Field of the invention 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.

Background of the invention

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

Ingredient, API) that are systemically active. However, even for 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

gastrointestinal fluids, only a small fraction of it, if at all, can be taken up by the organism and develop its desired pharmacological effect. Several approaches to overcome the problem of low API solubility and bioavailability have been suggested and tested, like, for instance, providing the API in the form of a better soluble crystal form or prodrug or in a pharmaceutical formulation containing solubility enhancers or in an amorphous state.

However, the success of these approaches is case specific and highly depends on various factors the interaction and interdependency of which are hardly predictable. Thus, it is constantly observed that even otherwise pharmacologically powerful APIs that are promising candidates for drug development fail to be developed into approved medicaments due to their insufficient solubility and bioavailability. There is therefore a persisting need for a technology that improves solubility and bioavailability of otherwise poorly soluble APIs.

The concept of Weakly Coordinating Anions (WCAs) is nowadays a widely accepted and adapted concept in both fundamental and applied chemistry. A WCA is a complex anion, like, e.g., tetraphenylborate (B(Ph) ₄ ^" ) or

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. 2004, 43, 2066-2090, and include, e.g., the carboranes [CB11 F12] ^" (C.A. Reed, Acc. Chem. Rev. 1998, 31 , 133-139) and [CB11F11CH3]-, borates like [B(CF ₃ )4]-, [B(C ₆ F ₅ )4]- and

[B(3,5-bis-CF3-C6H ₃ )4]- and aluminates like [AI(OC(CF ₃ ) ₃ ) ₄ ]-. US patent application US 2008/0033195 A1 discloses several WCAs of boron (B), aluminium (Al), gallium (Ga), indium (In), phosphorus (P), arsenic (As) and antimony (Sb) and methods for preparing salts (WFA Kat) thereof.

Due to their specific properties 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).

Description of the invention

It is an object of the present invention to provide a technology that improves solubility and/or dissolution rate and bioavailability of otherwise poorly soluble APIs. This object has surprisingly been solved by providing a composition comprising

(a) an organic compound; and

(b) a Weakly Coordinating Anion (WCA);

wherein that organic compound

(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.

Thus, 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.

Preferably, 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. Without wishing to be bound by a particular theory, it may be hypothesized that 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. These weak(er) interactions in the WCA comprising compositions may then allow for highly increased dissolution rates of the composition of the present invention in comparison to classical API salts and for the formation of supersaturated solutions of the API. Supersaturation implies that when dissolving the solid composition of the present invention much higher concentrations of the API in solution can be reached and maintained than by dissolving classical API salts which only provides API concentrations in the range of the API salt's solubility but does not provide supersaturated solutions. These effects overall cause increased solubility and bioavailability of the API when being present in the composition of the present invention.

In general, each weakly coordinating anion that forms a stabile composition with organic compound (a) may be suitable as the WCA (b) of the

composition of the present invention. 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.

In one embodiment 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). In still another embodiment the composition of the present invention comprises a WCA (b) that is selected from a boron (B) or phosphorous (P) containing WCA. Preferably, 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.

BMB B3B B4B

B5B B6B

BHAcB BSalB

BOMB BOxB

CSB

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. Some of these borates have been described in literature:

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.

The syntheses of the borates BCB and CSB in form of their lithium salts have been described by Z.-M. Xue et al., J. Power Sources 171 (2007) 944-947. The synthesis of the sodium salt of ThyCB is disclosed in J. Dale, J. Chem. Soc. 1961 , 922-930.

However, none of these borates (or any other WCA known in the art) has been disclosed as being comprised in a composition together with a pharmacologically active organic compound (a) and/or for the use of improving the solubility and/or bioavailability of APIs.

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) are available as well by applying methods described in WO

2002/068433 A1. 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

BOMB is readily accessible according Scheme 2:

Scheme 2

M = Li, Na

BTB (with X being OH) can be obtained as depicted in Scheme 3 (M.J. Taylor et al., Polyhedron 1992, 11 (8), 889-892), while BTB with X different than OH can easily be obtained therefrom by known methods: Scheme 3

ThyCB (with X being OH) is obtainable by the method described in J. Dale, J. Chem. Soc. 1961, 922-930.

It is to be noted that depending on the specific reaction conditions chosen, including the solvent(s) applied, the WCA salts may be obtained as solvates.

