Solubilizing compounds

Abstract

The present invention relates to a tertiary amide compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R7 comprises a group X which is-S (= O) 2OH,-S (= O) OH and-P (= O) (OH) 2. The compounds are capable of solubilizing drugs that are otherwise insoluble. By enhancing the solubility of poorly soluble or insoluble drugs, such as hydrophobic drugs, the compounds of the present invention make it possible to manufacture formulations of such drugs. The invention also relates to pharmaceutical compositions comprising a compound of formula (I), pharmaceutical micelles comprising a compound of formula (I) and a medicament, and the use of such pharmaceutical compositions or pharmaceutical micelles in the treatment of cancer. # imgabs0 # (II)

Description

Technical Field

[0001] The present invention relates to a tertiary amide compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound is capable of dissolving otherwise insoluble drugs. By enhancing the solubility of poorly soluble or insoluble drugs (e.g., hydrophobic drugs), the compound of the present invention makes it possible to manufacture the preparation of such drugs. The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), a drug micelle comprising a compound of formula (I) and a drug, and the use of such a pharmaceutical composition or drug micelle in cancer treatment. Background Art

[0002] Many important drugs have poor aqueous solubility. Typical examples include the taxane class of cytostatic compounds (paclitaxel, docetaxel and cabazitaxel), where lack of solubility complicates intravenous administration.

[0003] A variety of solutions to the solubility problem are disclosed in the literature, but none is without disadvantages. A good solubilizer should be non-toxic, stable, cost-effective and easy to handle. A solubilizer may also affect the pharmacokinetics and pharmacodynamics of the active ingredient in a desired or undesirable manner, depending on the current clinical situation. Ideally, a solubilizer enhances the effectiveness of the active ingredient while minimizing side effects.

[0004] WO 00 / 47589, WO 02 / 092600 and WO 2004 / 009538 disclose retinol derivatives capable of forming micelles and enhancing the efficacy of cytotoxic agents. Recently, WO 2021 / 008516 discloses acitretin derivatives capable of encapsulating insoluble drugs, wherein the formed micelles have high drug loading and good stability.

[0005] Although progress has been made in this field before, the need for more compounds that can solubilize poorly soluble drugs and provide stable formulations of such drugs continues. Therefore, it is an object of the present invention to provide additional solubilizing compounds that have optimized properties in terms of desired properties (e.g., micelle formation properties and stability of micellar formulations). Summary of the invention

[0006] The inventors have developed retinoyl derivatives that can be used in pharmaceutical formulations of drugs, such as those with poor water solubility. Examples 1-10 demonstrate the synthesis and characterization of 10 different compounds in the general formula described in more detail below. The examples also characterize pharmaceutical formulations with new compounds and drugs. The inventors demonstrated stable micellar formulations of compounds and drugs using docetaxel, cabazitaxel, and cyclosporin as model compounds.

[0007] The present invention is described in detail below. Certain main aspects of the present invention are defined in the attached independent claims. Certain preferred embodiments are described in the dependent claims. DETAILED DESCRIPTION OF THE INVENTION

[0009] In a first aspect, the present invention relates to compounds of formula (I),

[0010] (I)

[0011] in

[0012] A is or ;

[0013] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-4 Alkoxycarbonyl;

[0014] key is cis or trans;

[0015] R 6 Selected from halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 3-8 Cycloalkylcarbonyl, aminocarbonyl-C 1-4 Alkyl, -C(=NH)NH2 and phenyl, wherein the phenyl group is optionally substituted by one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups;

[0016] R 7 For-(CR 8A R 8B ) n -X, benzyl-X or C 3-7 -cycloalkyl-(CR 8A R 8B ) m -X, wherein n is an integer of 2 or 3, m is an integer of 1 or 2, and wherein the benzyl group is optionally further replaced by one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups;

[0017] or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered saturated heterocyclic ring, which is -(CR 8A R 8B ) p -X, phenyl-X or benzoyl-X, wherein p is an integer of 1 or 2, and wherein the phenyl or benzoyl group is optionally further substituted with one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups;

[0018] R 8A and R 8B Each independently selected from hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, -S(=O)2OH, -S(=O)OH and -P(=O)(OH)2; and

[0019] X is -S(=O)2OH, -S(=O)OH or -P(=O)(OH)2;

[0020] or a pharmaceutically acceptable salt thereof.

[0021] In a more preferred embodiment, the present invention relates to compounds of formula (I)

[0022] (II)

[0023] in

[0024] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-4 Alkoxycarbonyl;

[0025] R 6 Selected from halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 3-8 Cycloalkylcarbonyl, aminocarbonyl-C 1-4 Alkyl, -C(=NH)NH2 and phenyl, wherein the phenyl group is optionally substituted by one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C1-4 Substitution of alkoxy and amino groups;

[0026] R 7 For-(CR 8A R 8B ) n -X, benzyl-X or C 3-7- Cycloalkyl-(CR 8A R 8B ) m -X, wherein n is an integer of 2 or 3, and m is an integer of 1 or 2, wherein the benzyl group is optionally further replaced by one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups;

[0027] or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered saturated heterocyclic ring, which is -(CR 8A R 8B ) p -X, phenyl-X or benzoyl-X, wherein p is an integer of 1 or 2, and wherein the phenyl or benzoyl group is optionally further substituted with one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups;

[0028] R 8A and R 8B Each independently selected from hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, -S(=O)2OH, -S(=O)OH and -P(=O)(OH)2; and

[0029] X is -S(=O)2OH, -S(=O)OH or -P(=O)(OH)2;

[0030] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from hydrogen, hydroxy, methyl and methoxy. 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from hydrogen, methyl and methoxy. 1 , R 2 and R5 Each is a methyl group, R 3 is a methoxy group, and R 4 For hydrogen.

[0032] In some embodiments, R 6 Selected from C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl and aminocarbonyl-C 1-4 In some embodiments, R 6 is methyl, 2-hydroxyethyl, cyclohexyl, prop-2-enoyl, 1,1-bis(hydroxymethyl)-2-hydroxyethyl or aminocarbonylmethyl. 6 is methyl, 2-hydroxyethyl, cyclohexyl or aminocarbonylmethyl. In some embodiments, R 6 In some embodiments, R 6 It is cyclohexyl.

[0033] In some embodiments, R 7 For-(CR 8A R 8B ) n -X, where n is an integer of 2 or 3, and where R 8A and R 8B Each independently selected from hydrogen, hydroxyl, C 1-4 Alkyl and C 1-4 In a more preferred embodiment, R 7 For-(CR 8A R 8B ) n -X, where n is an integer of 2 or 3, and where R 8A and R 8B are each independently selected from hydrogen and hydroxy.

[0034] In some embodiments, R 7 is benzyl-X, wherein the benzyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl and amino. In a more preferred embodiment, R 7 is benzyl-X, wherein the benzyl group is additionally substituted by an amino group.

[0035] In some embodiments, R 7 C 3-7- Cycloalkyl-(CR 8A R 8B ) m -X, where m is an integer of 1 or 2, and where R 8A and R 8Bare each independently selected from hydrogen and hydroxy. In a more preferred embodiment, R 7 is cyclohexyl-methyl-X.

[0036] In some embodiments, R 6 and R 7 Together with the nitrogen atom to which it is attached, it forms a 6-membered saturated heterocyclic ring, which is -(CR 8A R 8B ) p -X, phenyl-X or benzoyl-X, wherein p is an integer of 1 or 2. In a more preferred embodiment, R 6 and R 7 Together with the nitrogen atom to which it is attached, it forms a piperidine ring or a piperazine ring, and the piperidine ring or the piperazine ring is substituted by ethyl-X, phenyl-X or benzoyl-X.

