inorganic substances which are suitable for oral administration (or, in case of topical or parenteral applications, which are suitable for topical or parenteral administration) and do not react with the composition of the present invention, for example vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • tablets, coated tablets, capsules, syrups, suspensions or drops are used for oral administration.
  • composition refers to a composition or product comprising a composition according to the present invention, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing at a composition of the present invention and a pharmaceutically acceptable carrier. It may further comprise physiologically acceptable excipients, auxiliaries, adjuvants, diluents and/or additional pharmaceutically active substance other than the composition of the invention.
  • Still another aspect of the present invention is a compound of formula "WCA * Kat", wherein in that formula
  • WCA* denotes a Weakly Coordinating Anion which is selected from the group
  • Kat' denotes a cation that forms a stable compound with WCA * , or solvates thereof.
  • Kat is a mono-valent metal cation.
  • Kat is an alkali metal cation bearing a +1 charge, e.g., lithium (Li + ), sodium (Na + ) or potassium (K + ) cation, but it may also be a different metal cation bearing a +1 charge like silver (Ag + ) or even a proton (H + ).
  • "Kat” is selected from silver (Ag + ), lithium (Li + ) and sodium (Na + ) cation.
  • Preferred embodiments of WCA * Kat compounds of the present invention are: B3B Na, B3B Li, B3B Ag, B4B Na, B4B Li, B4B Ag, B5B Na, B5B Li, B5B Ag, B6B Na, B6B Li, B6B Ag, BTB-OH Na, BTB-OH Li, BTB-OH Ag, BOMB Na, BOMB Li, BOMB Ag, or solvates thereof.
  • WCA* Kat compounds of the present invention or solvates thereof are particularly useful in the preparation of the compositions of the present invention comprising an organic compound (a) and a WCA (b).
  • WCA* Kat compounds and solvates thereof may be prepared as already described hereinabove or by adaption of the methods described in the references cited above with regard to WCAs known in the art.
  • solvates means addition forms of the compounds or compositions of the present invention with solvents, preferably pharmaceutically
  • solvents that contain either stoichiometric or non-stoichiometric amounts of solvent.
  • Some compounds or compositions have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.
  • the solvent is water, the solvate formed is a hydrate, e.g. a semi-, mono-, hemi- or dihydrate.
  • the solvent is alcohol, the solvate formed is an alcoholate, e.g., a methanolate or ethanolate.
  • the solvent is an ether, the solvate formed is an etherate, e.g., diethyl etherate.
  • Other solvent molecules that may form solvates with the compounds or compositions of the present invention include, but are not limited to, DMSO and acetonitrile.
  • compositions of API (a) with WCA (b) have been prepared
  • the following abbreviations are used:
  • API2H + 3-(1- ⁇ 3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]- benzyl ⁇ -6-oxo-1 ,6-dihydro-pyridazin-3-yl)-benzonitrile in its protonated form (methyl- ⁇ 3-[5-(2'-methyl-2-trifluoromethyl-biphenyl-4-yl)- [1 ,2,4]oxadiazol-3-yl]-benzyl ⁇ -amino)-acetic acid in its protonated form
  • the API as its hydrochloride salt and the WCA as its lithium, sodium or silver salt are dissolved in a suitable solvent (e.g., DMSO or acetonitrile) and stirred. After removing the solvent (either by distillation in vacuo or filtering off the remaining residue containing the API WCA composition of the present invention is washed with a suitable solvent (e.g., water, acetone, diethyl ether, n-hexane) in order to remove the sodium, lithium or silver chloride, as the case may be. The product is dried. Elementary analysis and NMR spectra are used to prove identity of the respective composition (Table 1). Table 1
  • compositions 8, 9, 10, 11 , 12 and the chloride salt of ⁇ 2 ⁇ - are performed in Simulated Intestinal Fluid sine pancreatin (SIFsp) at pH 6,8.
  • SIsp Simulated Intestinal Fluid sine pancreatin
  • SIFsp is prepared as described in United States Pharmacopeia 37-NF32 (2014) and European Pharmacopeia 8.4 (2014), but without addition of pancreatin. 6.8 g of monobasic potassium phosphate are dissolved in