In a further embodiment of the present invention the WCA (b) is selected from B3B, B4B, B5B, B6B, BMB, BHAcB and BSalB. In general, 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. Preferably, 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). Although 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. Even in these cases the 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.

It is, however, one particular embodiment of the present invention to provide compositions of a WCA (b) as described herein with an organic compound (a) 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, when that organic compound (a) is - in its unprotonated or protonated form - a poorly soluble API in any of the gastrointestinal fluids and/or exhibits a rather low dissolution rate and/or a rather poor bioavailability. 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. (According to the FDA's BCS 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. According to the BCS 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).

Another embodiment of the present invention comprises compositions of a WCA (b) as described herein with an organic compound (a) 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 wherein that organic compound (a) in that composition with a WCA (b) (i) shows a solubility under physiological conditions after 60 min which is at least 1.2 times greater than (> 1.2x), preferably at least 1.5 times greater than (≥ 1.5x), more preferably at least 2.0 times greater than (≥ 2.0x), the solubility of that organic compound (a), if present in unprotonated form or in protonated form in a salt together with an anion other than a WCA (b); and/or (ii) has a bioavailability from an immediate release oral dosage form which is improved by 10 % or more compared to the same dosage form containing that organic compound (a) in unprotonated form or in protonated form in a salt together with an anion other than a WCA (b).

Typical examples of 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;

fluoxetin; itraconazole; piroxicam; celecoxib; avitriptan; ziprasidone;

norfloxacin; haloperidol; indapamide; diazepam; tamoxifen; triamterene; nitrendipine; nifedipine; phenytoin; dipyridamole; ketoconazol; fexofenadine; gefitinib; rosuvastatin;; efavirenz; danazol; amiodarone; pimozide;

indomethacin; glibenclamide; hydrochlorothiazide; iopanoic acid;

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;

dexchlorpheniramine; dirithromycin; efavirenz; eprosartan; etodolac;

etoposide; famotidine; fentanyl; finasteride; fluconazole; fluvastatin;

fosphenytoin; frovatriptan; gabapentin; glyburide; glimepiride; halofantrine, irinotecan; ivermectin; lamotrigine; flutamide; glipizide; glyburide; isradipine; loratadine; mephalan; loperamide; mefloquine; methadone; midazolam;

miglitol; mitoxantrone; nabumetone; nalbuphine; naratriptan; nefinavir;

nilutamide; nizatidine; paclitaxel; docetaxel; pentazocine; naloxone;

pioglitazone; pizotifin; pyridostigmine; raloxifene; repaglinidine; rifapentine; rimexolone; rizatriptan; rosiglitazone; saquinavir; sibutramine; sildenafil;

sumatriptan; tacrine; tacrolimus; pimecrolimus; tamsulosin; tazarotene;

teniposide; terbinafine; tiagabine; tizanidine; topotecan; toremifene, troglitazone; moxifloxacin; verteporfin; vigatriptan; zafirlukast; zileuton;

zolmitriptan; Zolpidem; zopiclone; pralnacasan,; amiloride; amisulpride;

amoxicillin; atenolol; benserazide; camostat; losartan; methotrexate;

metoclopramide; nizatidine; nystatin; ondansetron; oseltamivir; primaquine; procaterol; propylthiouracil; ranitidine; ribaverin; stavudine; sulfadiazine;

taltirelin; tegafur; voglibose; zidovudine.

In one particular embodiment 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)

ureido]phenoxy}pyridin- 2-carbonsauremethylamid); (methyl-{3-[5-(2'-methyl- 2-trifluoromethyl-biphenyl-4-yl)-[1 ,2,4]oxadiazol-3-yl]-benzyl}-amino)-acetic acid; 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]- benzyl}-6- oxo-1 ,6-dihydro-pyridazin-3-yl)-benzonitrile. 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,

inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegeneration, psoriasis, restenosis, wound healing, transplant, metabolic and immune system disorders, including autoimmune diseases, cirrhosis, diabetes, and diseases of the blood vessels, including instability and permeability (permeability) and the like in mammals. Any of these compounds (a) can be combined with any suitable WCA (b) to form a composition of the present invention. Preferably, 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, B6B, BMB, BHAcB and BSalB. Particularly preferred compositions are:

[API1 H ⁺ ][BHAcB], [API1 H ⁺ ][BMB], [API1 H ⁺ ][BSalB], [API1 H ⁺ ][B3B],

[API1H ⁺ ][B4B], [API1 H ⁺ ][B5B], [API1 H ⁺ ][B6B], [API2H ⁺ ][BHAcB],

[API2H ⁺ ][BMB], [API2H ⁺ ][BSalB], [API2H ⁺ ][B3B], [API2H ⁺ ][B4B],

[API2H ⁺ ][B5B], [API2H ⁺ ][B6B], [API3H ⁺ ][BHAcB], [API3H ⁺ ][BMB],

[API3H ⁺ ][BSalB], [API3H ⁺ ][B3B], [API3H ⁺ ][B4B], [API3H ⁺ ][B5B],

[API3H ⁺ ][B6B]. Even more preferred compositions are: [API2H ⁺ ][BHAcB], [API2H ⁺ ][BMB], [API2H ⁺ ][BSalB], [API2H ⁺ ][B3B], [API2H ⁺ ][B4B],

[API2H ⁺ ][B5B], [API2H ⁺ ][B6B].

The 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. Suitable salts of the organic

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. As an example, the composition of 3-(1- {3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzy l}-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.

It is to be noted that depending on the specific reaction conditions applied, including the solvent(s) used, 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. In case of the APIs sorafenib (4-{4-[3-(4-Chlor-3- trifluormethylphenyl) ureido]phenoxy}pyridin- 2-carbonsauremethylamid); (2) (methyl-{3-[5-(2'-methyl-2-trifluoromethyl-biphenyl-4-yl)-[1 ,2,4]oxadiazol-3-yl]- benzyl}-amino)-acetic acid; (3) 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)- pyrimidin-2-yl]-benzyl}-6-oxo-1 ,6-dihydro-pyridazin-3-yl)-benzonitrile these diseases are various cancer and tumor diseases, for instance, angiogenesis, cancer, tumor formation, - growth and proliferation, atherosclerosis, eye diseases such as age-related macular degeneration, multiple sclerosis (MS), choroidal neovascularization, diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegeneration, psoriasis, restenosis, wound healing, transplant, metabolic and immune system disorders, including autoimmune diseases, cirrhosis, diabetes, and diseases of the blood vessels, including instability and permeability

(permeability) and the like in mammals.

As the 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. These

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.

In still another aspect of the present invention the composition or the medicament of the present invention is comprised by a pharmaceutical composition that further comprises at least one pharmaceutical acceptable carrier. In particular, 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. In particular, tablets, coated tablets, capsules, syrups, suspensions or drops are used for oral administration. For the purpose of the present invention the term "pharmaceutical

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. Accordingly, 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. The art of

manufacturing of pharmaceutical compositions comprising a composition of the present invention is well-known to the skilled person.

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

B3B B4B

BTB with X being OH; ^BUM ; and

Kat' denotes a cation that forms a stable compound with WCA ^* , or solvates thereof. Preferably, Kat is a mono-valent metal cation. Typically, 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 ⁺ ). Preferably, "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.

The "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). These "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.

The term "solvates" means addition forms of the compounds or compositions of the present invention with solvents, preferably pharmaceutically

acceptable 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. If the solvent is water, the solvate formed is a hydrate, e.g. a semi-, mono-, hemi- or dihydrate. If the solvent is alcohol, the solvate formed is an alcoholate, e.g., a methanolate or ethanolate. If 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. Experimental Part

The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Unless otherwise specified, all starting materials are obtained from

commercial suppliers and used without further purification. Unless otherwise specified, all temperatures are expressed in °C and all reactions are conducted at room temperature (RT). Compounds are purified by

recrystallization or other usual means.

A. Preparation of WCA

BHAcB:

1 ,4,6,9-tetraoxa-5-boranuidaspiro[4.4]nonane-3,8-dione as sodium salt 2 mol 2-hydroxyacetic acid, 1 mol boric acid and 1 mol sodium hydroxide are suspended in about 500 ml toluene. 15 ml water are added and the resulting mixture is heated to reflux. Water is removed by azeotropic distillation and the toluene solvent is distilled off in vacuo. The resulting white solid (sodium salt of 1 ,4,6,9-tetraoxa-5-boranuidaspiro[4.4]nonane-3,8-dione) is dried. Yield: 95%. NMR in d6-DMSO: δ ( ¹ B) = 11.28 ppm.