[0037] In some embodiments, X is -S(=0)2OH.

[0038] In a more preferred embodiment, the present invention relates to compounds of formula (II), wherein

[0039] R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, methyl and methoxy;

[0040] R 6 is methyl, 2-hydroxyethyl, cyclohexyl or aminocarbonylmethyl; and

[0041] X is -S(=O)2OH;

[0042] or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the present invention relates to compounds of formula (III),

[0044] (III)

[0045] in

[0046] R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C(=O)OR 10 ; where R 10 C 1-4 alkyl;

[0047] R 6 Selected from halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 3-8 Cycloalkylcarbonyl, -C(=NH)NH2 and phenyl, wherein the phenyl group is optionally substituted with one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups;

[0048] Each R 9 independently selected from hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, -S(=O)2OH, -S(=O)OH and -P(=O)(OH)2, or R 6 and R 9 One of them, together with the atoms to which they are attached, forms a piperidine ring;

[0049] Each R 10 independently selected from hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, -S(=O)2OH, -S(=O)OH, and -P(=O)(OH)2;

[0050] Each R 11 independently selected from hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, -S(=O)2OH, S(=O)OH, and -P(=O)(OH)2;

[0051] n is an integer 0 or 1; and

[0052] X is -S(=O)2OH, -S(=O)OH or -P(=O)(OH)2;

[0053] or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the present invention relates to compounds of formula (III),

[0055] (III)

[0056] in

[0057] R 1 , R 2 , R 3 , R 4 and R 5are each independently selected from hydrogen, methyl and methoxy;

[0058] R 6 is methyl, cyclohexyl, prop-2-enoyl or 1,1-bis(hydroxymethyl)-2-hydroxyethyl;

[0059] Each R 9 are independently selected from hydrogen and methyl;

[0060] R 10 is hydrogen or hydroxy; and

[0061] n is an integer 0 or 1;

[0062] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments of Formula (III), R 1 , R 2 and R 5 Each is a methyl group, R 3 is methoxy and R 4 For hydrogen.

[0064] In a particular embodiment, the invention relates to a compound selected from the group consisting of:

[0065] ;

[0066] ;

[0067] ;

[0068] ;

[0069] ;

[0070] ;

[0071] ;

[0072] ;

[0073] ; and

[0074] ;

[0075] or a pharmaceutically acceptable salt thereof.

[0076] As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo.

[0077] As used herein, the term “C 1-6"Alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and the term "C 1-4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. 1-4 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0078] As used herein, the term “C 2-4 "Alkenyl" refers to a straight or branched alkenyl group having 2 to 4 carbon atoms and at least one double bond. 2-4 Examples of the alkenyl group include ethenyl (vinyl), allyl, and 1,3-butadienyl.

[0079] As used herein, the term “C 1-6 "Haloalkyl" refers to a straight or branched chain C 1-6 An alkyl group in which one or more hydrogen atoms have been replaced by a halogen. 1-6 Examples of the haloalkyl group include chloromethyl, fluoroethyl and trifluoromethyl.

[0080] As used herein, the term “C 1-4 "Hydroxyalkyl" refers to a straight or branched chain C 1-4 An alkyl group in which one or more hydrogen atoms have been replaced by a hydroxyl group (-OH). 1-4 Examples of the hydroxyalkyl group include a hydroxymethyl group, a 2-hydroxyethyl group, and a 1,1-bis(hydroxymethyl)-2-hydroxyethyl group.

[0081] As used herein, the term “C 1-4 "Alkoxy" refers to a straight or branched C-chain group attached to the remainder of the molecule through an oxygen atom. 1-4 Alkyl group.

[0082] As used herein, the term “C 3-8 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3 to 8 carbon atoms. 3-8 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0083] As used herein, the term “C 1-4 "Alkylcarbonyl" means a straight or branched chain C 1-4 The term "C 2-4 Alkenylcarbonyl" and "C 3-8 "Cycloalkylcarbonyl" should be interpreted accordingly. 1-4 Examples of the alkylcarbonyl group include ethylcarbonyl and tert-butylcarbonyl. 2-4 Examples of alkenylcarbonyl groups include prop-2-enoyl (acryloyl).3-8 Examples of the cycloalkylcarbonyl group include cyclopropylcarbonyl and cyclohexylcarbonyl.

[0084] Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, base addition salts of the compounds of the invention, such as alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); ammonium salts; basic amino acids (e.g., arginine, lysine, histidine); betaine; or salts with organic bases providing physiologically acceptable cations, such as salts with methylamine, dimethylamine, trialkylamines (e.g., trimethylamine), piperidine, pyrrolidine, morpholine, choline, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS) or triethanolamine (tris-(2-hydroxyethyl)amine).

[0085] Pharmaceutical composition

[0086] Unless expressly stated otherwise, references herein to compounds of formula (I) are to be understood as also including compounds of formula (II) and (III).

[0087] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition optionally further comprises one or more pharmaceutically acceptable excipients. Excipients may for example include water, aqueous buffer, saline, co-solvents, fillers, binders, disintegrants, glidants and lubricants. In general, pharmaceutical compositions can be prepared in a conventional manner using conventional excipients.

[0088] Examples of suitable co-solvents include, but are not limited to, ethanol, propylene glycol, and polyethylene glycol (eg, PEG 400).

[0089] Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (eg, lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0090] Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., gum arabic, xanthan gum, tragacanth and carrageenan), sodium alginate, cellulose derivatives (e.g., hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose and ethyl cellulose), and synthetic polymers (e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers and polyvinylpyrrolidone (povidone)).

[0091] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starches (e.g. (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (e.g. sodium carboxymethylcellulose, hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose (L-HPC)), and cross-linked polymers (e.g. carboxymethylcellulose, croscarmellose sodium, carboxymethylcellulose calcium and cross-linked PVP (crospovidone)).

[0092] Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, colloidal silicon dioxide, aqueous silicon dioxide, synthetic magnesium silicate, fine particle silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (e.g., carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0093] The pharmaceutical composition can be in a form suitable for oral administration, parenteral administration (including intradermal, intradermal, intravenous, subcutaneous, intramuscular, intraperitoneal and intravascular injection or infusion), topical administration, ophthalmic administration, oral administration (including sublingual administration), nasal administration (e.g., inhalation), or rectal administration. In a preferred embodiment, the pharmaceutical composition is in the form of a liquid preparation suitable for oral or parenteral administration. In another embodiment, the pharmaceutical composition is in the form of a solid preparation suitable for oral administration, such as a tablet or capsule. In yet another embodiment, the pharmaceutical composition is in the form of a preparation suitable for topical administration, such as an ointment or cream.

[0094] In some embodiments, the pharmaceutical composition further comprises at least one active pharmaceutical ingredient (also referred to herein as "drug" or "API"). In some embodiments, the composition contains more than one active pharmaceutical ingredient. The active pharmaceutical ingredient can be a small molecule, a macromolecule, a peptide, a protein (e.g., an enzyme), a nucleic acid, an antigen, an antibody, or a viral vector. As shown in the experimental section, the compounds of the present invention form micelles, which can encapsulate the active pharmaceutical ingredient or contain the active pharmaceutical ingredient in the micellar structure. This enhances the solubility of otherwise poorly soluble or insoluble drugs, and makes it possible to manufacture pharmaceutical preparations containing poorly soluble or insoluble drugs. This preparation of poorly soluble or insoluble drugs also allows the drug to be administered in a liquid formulation. In addition, this preparation can increase the bioavailability of the drug.