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions comprenant un composé organique (a) et un anion faiblement coordinateur (WCA) (b), l'utilisation de ces compositions en tant que médicament ainsi que pour le traitement de maladies spécifiques et des composés de WCAs avec des contre-cations adaptés. Les compositions de la présente invention présentent une solubilité et/ou biodisponibilité par rapport aux composés organiques (a) tels quels ou des sels des composés organiques (a) avec des contre-anions usuels, c'est-à-dire, non-WCA.
PCT/EP2016/000745 2015-05-29 2016-05-06 Compositions d'anions et de cations ayant une activité pharmacologique Ceased WO2016192831A1 (fr)

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EP15001618 2015-05-29

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Citations (6)

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Publication number Priority date Publication date Assignee Title
WO2002068433A1 (fr) 2001-02-22 2002-09-06 Chemetall Gmbh Procede de production de bis(chelato)borates d'hydrogene et de bis(chelato)borates de metaux alcalins
US20080033195A1 (en) 2003-12-04 2008-02-07 Ingo Krossing Method For The Production Of Salts Of Weakly Coordinating Anions, Salts Thereof And Use Thereof
WO2008058490A1 (fr) 2006-11-15 2008-05-22 Univerzita Pardubice Composés complexes d'acide borique, d'acide salicylique ou de ses dérivés et d'argent, leur procédé de préparation et une préparation contenant ces composés pour éradiquer les moisissures, les mycètes et les insectes ligniperdus
WO2009007074A1 (fr) 2007-07-12 2009-01-15 Merck Patent Gmbh Dérivés de pyrimidinylpyridazinone
WO2010078897A1 (fr) 2009-01-08 2010-07-15 Merck Patent Gmbh Nouvelles formes polymorphes de sel chlorhydrate de 3-(1-{3-[5-(1-méthyl-pipéridin-4ylméthoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile et leurs procédés de fabrication
WO2011032681A1 (fr) 2009-09-17 2011-03-24 Universität Heidelberg Métallates lipophiles

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002068433A1 (fr) 2001-02-22 2002-09-06 Chemetall Gmbh Procede de production de bis(chelato)borates d'hydrogene et de bis(chelato)borates de metaux alcalins
US20080033195A1 (en) 2003-12-04 2008-02-07 Ingo Krossing Method For The Production Of Salts Of Weakly Coordinating Anions, Salts Thereof And Use Thereof
WO2008058490A1 (fr) 2006-11-15 2008-05-22 Univerzita Pardubice Composés complexes d'acide borique, d'acide salicylique ou de ses dérivés et d'argent, leur procédé de préparation et une préparation contenant ces composés pour éradiquer les moisissures, les mycètes et les insectes ligniperdus
WO2009007074A1 (fr) 2007-07-12 2009-01-15 Merck Patent Gmbh Dérivés de pyrimidinylpyridazinone
WO2010078897A1 (fr) 2009-01-08 2010-07-15 Merck Patent Gmbh Nouvelles formes polymorphes de sel chlorhydrate de 3-(1-{3-[5-(1-méthyl-pipéridin-4ylméthoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile et leurs procédés de fabrication
WO2011032681A1 (fr) 2009-09-17 2011-03-24 Universität Heidelberg Métallates lipophiles

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C.A. REED, ACC. CHEM. REV., vol. 31, 1998, pages 133 - 139
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SVARCE, E. ET AL: "Thermal analysis of boron complexes containing ligands of the type [lethroil or metriol] R-C(CH2OH)3", JOURNAL OF THERMAL ANALYSIS , 6(5), 577-84 CODEN: JTHEA9; ISSN: 0368-4466, 1974, XP008181023 *
TAYLOR, MICHAEL J. ET AL: "The structure of the cage-like complex anion formed by sodium borate and 1,1,1-tris(hydroxymethyl)ethane", POLYHEDRON , 11(8), 889-92 CODEN: PLYHDE; ISSN: 0277-5387, 1992, XP008181024, DOI: 10.1016/S0277-5387(00)83337-9 *
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