1 ,5,7,11-tetraoxa-6-boranuidaspiro[5.5]undecane-2,4, 8, 10-tetrone as lithium salt

2 mol malonic acid, 1 mol boric acid and 0.5 mol lithium carbonate are suspended in about 500 ml toluene. 15 ml water are added and the resulting mixture is heated to reflux. Water is removed by azeotropic distillation and the toluene solvent is distilled off in vacuo. The resulting white solid (lithium salt of 1 ,5,7,11-tetraoxa-6-boranuidaspiro[5.5]undecane-2,4,8,1O-tetr one) is dried. Yield: 91%. NMR in d6-DMSO: δ ( ¹ B) = 3.35 ppm.

BSalB:

4,4'-spirobi[3,5-dioxa-4-boranuidabicyclo[4.4.0]deca-1(6),7, 9-triene]-2,2'- dione as sodium salt

2 mol salicylic acid, 1 mol boric acid and 1 mol sodium hydroxide are suspended in about 500 ml toluene. 15 ml water are added and the resulting mixture is heated to reflux. Water is removed by azeotropic distillation and the toluene solvent is distilled off in vacuo. The resulting white solid (sodium salt of 4,4 ^, -spirobi[3,5-dioxa-4-boranuidabicyclo[4.4.0]deca-1 (6),7,9-triene]- 2,2'-dione) is dried. Yield: 97%. NMR in d6-DMSO: δ ( ¹¹ B) = 3.61 ppm.

5.7.13.14- tetraoxa-6-boranuidatrispiro[2.2.2.2{9}.2{6}.2{3}]pentadecan e-

4.8.12.15- tetrone as sodium salt

1 mol cyclopropane-1 ,1-dicarboxylic acid, 1 mol boric acid and 1 mol sodium hydroxide are suspended in about 500 ml toluene. 15 ml water are added and the resulting mixture is heated to reflux. Water is removed by azeotropic distillation and the toluene solvent is distilled off in vacuo. The sodium salt of

5.7.13.14- tetraoxa-6-boranuidatrispiro[2.2.2.2{9}.2{6}.2{3}]pentadecan e-

4.8.12.15- tetrone as sodium salt is obtained with a slight impurity (structure unknown). NMR in d6-DMSO: δ ( ¹¹ B) = 2.67 ppm. Elementary analysis: cal. (CioHsBNaOs) C 41.42%, H 2.78%; found C 40.27%, H 3.02%.

6.8.15.16- ΙθίΓ3θΧ3-7- θΓ3ηυϊά3ΐπ8ρΪΓθ[3.2.2.3{10}.2{7}.2{4}]Μθρί3� ��ΐθθ3ηθ-

5.9.14.17- tetrone as lithium salt

1 mol cyclobutane-1 ,1-dicarboxylic acid, 1 mol boric acid and 0.5 mol lithium carbonate are suspended in about 500 ml toluene. 15 ml water are added and the resulting mixture is heated to reflux. Water is removed by azeotropic distillation and the toluene solvent is distilled off in vacuo. The resulting solid (lithium salt of 6,8,15,16-tetraoxa-7-boranuidatrispiro[3.2.2.3{10}.2{7}.2{4} ]- heptadecane-5,9,14,17-tetrone) is dried. Yield: 99%. NMR in d6-DMSO: δ ( ¹¹ B) = 2.05 ppm. Elementary analysis: cal. (C12H12BUO6) C 47.73%, H 4.01 %; found C 47.24%, H 4.04%.

The respective sodium salt is obtained in a similar manner by using 1 mol sodium hydroxide instead of 0.5 mol lithium carbonate. Yield: 95%. NMR in d6-DMSO: δ ( ¹¹ B) = 2.06 ppm.