[0095] Pharmaceutical compositions comprising an active pharmaceutical ingredient (e.g., a poorly soluble or insoluble drug) and at least one compound of formula (I) may further exhibit enhanced pharmacological activity and / or improved therapeutic efficacy. Such compositions may also enhance the distribution of the drug to target tissues and may additionally result in fewer undesirable side effects. Such compositions may also improve the pharmacokinetic properties of the active pharmaceutical ingredient, including elimination half-life, maximum plasma concentration, clearance, distribution volume, and / or mean residence time.

[0096] In some embodiments, the active pharmaceutical ingredient is a hydrophobic drug. For example, such a drug is characterized by a water solubility of less than 100 μg / mL at 20°C.

[0097] In some embodiments, the active pharmaceutical ingredient is a macrocyclic drug, such as a macrolide, a macrocyclic peptide, or a metal supramolecular compound, such as cyclosporine, rifamycin, rapamycin, vancomycin, dactinomycin, amphotericin B, ivermectin, simeprevir, ixabepilone, rapamycin, or tacrolimus.

[0098] In some embodiments, the active pharmaceutical ingredient is a cytotoxic drug, such as a taxane, e.g., docetaxel, paclitaxel, or cabazitaxel; an anthracycline, e.g., aclarubicin, amrubicin, daunomycin, doxorubicin, epidoxorubicin, idarubicin, pirarubicin, valrubicin, or daurubicin; an anthraquinone, e.g., mitoxantrone, losoxantrone, pixantrone, amsacrine, or bisantrene; or a vinca alkaloid, e.g., vinblastine, vincristine, vindesine, vinflunine, or vinorelbine.

[0099] Also provided herein is a drug micelle comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a drug. In some embodiments, the drug is a hydrophobic drug. In some embodiments, the drug is a cytotoxic drug. In some embodiments, the cytotoxic drug is selected from docetaxel, paclitaxel, cabazitaxel, doxorubicin and mitoxantrone.

[0100] In some embodiments, the compound of formula (I) and the drug are present in the composition at a ratio of about 20: 1 to about 1: 20 (w / w), such as about 15: 1 to about 1: 15, or such as about 10: 1 to about 1: 10. In some embodiments, the compound of formula (I) and the hydrophobic drug are present in the micelle at a ratio of about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1: 1, about 1: 2, about 1: 3, about 1: 4, about 1: 5, about 1: 6, about 1: 7, about 1: 8, about 1: 9 or about 1: 10 (w / w).

[0101] The particle size of the micelles in the composition is typically in the range of about 5 to about 150 nm. The particle size can be measured, for example, using dynamic light scattering (DLS) in 0.9% NaCl at a drug concentration of 1 mg / mL, preferably using a red laser with a wavelength of 633 nm.

[0102] It has been found that the particle size depends on the properties of the compound of formula (I) and the properties of the drug, the ratio between the compound of formula (I) and the drug, and the concentration of the compound in the composition. By changing these conditions, the particle size of the micelle can be adjusted as needed. Depending on the situation, the micelle can maintain equilibrium with the "free" compound of formula (I) or its pharmaceutically acceptable salt and / or the "free" drug. Alternatively, the micelle can be reshaped over time. Therefore, the particle size (and therefore the polydispersity index) may change slightly over time, for example, after 4 hours, 8 hours, 12 hours or 24 hours after the micelle is formed. In some embodiments, the particle size is about 5 to about 125 nm, for example, about 25 to about 125 nm, about 50 to about 125 nm, about 75 to about 125 nm, or about 100 to 125 nm; for example, about 25 to about 100 nm, about 25 to about 75 nm, or about 25 to about 50 nm; or for example, about 50 to 100 nm, about 50 to about 75 nm, or about 75 to 100 nm. Preferably, the particle size is less than 100 nm. Preferably, the polydispersity index is less than 0.5, more preferably less than 0.4, and even more preferably less than 0.3. In some embodiments, the polydispersity index is between 0 and 0.5, such as between 0 and 0.4, or such as between 0 and 0.3. Preferably, the particle size distribution is substantially unimodal.

[0103] Methods and uses

[0104] In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a medicament for use in therapy.

[0105] In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a cytotoxic drug for use in the treatment of cancer.

[0106] In another aspect, the present invention relates to cytotoxic drug micelles comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a cytotoxic drug for use in treating cancer.

[0107] The present invention also relates to the use of the pharmaceutical composition or the cytotoxic drug micelle in the manufacture of a drug for treating cancer. The present invention also relates to a method for treating cancer in a subject (e.g., a human being), comprising administering a therapeutically effective amount of the pharmaceutical composition or the cytotoxic drug micelle to a subject in need of such treatment.

[0108] Also provided herein is a method of enhancing the efficacy of a pharmaceutically active substance, wherein the substance is prepared in micellar form with at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0109] Also provided herein is a method for increasing the solubility of a pharmaceutically active substance, wherein the substance is prepared in micellar form with at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0110] Also provided herein is a method for improving the pharmacokinetic or pharmacodynamic properties of a pharmaceutically active substance, wherein the substance is prepared in micellar form with at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0111] Also provided herein is a method for improving the storage properties of a pharmaceutically active substance, wherein the substance is prepared in micellar form with at least one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0112] radioactive isotopes

[0113] In another aspect, the present invention also relates to compounds of formula (I), (II) or (III) as defined herein, wherein the compound contains at least one atom of a halogen radioisotope (radioisotope).

[0114] Preferably, R 1 , R 2 , R 3 , R 4 and R 5 In some embodiments, at least one of R 1 , R 2 , R 3 , R 4 and R 5 One, two, three or four of the isotopes are halogen radioisotopes, and the others are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C(=O)OR 10 ; where R 10 C 1-4 In some embodiments, R 1 , R 2 , R 3 , R 4 and R 5 One, two, three or four of R are halogen radioisotopes, and the remainder are each independently selected from hydrogen, methyl and methoxy. 1 , R 2 , R 3 , R4 and R 5 All are halogen radioisotopes. Specific examples of halogen radioisotopes include fluorine-18, iodine-123, iodine-125, and iodine-131.

[0115] Compounds of formula (I) labelled with radioisotopes may be used as radiopharmaceuticals for diagnostic or therapeutic purposes.

[0116] definition

[0117] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for human pharmaceutical use and that are generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0118] As used herein, the terms "treatment", "treat", "treating" refer to reversing, alleviating, delaying the onset of a disease or disorder as described herein, or one or more symptoms thereof, or inhibiting the progression of a disease or disorder as described herein, or one or more symptoms thereof. In some embodiments, treatment can be administered after the onset of one or more symptoms. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other predisposing factors). Treatment can also continue after symptoms subside, for example to prevent or delay their recurrence.

[0119] The term "including" should be interpreted as including but not limited to. All references are incorporated herein by reference. The arrangement of the disclosure into sections with titles and subtitles is only for readability and should not be interpreted as limiting in any way. In particular, this division does not exclude or limit in any way the combination of features under different titles and subtitles.

[0120] As used herein, the term "about" refers to a value or parameter herein, which includes (and describes) embodiments for the value or parameter itself. For example, a description of "about 20" includes a description of "20". Numerical ranges include numbers that define ranges. In general, the term "about" refers to the indicated value of a variable and all values ​​of the variable, which are within the experimental error of the indicated value (e.g., within a 95% confidence interval of the mean value) or within 10% of the indicated value, whichever is greater. Example

[0121] The present invention will now be described by the following examples, which are not intended to limit the invention in any respect.