7,9, 17,18-tetraoxa-8-boranuidatrispiro[4.2.2.4{11 }.2{8}.2{5}]nonadecane- 6,10,16,19-tetrone as sodium salt

1 mol cyclopentane-1 ,1-dicarboxylic acid, 1 mol boric acid and 1 mol sodium hydroxide are suspended in about 500 ml toluene. 15 ml water are added and the resulting mixture is heated to reflux. Water is removed by azeotropic distillation and the toluene solvent is distilled off in vacuo. The resulting solid product mixture is extracted with acetonitrile which yields after evaporating the solvent and drying in vacuo the hygroscopic sodium salt of 7,9,17,18- tetraoxa-8-boranuidatrispiro[4.2.2.4{11 }.2{8}.2{5}]nonadecane-6, 10,16,19- tetrone. NMR in d6-DMSO: δ ( ¹¹ B) = 1.95 ppm; ( ¹ H) = 2.08 (m, 4H), 1.68 ppm (m, 4H); ( ³ C) = 172.44, 55.58, 36.41 , 26.12 ppm. Elementary analysis: cal. (CuHieBNaOs) C 48.59%, H 4.66%; found C 47.11%, H 4.98%.

8,10,19,20-tetraoxa-9-boranuidatrispiro[5.2.2.5{12}.2{9}. 2{6}]henicosane- 7,11,18,21-tetrone as silver salt

1 mol cyclohexane-1 ,1-dicarboxylic acid is reacted with 2 mol silver nitrate and 2 mol triethylamine in ethanol/acetonitrile mixture at 0°C; the reaction mixture is allowed to warm to room temperature. Work-up yields the disilver salt of cyclohexane-1 ,1-dicarboxylic acid in about 97%. This salt (2 mol) is then reacted with 1 mol boron trichloride in acetonitrile to yield the silver salt of 8,10,19,20-tetraoxa-9-boranuidatrispiro[5.2.2.5{12}.2{9}.2{6 }]henicosane- 7,11 ,18,21-tetrone. NMR in d6-DMSO: δ ( ¹¹ B) = 1.67 ppm. Elementary analysis: cal. (CiehboAgBOe ^■ CHaCN) C 43.23%, H 4.64%, N 2.80%; found C 42.62%, H 4.53%, N 2.70%.

B. Preparation of API-WCA compositions

The following compositions of API (a) with WCA (b) have been prepared The following abbreviations are used:

AP1 H ⁺ : sorafenib (4-{4-[3-(4-Chlor-3- trifluormethylphenyl)

ureido]phenoxy}pyridin- 2-carbonsauremethylamid) in its protonated form;

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

BHAcB:

1 ,4,6,9-tetraoxa-5-boranuidaspiro[4.4]nonane-3,8-dione anion

1 ,5,7,11 -tetraoxa-6-boranuidas iro[5.5]undecane-2,4,8, 10-tetrone anion

BSalB:

4,4'-spirobi[3 ₎ 5-dioxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene] -2,2 ^, - dione anion

5.7.13.14- tetraoxa-6-boranuidatrispiro[2.2.2.2{9}.2{6}.2{3}]pentadecan e-

4.8.12.15- tetrone anion

6.8.15.16- tetraoxa-7-boranuidatrispiro[3.2.2.3{10}.2{7}.2{4}]heptadeca ne-

5.9.14.17- tetrone anion

7,9,17,18-tetraoxa-8-bdfanuidatrispiro[4.2.2.4{11}.2{8}.2 {5}]nonadecane- 6,10,16,19

8.10.19.20- tetraoxa-9-boranuidatrispiro[5.2.2.5{12}.2{9}.2{6}]henicosan e-

7.11.18.21 - tetrone anion

General procedure for preparing API WCA compositions of the present invention

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

No. Composition Elementary Calculated Found

(or solvate Analysis

thereof)