[0122] abbreviation

[0123] API Active Pharmaceutical Ingredients

[0124] Boc tert-butyloxycarbonyl

[0125] CAPS3-(cyclohexylamino)-1-propanesulfonic acid

[0126] CAPSO3-(Cyclohexylamino)-2-hydroxy-1-propanesulfonic acid

[0127] CHES2-(Cyclohexylamino)ethanesulfonic acid

[0128] DCM dichloromethane

[0129] DIPEAN,N-Diisopropylethylamine

[0130] DLS Dynamic Light Scattering

[0131] DMF dimethylformamide

[0132] MTBE Methyl tert-butyl ether

[0133] PyBOPBenzotriazol-1-yloxy-tripyrrolidino Hexafluorophosphate

[0134] RSDRelative standard deviation

[0135] SDS Sodium dodecyl sulfate

[0136] TEA triethylamine

[0137] TFA trifluoroacetic acid

[0138] THF Tetrahydrofuran

[0139] TLC Thin Layer Chromatography

[0140] Experimental methods

[0141] Reagents and solvents were purchased from Sigma-Aldrich (Merck) or Biosynth. Room temperature refers to 20-25°C. Solvent mixture compositions are given in volume percentage or volume ratio.

[0142] Recorded at 500 MHz using a Variant Unity-500 spectrometer 1 H NMR spectra were recorded at 300 MHz using a Bruker spectrometer. 1 H NMR spectrum. DMSO-d6 was used as solvent.

[0143] Mass spectrometer readings were recorded using a Dionex UHPLCUltimate 3000 with DAD detector / Thermo Scientific ISQ EC-mass spectrometer.

[0144] Thin layer chromatography (TLC) was performed using Merck silica gel RP-18 plates and developed in a solvent system consisting of methanol: water (7:3, v / v).

[0145] Micellar size was measured using a ZetaSizer from Malvern Panalytical.

[0146] HPLC was performed on a Chromaster HPLC system (Hitachi). Analysis was performed using a Hypurity C18 column, 250 x4.6 mm, 3.0 µm (Thermo Scientific). Mobile phase: Solvent A: 10% NH4OAc (aq.), 10% SDS (aq.) and 80% acetonitrile, Solvent B: 10% NH4OAc (aq.), 10% SDS (aq.) and 80% water. Flow rate: 1 mL / min. Run time: 65 min. Pump program:

[0147]

[0148] Example 1

[0149] 1.1 Synthesis of compound 1

[0150]

[0151] In a 25 mL two-necked flask, acitretin (250 mg, 0.77 mmol) and TEA (92 µL, 0.91 mmol) were dissolved in anhydrous THF (10 mL), and the mixture was cooled to 5-10 ° C. A solution of isobutyl chloroformate (129 µL, 0.99 mmol) in THF (0.5 mL) was added dropwise to the frozen solution. The resulting mixture was stirred at 5-10 ° C for 30 minutes under inert conditions and light protection.

[0152] A solution of CHES (222 mg, 1.07 mmol) and TEA (149 µL, 1.07 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred at room temperature under inert conditions for 2.5 hours. Acetic acid (200 µL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20 mL) and water (25 mL). The layers were separated and the organic layer was discarded. Sodium bicarbonate (300 mg) was carefully added to the aqueous layer. When the bubbling stopped, brine (25% NaCl solution, 20 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (20 mL). The layers were separated and the aqueous phase was discarded. The organic layer was washed with a mixture of brine (12.5% ​​NaCl solution, 20 mL) and methanol (2 mL). The aqueous layer was discarded, and the organic layer was evaporated under reduced pressure (40-70 mbar at 39°C). The vacuum was released with an inert gas (N2). The product was washed with MTBE (10 mL) and dried under vacuum. The resulting product was purified by column chromatography (RP-C18; eluent: MeOH / water 7:3) to give the product (purity 94.8%) as a yellow solid. Yield: 50%.

[0153] 1 H NMR (500 MHz, DMSO-d6): δ 6.85 (ddd, 1H, J = 30.2, 15.2, 11.4 Hz,CH=CH-); 6.67 (s, 1H, Ph-H); 6.65 (d, 1H, J = 16.4 Hz, -CH=CH-); 6.42 (dd,1H, J = 16.4 Hz, -CH=CH-); 6.31 (s, 1H, =C-CH); 6.25–6.19 (m, 2H, -CH=CH-); 3.78 (s, 3H, -O-CH3); 3.45 (m, 2H, CH2); 3.35 (m, 2H, CH2); 2.65 (m, 1H, CHcyclohexyl); 2.50 (s, 3H, : 1.5 (s, 3H, CH3); 2.23 (s, 3H, CH3); 2.21 (s, 3H, CH3); 2.12 (s, 6H,CH3);1.9 (s, 3H, CH3); 1.77, (m, a (2H)cyclohexyl); 1.62, (m, e (2H)cyclohexyl); 1.28,(m, a (2H)cyclohexyl); 1.10, (m, e (2H)cyclohexyl); 1.05, (m, 2H,cyclohexyl).

[0154] m / z = 538.26; 516.27.

[0155] 1.2. Drug products with API

[0156] 1.2.1 Formulations with docetaxel

[0157] 3.8 mg of compound 1 was dispensed into a 25 mL round-bottom flask and dissolved in methanol (2 mL). 240 μL of a stock solution of docetaxel in methanol (5 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.2 mL). Finally, 0.9% sodium chloride solution (1.0 mL) was added and a yellow transparent solution was obtained. The drug loading capacity was defined as the ratio of API amount: (API+excipients).

[0158]

[0159] 20 mg of Example 1 was dispensed into a 25 mL round bottom flask and dissolved in methanol (3 mL). 800 μL of a stock solution of docetaxel in methanol (5 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 4 mg / mL of docetaxel. The 4 mg / mL concentration was further diluted with 0.9% sodium chloride according to the table below.

[0160] Ratio 5:1

[0161]

[0162] 11 mg of Example 1 was dispensed into a 25 mL round bottom flask and dissolved in methanol (2 mL). 740 μL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding 0.9% sodium chloride to a concentration of 1 mg / mL of docetaxel to obtain a yellow transparent solution.

[0163] Ratio 3:1

[0164]

[0165] A stock solution of docetaxel in methanol was mixed with a stock solution of compound 1 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 µm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of docetaxel. The final weight ratio of docetaxel to micelle former was 1:5. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the particle size and polydispersity index increased slightly over time. The changes were within an acceptable range.

[0166]

[0167] The docetaxel: compound 1 system was serially diluted. A stock solution of docetaxel in methanol was mixed with a stock solution of the micelle former (compound 1) in a round-bottom flask at a weight ratio of 1:5. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a docetaxel concentration of 1 mg / mL. The resulting solution was filtered through a 0.22 µm sterile filter and further diluted with 0.9% sodium chloride solution. The micelle size and RSD showed no clear trend during the dilution.

[0168]

[0169] 1.2.2 Formulations containing cabazitaxel

[0170] 4.5 mg of compound 1 was dispensed into a 25 mL round bottom flask and dissolved in methanol (2 mL). 1500 µL of a stock solution of cabazitaxel in methanol (1.00 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding 0.9% sodium chloride to a concentration of 1 mg / mL of cabazitaxel to obtain a yellow transparent solution. The results of different dilutions are shown in the table below.

[0171] Ratio 3:1

[0172]

[0173] 1.2.3 Preparations with cyclosporine

[0174] 4.5 mg of compound 1 was dispensed into a 25 mL round bottom flask and dissolved in methanol (2 mL). 1500 µL of a stock solution of cyclosporine in methanol (1.00 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding 0.9% sodium chloride to a concentration of 1 mg / mL of cyclosporine to obtain a yellow transparent solution. The results of different dilutions are shown in the table below.

[0175] Ratio 3:1

[0176]

[0177] A stock solution of cyclosporin in methanol was mixed with a stock solution of compound 1 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of cyclosporin. The resulting solution was filtered through a 0.22 µm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of cyclosporin. The final weight ratio of cyclosporin to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the following table. It was noted that the particle size increased slightly over time and the polydispersity index changed over time. The changes were within an acceptable range.

[0178]

[0179] Example 2

[0180] 2.1 Synthesis of compound 2

[0181]

[0182] In a 25 mL two-necked flask, acitretin (500 mg, 1.5 mmol) and TEA (216 µL, 1.68 mmol) were dissolved in anhydrous THF (10 mL), and the mixture was cooled to 5-10°C. A solution of isobutyl chloroformate (260 µL, 1.97 mmol) in THF (0.5 mL) was added dropwise to the frozen solution, and the resulting mixture was stirred at 5-10°C for 30 min under inert conditions and protected from light.

[0183] A solution of CAPS (475 mg, 2.14 mmol) and TEA (276 µL, 2.14 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred at room temperature under inert conditions for 2 hours. Acetic acid (600 µL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20 mL) and water (25 mL). The layers were separated, and the organic layer was discarded. Sodium bicarbonate (600 mg) was carefully added to the aqueous layer. When the bubbling stopped, brine (25% NaCl solution, 20 mL) was added, and the resulting aqueous solution was extracted with ethyl acetate (20 mL). The layers were separated, and the aqueous phase was discarded. The organic layer was washed with a mixture of brine (12.5% ​​NaCl solution, 20 mL) and methanol (1-3 mL). The aqueous layer was discarded, and the organic layer was evaporated under reduced pressure (40-70 mbar at 39°C). The vacuum was released with an inert gas (N2). The obtained product was purified by column chromatography (RP-C18; eluent: MeOH / water 7:3) to give a yellow product (purity 88.2%). Yield: 10%.

[0184] 1 H NMR (500 MHz, DMSO-d6): δ 6.75 (m, 1H, CH=CH -); 6.70 (s, 1H, Ph-H); 6.65 (m, 1H, -CH=CH-); 6.45 (dd, 1H, -CH=CH-); 6.27 (s, 1H, C=CH-); 6.20–6.25 (m, 2H, -CH=CH-); 3.75 (s, 3H, -O-CH3); 3.40-3.35 (m, 4H, CH2); 3.48 (m,2H,); 2.60 (m, (1H)cyclohexyl); 2.26 (s, 3H, CH3); 2.05 (s, 3H, CH3); 1.95 (s, 3H,CH3 ); 1.75 (s, 6H, CH3); 1.55 (m, 6H, cyclohexyl); 1.25, (m, 2H, cyclohexyl); 1.14, (m, 2H, cyclohexyl).

[0185] 2.2 Preparations with API

[0186] 2.2.1 Formulations containing docetaxel

[0187] 4.0 mg of compound 2 was dispensed into a 25 mL round bottom flask and dissolved in methanol (3 mL). 250 µL of a stock solution of docetaxel in methanol (5 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.25 mL). The solution was mixed with 0.9% sodium chloride solution 1:1 v / v to obtain a yellow transparent solution. The results are shown below.

[0188]

[0189] Example 3

[0190] 3.1 Synthesis of compound 3

[0191]

[0192] In a 25 mL two-necked flask, acitretin (500 mg, 1.53 mmol) and TEA (236 µL, 1.80 mmol) were dissolved in anhydrous THF (15 mL), and the reaction mixture was cooled to 5-10 °C. A solution of isobutyl chloroformate (260 µL, 1.97 mmol) in THF (0.8 mL) was added dropwise to the cold solution. The resulting mixture was stirred at 5-10 °C for 30 min under inert conditions and light protection.

[0193] A solution of 2-(methylamino)ethane-1-sulfonic acid (298 mg, 2.14 mmol) and TEA (286 µL, 2.17 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred at room temperature under inert conditions for 2.5 hours. Acetic acid (500 µL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20 mL) and water (25 mL). The layers were separated and the organic layer was discarded. Sodium bicarbonate (400 mg) was carefully added to the aqueous layer. When the bubbling stopped, brine (25% NaCl solution, 20 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (20 mL). The layers were separated and the aqueous phase was discarded. The organic layer was washed with a mixture of brine (12.5% ​​NaCl solution, 20 mL) and methanol (1-3 mL). The aqueous layer was discarded, and the organic layer was evaporated under reduced pressure (40-70 mbar at 39°C). The vacuum was released with an inert gas (N2). The resulting product was purified by column chromatography (RP-C18; eluent: MeOH / water 7:3) to give the product as a yellow solid (purity 99.4%). Yield: 55%.

[0194] 1H NMR (500 MHz, DMSO-d6): δ 6.86 (t, 1H, J = 13.3 Hz, CH=CH-), 6.72-6.57 (m, 2H); 6.44 (s, 1H, -CH=CH-); 6.32-6.18 (m, 3H, -CH=CH); 3.70 (s, 3H,-O-CH3); 3.70-3.50 (d, 2H, CH2); 3.20-2.70 (t, 3H, N-CH3); 2.70-2.67 (d, CH2); 2.25 (s, 3H, CH3); 2.24 (s, 3H, CH3); 2.07 (s, 9H, CH3).

[0195] m / z = 470.19; 448.21.

[0196] 3.2 Preparations with API

[0197] 3.2.1 Formulations with docetaxel

[0198] 4.5 mg of compound 3 was dispensed into a 25 mL round bottom flask and dissolved in methanol (3 mL). 305 µL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was rehydrated by adding 0.9% sodium chloride solution (1.5 mL) and a clear yellow solution was obtained. The results of different dilutions are shown in the following table.

[0199] Ratio 3:1

[0200]

[0201] 4.5 mg of compound 3 was dispensed into a 25 mL round bottom flask and dissolved in methanol (3 mL). 0.455 µL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was rehydrated by adding 0.9% sodium chloride solution (2.25 mL) and a clear yellow solution was obtained. The results of different dilutions are shown in the table below.

[0202] Ratio 2:1

[0203]

[0204] A stock solution of docetaxel in methanol was mixed with a stock solution of compound 3 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 µm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of docetaxel. The final weight ratio of docetaxel to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the changes in particle size and polydispersity index over time were small. The changes were within an acceptable range.

[0205]

[0206] 3.2.2 Preparations containing cyclosporine

[0207] A stock solution of cyclosporin in methanol was mixed with a stock solution of compound 3 in a round bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of cyclosporin. The resulting solution was filtered through a 0.22 µm sterile filter and further diluted to 0.5 mg / mL cyclosporin with 0.9% sodium chloride solution. The final weight ratio of cyclosporin to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the changes in particle size and polydispersity index over time were small (see the table below). The changes were within an acceptable range.