1 [API1 H ⁺ ][BHAcB] C25H20BCIF3N4O9* C 44.60%, H C 44.25%, H

2 DMSO 4.26%, N 7.17% 4.15%, N 7.21%

2 [API1H ⁺ ][BMB] C27H21BCIF3N4O11 C 47.64%, H

3.11%, N 8.23%

3 [API1H ⁺ ][BSalB] C35H25BCIF3N4O9 C 56.14%, H

3.37%, N 7.48% [API1 H ⁺ ][B3B] C31H25BCIF3N4O11* C 45.95% H 4.48%, C 46.41 %, H 3 DMSO N 5.79% 4.00%, N 5.95%

[API1H ⁺ ][B4B] C33H29BCIF3N4O11* C 49.24%, H C 49.36%, H

1.5 DMSO 4.66%, N 6.38% 4.30%, N 6.27%

[API1 H ⁺ ][B5B] C35H33BCIF3N4O11 C 55.79%, H C 51.25%, H

4.41%, N 7.44% 4.12%, N 7.04%

[API1H ⁺ ][B6B] C37H37BCIF3N4O11* C 52.33%, H4.84%, C 51.02%, H

DMSO N 6.26% 4.84%, N 6.19%

[API2H ⁺ ][BHAcB] C33H33BN6O6 C 60.75%, H

5.10%, N 12.88%

[API2H ⁺ ][BMB] C35H33BN6O10 C 59.34%, H C 59.07%, H

4.70%, N 11.86% 4.55%, N 1.85%

[API2H ⁺ ][BSalB] C43H ₃ 7B ₆ 0 ₈ *H20 C 65.00%, H C 64.24%, H

4.95%, N 10.58% 4.68%, N 10.47%

[API2H ⁺ ][B3B] C39H37BN6O10 ^* H ₂ 0 C 60.16%, H C 60.17%, H

5.05%, N 10.79% 4.99%, N 10.88%

[API2H ⁺ ][B4B] C4i H4iBN ₆ Oio *H ₂ 0 C 61.05%, H C 60.92%, H

5.37%, N 10.42% 5.40%, N 10.45%

[API2H ⁺ ][B5B] C43H45BN6O10 ^* H ₂ 0 C 61.88%, H C 62.17%, H

5.68%, N 10.07% 5.73%, N 9.74%

[API2H ⁺ ][B6B] C45H49BN6O10* C 61.17%, H C 60.73%, H

DMSO 6.01%, N 9.11% 6.14%, N 8.92%

[API3H ⁺ ][BHAcB] C30H27BF3N3O9* C 52.25%, H C 51.94%, H

1.5 DMSO 4.78%, N 5.54% 4.68%, N 5.60%

[API3H ⁺ ][BMB] C33H27BF3N3O11* C 52.66%, H C 52.12%, H

DMSO 4.29%, N 5.42% 4.49%, N 5.30%

[API3H ⁺ ][BSalB] C40H31BF3N3O9* C 59.80%, H C 59.66%, H

DMSO 4.42%, N 4.98% 4.60%, N 4.85%

[API3H ⁺ ][B3B] C36H31BF3N3O11* C 53.04%, H C 53.05%, H

2 DMSO 4.79%, N 4.64% 4.85%, N 4.66%

[API3H ⁺ ][B4B] C38H35BF3N3O11* C 54.02%, H C 53.75%, H

2 DMSO 5.07%, N 4.50% 4.88%, N 4.59%

[API3H ⁺ ][B6B] C42H43BF3N3O11 H3 C 60.42%, H C 59.65%, H

CN 5.30%, N 5.74% 5.21%, N 5.64% C. Dissolution experiments

Dissolution experiments of compositions 8, 9, 10, 11 , 12 and the chloride salt of ΑΡΙ2Ι- are performed in Simulated Intestinal Fluid sine pancreatin (SIFsp) at pH 6,8.

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

250 ml_ of water and then 77 ml_ of 0.2 N sodium hydroxide and 500 ml_ of water are added and the resulting solution is adjusted with 0.2 N sodium hydroxide or 0.2 N hydrochloric acid to a pH of 6.8 ± 0.1 and finally diluted to 1000 ml_.

To assess dissolution 1-10 mg of the respective compound are introduced into a glass vial. SIFsp is added and the suspension is stirred for 120 minutes at 37 °C. After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 minutes and 120 minutes samples are drawn from the suspension, filtered and analyzed by HPLC with regard concentration of the API. Dissolution experiments are carried out in duplicate for each compound. The results of the dissolution experiments are summarized in Table 2 showing API concentration (pg/ml) over time (min).

Table 2

It can be seen therefrom that the dissolution of classical API salt [API2H ⁺ ]CI goes through a supersaturated state with a concentration of up to about 85 pg/ml and then quickly reaches a plateau level of only about 50-60 pg/ml which keeps constant even after 10 min. In contrast thereto [API2H ⁺ ]WCA compositions in accordance with the present invention reach dissolution values of up to about 140 g/ml after 60 min and up to about 160 pg/ml after 120 min.