[0208]

[0209] Example 4

[0210] 4.1 Synthesis of compound 4

[0211]

[0212] In a 25 mL two-necked flask, acitretin (250 mg, 0.77 mmol) and TEA (95 µL, 0.80 mmol) were dissolved in anhydrous THF (10 mL), and the mixture was cooled to 5-10°C. A solution of isobutyl chloroformate (129 µL, 1.0mmol) in THF (0.5 mL) was added dropwise to the frozen solution. The resulting mixture was stirred at 5-10 °C for 30 min under inert conditions and light protection. A solution of CAPSO (260 mg, 1.1 mmol) and TEA (149 µL, 1.16 mmol) in methanol (3 mL) was added to the reaction mixture, and the resulting solution was stirred at room temperature under inert conditions for 2 hours. Acetic acid (400 µL) was then carefully added to the reaction mixture. The solution was evaporated to dryness, and the resulting crude product was extracted with MTBE (20mL) and water (25 mL). The layers were separated, and the organic layer was discarded. Sodium bicarbonate (300mg) is carefully added to the water layer. When bubbling stops, saline (25% NaCl solution, 20 mL) is added, and the resulting aqueous solution is extracted with ethyl acetate (20 mL). Separate the layers, and discard the aqueous phase. Wash the organic layer with a mixture of saline (12.5% ​​NaCl solution, 20 mL) and methanol (1-3 mL). Discard the water layer, and evaporate the organic layer under reduced pressure (40-70 mbar at 39 ° C). Release the vacuum with an inert gas (N2). The resulting product is purified by column chromatography (RP-C18; eluent MeOH / water 7:3) to obtain the product, which is a yellow solid. Yield: 35%.

[0213] 1H NMR (500 MHz, DMSO-d6): δ 6.90-6.75 (m, 1H, CH=CH-); 6.69 (s, 1H,Ph-H); 6.64 (dd, 1H, J = 16.4, 7.9 Hz, -CH=CH-); 6.44 (dd, 2H, J = 24.0, 15.1Hz, -CH=CH-); 6.20–6.30 (m, 2H, -CH=CH-); 3.75 (s, 3H, -O-CH3); 3.40-3.35 (m,4H, CH2); 3.48 (m, 1H, =CH); 2.50 (s, 3H, CH3); 2.25 (s, 3H, CH3); 2.22 (s,3H, CH3); 2.15 (s, 1H, CH ); 2.14 (s, 6H, CH 3 ); 1.75, (m, a (2H) cyclohexyl); 1.65, (m, e (2H) cyclohexyl); 1.60, (m, a (2H) cyclohexyl); 1.58, (m, a (2H) cyclohexyl); 1.25, (m, e (2H) cyclohexyl).

[0214] HPLC: Rt 27.03 min, 99,21% (Max); m / z = 568.26; 544.37.

[0215] 4.2 Preparations with API

[0216] 4.2.1 Formulations with docetaxel

[0217] 4.5 mg of compound 4 was dispensed into a round bottom flask and dissolved in methanol (3 mL). 0.305 µL of a stock solution of docetaxel in methanol (4.96 mg / mL) was added. The solution was evaporated to dryness in a rotary evaporator. Final drying (40 min) was performed in a desiccator to remove residual solvent. The dried film was rehydrated by adding 0.9% sodium chloride solution (1.5 mL). The solution was then further diluted with 0.9% sodium chloride solution to obtain a yellow transparent solution. The results of different dilutions are shown in the table below.

[0218] Ratio 3:1

[0219]

[0220] The stock solution of docetaxel in methanol was mixed with the stock solution of compound 4 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of docetaxel. The final weight ratio of docetaxel to micelle former was 1:5. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the particle size increased over time and the polydispersity index changed over time (see the table below).

[0221]

[0222] Example 5

[0223] 5.1 Synthesis of compound 5

[0224]

[0225] Acitretin (250 mg, 0.77 mmol) was suspended in DMF (2.5 mL), and N-(2-acetylamino)-taurine (140 mg, 0.77 mmol) was added, followed by DIPEA (400 μL, 2.3 mmol). The yellow suspension was cooled to 15 ° C, and PyBOP (478 mg, 0.9 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into cold water (10 mL), acidified to pH 1 with 1M HCl, and extracted with EtOAc (3x15 mL). Since UPLC showed that there was no product in the organic extract, the organic layer was discarded. The water layer was saturated with solid NaCl. After a few minutes, a yellow solid precipitated. The suspension was ultrasonically treated for 1 minute, then stirred at room temperature for 15 minutes. The solid was filtered out, washed with a small amount of water and dried under vacuum to obtain 240 mg of the product, which was a yellow solid (purity 99.9%).

[0226] 235 mg of the solid was dissolved in MeOH (5 mL), and then a solution of NaOH (19 mg) in MeOH (0.5 mL) was added. The solution was stirred for 1 hour, and a yellow solid was precipitated. The mixture was concentrated to about 3 mL, stirred for 30 minutes, and then filtered. The solid was washed with a small amount of MeOH and dried. Yield: 41% (160 mg).

[0227] 1H NMR (300 MHz, DMSO-d6): δ 7.51 (d, J = 9.5 Hz, 1H), 7.14-6.79 (m,2H), 6.66 (d, J = 19.1 Hz, 2H), 6.45-5.94 (m, 4H), 3.90 (d, J = 31.6 Hz, 2H), 3.76 (s, 3H), 3.56 (dt, J = 23.1, 7.4 Hz, 2H), 2.66 (dt, J = 13.9, 7.0 Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 2.06 (d, J = 6.8 Hz, 9H).

[0228] m / z = 513.19; 491.41.

[0229] 5.2 Preparations with API

[0230] 5.2.1 Formulations with docetaxel

[0231] A stock solution of docetaxel in methanol was mixed with a stock solution of compound 5 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of docetaxel. The final weight ratio of docetaxel to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the particle size increased over time and that the polydispersity index changed very little over time.

[0232]

[0233] 5.2.2 Formulations with Cabazitaxel

[0234] A stock solution of cabazitaxel in methanol was mixed with a stock solution of compound 5 in a round bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of cabazitaxel. The resulting solution was filtered through a 0.22 µm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of cabazitaxel. The final weight ratio of cabazitaxel to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the table below. It is noted that the changes in particle size and polydispersity index over time are small (see table below).

[0235]

[0236] Example 6

[0237] 6.1 Synthesis of compound 6

[0238]

[0239] Acitretin (300 mg, 0.92 mmol) was suspended in DMF (3 mL), and DIPEA (380 µL, 2.9 mmol) was added, followed by PyBOP (622 mg, 1.2 mmol). The red solution was stirred at room temperature for 15 minutes, and 4-(piperazine-1-yl)benzene-1-sulfonic acid (223 mg, 0.92 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours. UPLC showed 93% conversion to product. The reaction mixture was poured into cold water (20 mL), acidified to pH 1 with 1M HCl, and treated with EtOAc, which resulted in the precipitation of an oily solid. The mixture was then saturated with solid NaCl. The organic solvent was evaporated, and the remaining aqueous suspension was stirred at room temperature for 20 minutes. The precipitated solid was filtered out, washed twice with water, and dried under vacuum to give 575 mg of solid (purity>91%). The crude product was treated with EtOAc (15 mL) at room temperature for 1 hour, and the mixture was then centrifuged. The solvent was decanted, the residue was washed with EtOAc and centrifuged again. The contents were poured into a flask and dried to give 365 mg of a beige solid (purity>98%).

[0240] 360 mg of the solid was suspended in MeOH (20 mL), and then a solution of NaOH (49 mg) in MeOH (1.5 mL) was added to give a clear yellow solution. The solution was concentrated, and the residue was triturated with MeOH (about 8 mL) at room temperature for 1.5 hours. The precipitated solid was filtered off, washed with MeOH, and dried under vacuum (purity 99.5%). Yield: 21% (110 mg).

[0241] 1H NMR (300 MHz, DMSO-d6): δ 7.49-7.41 (m, 2H), 6.96-6.82 (m, 3H), 6.67 (d, J = 17.1 Hz, 2H), 6.47 (d, J = 15.1 Hz, 1H), 6.28 (dd, J = 15.8, 3.6Hz, 3H), 3.76 (s, 3H), 3.69-3.55 (m, 4H), 3.22-3.09 (m, 4H), 2.26 (s, 3H), 2.19 (s, 3H), 2.06 (d, J = 3.4 Hz, 9H).

[0242] m / z (M-23) = 549.24.

[0243] 6.2 Preparations with API

[0244] 6.2.1 Formulations with docetaxel

[0245] A stock solution of docetaxel in methanol was mixed with a stock solution of compound 6 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of docetaxel. The final weight ratio of docetaxel to micelle former was 1:3. Particle size and polydispersity index were measured over time. It was noted that the changes in particle size and polydispersity index over time were small (see table below).

[0246]

[0247] Example 7

[0248] 7.1 Synthesis of compound 7

[0249]

[0250] Acitretin (250 mg, 0.8 mmol) was suspended in anhydrous DMF (5 mL). DIPEA (297 mg, 2.3 mmol) was then added, followed by PyBOP (518 mg, 1.0 mmol). The reaction was stirred at room temperature under argon atmosphere for 10 minutes, and then trans-(4-methylamino)cyclohexyl)methanesulfonic acid (159 mg, 0.8 mmol) was added in one portion. The progress of the reaction was followed by UPLC (conversion reached 91% after 24 hours).

[0251] The reaction mixture is poured into cold water (15 mL) and acidified to pH 1 with 1M HCl. An attempt is made to extract with ethyl acetate, but each phase is not separated. The organic solvent is then evaporated and solid NaCl is added until the mixture is saturated. The solid formed is filtered off, dried and purified by column chromatography (FC, RP-C18, 30-70% MeOH / water in 35 minutes). The fraction containing the product is concentrated and then dissolved in 5 mL of MeOH containing 1.0 eq. NaOH. The mixture is stirred at room temperature for 1 hour and then evaporated to dryness. The obtained powder is ground with acetone and then dried at room temperature under vacuum (0.2 mbar) for 24 hours. In this way, 180 mg yellow powder (purity 99.5%) is obtained.

[0252] 1 H NMR (300 MHz, DMSO-d6): δ 6.92-6.75 (m, 1H), 6.72-6.58 (m, 2H), 6.53-6.36 (m, 1H), 6.34-6.01 (m, 2H), 4.21 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H), 3.55 (d, J = 18.2 Hz, 1H), 2.78 (d, J = 21.5 Hz, 3H), 2.31 (dd, J = 8.2, 6.0Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 2.10-2.04 (m, 6H), 1.99 (d, J = 8.2 Hz, 3H), 1.52 (d, J = 20.0 Hz, 5H), 1.00 (s, 2H).

[0253] m / z (M-23) = 514.23.

[0254] 7.2 Preparations with API

[0255] 7.2.1 Formulations with docetaxel

[0256] A stock solution of docetaxel in methanol was mixed with a stock solution of compound 7 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of docetaxel. The final weight ratio of docetaxel to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the changes in particle size and polydispersity index over time were small (see table below).

[0257]

[0258] Example 8

[0259] 8.1 Synthesis of compound 8

[0260]

[0261] Acitretin (250 mg, 0.8 mmol) was suspended in anhydrous DMF (5 mL). DIPEA (297 mg, 2.3 mmol) was then added, followed by PyBOP (518 mg, 1.0 mmol). The reaction was stirred at room temperature for 10 minutes under an argon atmosphere. 2-(piperidin-4-yl)ethane-1-sulfonic acid (148 mg, 0.8 mmol) was then added in one portion. The progress of the reaction was followed by UPLC.

[0262] The reaction mixture is poured into cold water (15 mL), and acidified to pH 1 with 1M HCl. The mixture is saturated with solid NaCl, but no solid is formed. Purification of solution by column chromatography (FC, RP-C18, 30-70% MeOH / water in 35 minutes). The fractions containing the product are concentrated and then dissolved in the MeOH containing 1.0 eq. NaOH of 5 mL. The mixture is stirred at room temperature for 1 hour, then evaporated to dryness. The gained powder is ground with acetone, then dried 24 hours at room temperature under vacuum (0.2 mbar). In this way, 190 mg yellow powder (purity 99.7%) is obtained.

[0263] 1H NMR (300 MHz, DMSO-d6): δ 6.83 (dd, J = 15.2, 11.3 Hz, 1H), 6.74-6.60 (m, 2H), 6.43 (d, J = 15.1 Hz, 1H), 6.33-6.11 (m, 3H), 4.38 (d, J = 12.9Hz, 1H), 3.83 (d, J = 13.6 Hz, 1H), 3.76 (s, 3H), 2.96 (t, J = 12.9 Hz, 1H), 2.46-2.35 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 2.08-2.02 (m, 7H), 1.99 (d, J= 1.0 Hz, 3H), 1.67 (d, J = 12.8 Hz, 2H), 1.60-1.45 (m, 3H), 1.07-0.83 (m,3H).

[0264] m / z = 502,19; 500.21.

[0265] 8.2 Preparations with API

[0266] 8.2.1 Formulations with docetaxel

[0267] The stock solution of docetaxel in methanol was mixed with the stock solution of compound 8 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted with 0.9% sodium chloride solution to 0.5 mg / mL of docetaxel. The final weight ratio of docetaxel to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the particle size increased over time and that the polydispersity index changed very little over time (see table below).

[0268]

[0269] Example 9

[0270] 9.1 Synthesis of compound 9

[0271] Step 1:

[0272]

[0273] Boc-piperazine (1.0 g, 5.37 mmol) was dissolved in anhydrous DMF (10 mL) under an inert atmosphere, and then PyBop (3.63 g, 7.0 mmol) and DIPEA (2.81 mL, 16.1 mmol, 3.0 eq.) were added, and the reaction mixture was stirred at room temperature for 5 minutes, and then 4-sulfobenzoic acid potassium salt (1.29 g, 5.37 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight. The precipitated product was filtered and dried. Yield: 76%.

[0274] Step 2:

[0275]

[0276] The compound of step 1 (0.5 g, 1.22 mmol) was added to a mixture of TFA and DCM (1:1, 5 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was then evaporated. MeOH (5 mL) was added, and a white solid precipitated after a while. The solid was filtered out and washed with a small amount of MeOH. Yield: 0.217 g (42%); purity 97%.

[0277] Step 3:

[0278]

[0279] Acitretin (100 mg, 0.31 mmol) was suspended in anhydrous DMF (2 mL) under an argon atmosphere, and DIPEA (215 µL, 1.2 mmol) and PyBop (208 mg, 0.4 mmol) were added. The reaction mixture was stirred at room temperature for 3 minutes, and then the compound of step 2 (130 mg, 0.3 mmol) was added in one go. The solution was stirred at room temperature overnight. The product was separated by a chromatographic column (RP-C18, water / MeOH). The residue was ground with acetone to obtain the product as a yellow powder (purity 99.4%). Yield: 24 mg (13%).

[0280] 1H NMR (300 MHz, DMSO-d6): δ 7.66 (d, J = 8.1 Hz, 2H), 7.48-7.31 (m,2H), 6.89 (dd, J = 15.3, 11.4 Hz, 1H), 6.67 (d, J = 16.9 Hz, 2H), 6.43 (d, J= 15.1 Hz, 1H), 6.26 (t, J = 14.9 Hz, 2H), 3.76 (s, 3H), 3.55 (s, 8H), 2.26(s, 3H), 2.19 (s, 3H), 2.10-2.03 (m, 9H).

[0281] m / z = 579.29; 577.19.

[0282] 9.2 Preparations with API

[0283] 9.2.1 Formulations with docetaxel

[0284] The stock solution of docetaxel in methanol was mixed with the stock solution of compound 9 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted to 0.5 mg / mL of docetaxel with 0.9% sodium chloride solution. The final weight ratio of docetaxel to micelle former was 1:3. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the particle size increased over time and the polydispersity index changed very little over time (see table below).

[0285]

[0286] Example 10

[0287] 10.1 Synthesis of compound 10

[0288]

[0289] Acitretin (400 mg, 1.23 mmol) was suspended in DMF (4 mL) and DIPEA (640 µL, 3.7 mmol) was added followed by PyBOP (765 mg, 1.5 mmol, 1.2 eq.). The solution was stirred at room temperature for 5 minutes and then 5-amino-2-[(2-hydroxy-ethylamino)-methyl]-benzenesulfonic acid (302 mg, 1.23 mmol) was added. The resulting mixture was stirred at room temperature for 21 hours. UPLC showed 86% conversion to product. The reaction mixture was poured into cold water (40 mL) and acidified to pH 1 with 1M HCl. The mixture was saturated with NaCl and a sticky solid was formed. The mixture was sonicated for 20 minutes and then stirred at room temperature for 30 minutes. The precipitated solid was centrifuged. The solvent was decanted, the residue was washed with water (15 mL) and centrifuged again. The washing and centrifugation procedure was then repeated 2 times. The contents were poured into a flask and dried. The solid was ground with EtOAc (25 mL) at room temperature for 1 hour and then centrifuged. The solvent was decanted, the residue was washed with EtOAc (15 mL) and centrifuged again. The washing and centrifugation procedures were then repeated 2 times. The residue was then dried to obtain 560 mg of solid (purity 84%).

[0290] 555 mg of solid was suspended in MeOH (50 mL). A solution of NaOH (75 mg) in MeOH (1.5 mL) was added to give a clear solution. The solution was stirred at room temperature for 10 minutes and concentrated. The resulting brown foam was dissolved in MeOH (5 mL) and purified by column chromatography (C18; eluent MeOH / water 3:7 to 7:3) to give the product (purity 99.5%). Yield: 110 mg (21%).

[0291] 1 H NMR (300 MHz, DMSO-d6) δ 7.08 (dd, J = 4.2, 2.5 Hz, 1H), 6.93-6.58(m, 4H), 6.52-6.36 (m, 2H), 6.34-6.06 (m, 3H), 5.02 (d, J = 15.6 Hz, 2H), 4.89 (d, J = 9.4 Hz, 2H), 4.66 (d, J = 15.3 Hz, 1H), 3.75 (d, J = 2.7 Hz, 3H), 3.58-3.36 (m, 3H), 3.25 (t, J = 6.3 Hz, 1H), 2.25 (d, J = 6.4 Hz, 3H),2.18 (d, J = 6.8 Hz, 3H), 2.14-1.99 (m, 9H).

[0292] m / z (M-Na) = 533.18; 554.93.

[0293] 10.2 Preparations with API

[0294] 10.2.1 Formulations with docetaxel

[0295] The stock solution of docetaxel in methanol was mixed with the stock solution of compound 10 in a round-bottom flask. The mixture was evaporated to dryness in a rotary evaporator. Final drying was performed in a desiccator to remove residual solvent. The dried film was hydrated by adding water for injection (1.0 mL) to a concentration of 1 mg / mL of docetaxel. The resulting solution was filtered through a 0.22 μm sterile filter and further diluted to 0.5 mg / mL of docetaxel with 0.9% sodium chloride solution. The final weight ratio of docetaxel to micelle former was 1:5. Particle size and polydispersity index were measured over time, as shown in the table below. It was noted that the particle size increased over time and the polydispersity index decreased slightly over time (see table below).

[0296]

Claims

1. Compound of formula (I) (II) in R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-4 Alkoxycarbonyl; R 6 Selected from halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 3-8 Cycloalkylcarbonyl, aminocarbonyl-C 1-4 Alkyl, -C(=NH)NH2 and phenyl, wherein the phenyl group is optionally substituted by one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups; R 7 For-(CR 8A R 8B ) n -X, benzyl-X or C 3-7- Cycloalkyl-(CR 8A R 8B ) m -X, wherein n is an integer of 2 or 3, and m is an integer of 1 or 2, and wherein the benzyl group is optionally further replaced by one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups; or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- to 7-membered saturated heterocyclic ring, which is replaced by -(CR 8A R 8B ) p -X, phenyl-X or benzoyl-X, wherein p is an integer of 1 or 2, and wherein the phenyl or benzoyl group is optionally further substituted with one or more selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Substitution of alkoxy and amino groups; R 8A and R 8B Each independently selected from hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, -S(=O)2OH, -S(=O)OH and -P(=O)(OH)2; and X is -S(=O)2OH, -S(=O)OH or -P(=O)(OH)2; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 1 , R 2 , R 3 , R 4 and R 5 Each is independently selected from hydrogen, hydroxy, methyl and methoxy.

3. The compound according to claim 1 or 2, wherein R 1 , R 2 and R 5 Each is a methyl group, R 3 is methoxy and R 4 For hydrogen.

4. A compound according to any one of claims 1 to 3, wherein R 6 It is methyl, 2-hydroxyethyl, cyclohexyl, prop-2-enoyl, 1,1-bis(hydroxymethyl)-2-hydroxyethyl or aminocarbonylmethyl.

5. A compound according to any one of claims 1 to 4, wherein R 7 For-(CR 8A R 8B ) n -X, where n is an integer of 2 or 3, and where R 8A and R 8B are each independently selected from hydrogen and hydroxy.

6. A compound according to any one of claims 1 to 4, wherein R 7 is benzyl-X, and wherein the benzyl group is additionally substituted by an amino group.

7. A compound according to any one of claims 1 to 4, wherein R 7 is cyclohexyl-methyl-X.

8. A compound according to any one of claims 1 to 4, wherein R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a piperidine ring or a piperazine ring, which is substituted by ethyl-X, phenyl-X or benzoyl-X.

9. A compound according to any one of claims 1 to 8, wherein X is -S(=0)2OH.

10. The compound according to claim 1, which is selected from the following: ; ; ; ; ; ; ; ; ; and ; or a pharmaceutically acceptable salt thereof.

11. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10.

12. The pharmaceutical composition according to claim 11, further comprising an active pharmaceutical ingredient.

13. The pharmaceutical composition of claim 12, wherein the active pharmaceutical ingredient is a hydrophobic drug.

14. The pharmaceutical composition according to claim 12, wherein the active pharmaceutical ingredient is a cytotoxic drug, preferably selected from docetaxel, paclitaxel, cabazitaxel, doxorubicin and mitoxantrone.

15. The pharmaceutical composition according to any one of claims 12 to 14, wherein at least one compound according to any one of claims 1 to 10 and the active pharmaceutical ingredient form micelles.

16. A drug micelle comprising at least one compound according to any one of claims 1 to 10 and a drug.

17. The drug micelle according to claim 16, wherein the drug is a cytotoxic drug, preferably selected from docetaxel, paclitaxel, cabazitaxel, doxorubicin and mitoxantrone.

18. The pharmaceutical composition according to claim 14 or the pharmaceutical micelle according to claim 17, for use in treating cancer.

19. A method for enhancing the efficacy of a pharmaceutically active substance, wherein the substance is prepared in micellar form using a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

20. A method for increasing the solubility of a pharmaceutically active substance, wherein the substance is prepared in micellar form using a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

21. A method for improving the pharmacokinetic or pharmacodynamic properties of a pharmaceutically active substance, wherein the substance is prepared in micellar form using a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

22. A method for improving the storage properties of a pharmaceutically active substance, wherein the substance is prepared in the form of micelles using a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

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