Use of thienopyridone derivatives in treating autosomal dominant polycystic kidney disease ADPKD

Abstract

The present invention relates to use of a thienopyridone derivative or a pharmaceutical composition containing the same in treating autosomal dominant polycystic kidney disease (ADPKD).

Description

Technical Field

[0001] The present invention relates to the use of thienopyridone derivatives in treating autosomal dominant polycystic kidney disease (ADPKD). Background Art

[0002] Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic inherited kidney disease, with an individual incidence of 1 in 500 to 1 in 1,000 (P. Igarashi et al., J. Am. Soc. Nephrol., 13 (9), 2384-2398, 2002). Mutations in the PKD1 and PKD2 genes encoding polycystin-1 and polycystin-2 cause 85% and 15% of ADPKD cases, respectively. ADPKD is characterized by the progressive development and growth of a large number of cysts in both kidneys, leading to many abnormalities, such as acute and chronic pain, kidney stones and urinary tract infections, the most important of which is loss of renal function. About 70% of ADPKD patients progress to end-stage renal disease (ESRD) at a median age of 58 years (EMSpithoven et al., Kidney Int., 86 (6), 1244-1252, 2014).

[0003] Many therapies have been proposed for ADPKD, targeting various signaling pathways that drive cyst growth. They include vasopressin receptor inhibitors such as Tolvaptan, somatostatin analogs such as Octreotide and Lanreotide, Pravastatin, and tyrosine kinase inhibitors such as Tesevatinib. Among them, Tolvaptan is the first drug treatment approved by the FDA to slow the decline of renal function in adults at risk of rapidly progressive ADPKD. However, due to its potential hepatocellular toxicity, Tolvaptan requires frequent monitoring of liver function in patients treated with it. These compounds target one of the key processes (proliferation or secretion) believed to be involved in the pathogenesis of ADPKD.

[0004] Recently, it has been shown that the cystic fibrosis transmembrane conductance regulator (CFTR), which is involved in the secretion of cystic fluid, and the mammalian target of rapamycin (mTOR) pathway, which can drive the proliferation of cystic epithelial cells, may both be negatively regulated by AMP-activated protein kinase (AMPK). Therefore, AMPK activators can simultaneously target these two key processes of ADPKD. In this case, it is recommended to use the known AMPK indirect activator metformin to simultaneously inhibit the secretory and proliferative components of cyst expansion, thereby slowing down the formation of renal cysts (V. Takiar et al., PNAS, Vol. 108, No. 6, 2462-2467, 2011). However, metformin is known to cause lactic acidosis as a side effect. Since metformin is cleared by the kidneys, chronic kidney disease is considered a potential cause of this complication. In addition, it is worried that therapeutic AMPK activation of metformin in human kidneys may require high oral doses of metformin, at least because of its reduced bioavailability.

[0005] It has been suggested that, in addition to metformin, other AMPK activators may also be used to treat ADPKD. Thus, WO2017 / 011917 discloses a number of thienopyridones defined by broad chemical formulas, but does not describe how they can be synthesized and which specific compounds are included.

[0006] Recently, salsalate, a prodrug dimer of salicylate and a direct AMPK activator, was shown to be more effective than metformin in reducing the severity of cystic kidney disease in mutant mice (WN Lehnard et al., EBioMedicine, Vol. 47, 436-445, 2019). Salsalate activates AMPK by directly interacting with the drug binding domain of the AMPKβ1 isoform. However, despite the better bioavailability of salsalate compared to metformin, the oral dose required to provide a therapeutic effect is still high.

[0007] Therefore, there remains a need for alternative compounds that would be useful for treating ADPKD at lower dosages and / or with greater efficacy and / or reduced side effects than compounds proposed for this purpose.

[0008] The inventors have now shown that specific thienopyridone derivatives can be used to treat ADPKD at lower oral doses than other AMPK activators. These compounds are broadly disclosed as AMPK activators in WO 2014 / 001554, but so far there has been no suggestion of their use in treating ADPKD. They have been shown to be direct activators of various AMPK isoforms, including the β1 subunit. Summary of the invention

[0009] The present invention relates to a thienopyridone derivative represented by formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same, and use thereof in treating ADPKD:

[0010]

[0011] in:

[0012] R1 represents a hydrogen atom or a halogen atom,

[0013] R2 represents an indanyl or tetrahydronaphthyl group which may be substituted or unsubstituted by one or more (e.g. 2, 3, 4, 5, 6 or 7) groups selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, amino groups, mono- or di-alkylamino groups, carboxyl groups, alkoxycarbonyl groups, mono- or di-alkylaminocarbonyl groups, formamide, cyano groups, alkylsulfonyl groups and trifluoromethyl groups,

[0014] R3 represents an aryl group which may be substituted or unsubstituted by one or more (e.g. 2, 3, 4 or 5) atoms or groups selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, aralkyloxy groups, amino groups, mono- or di-alkylamino groups, carboxyl groups, alkoxycarbonyl groups, mono- or di-alkylaminocarbonyl groups, formamide, cyano groups, alkylsulfonyl groups and trifluoromethyl groups.

[0015] The present invention also relates to a method for treating ADPKD, comprising administering to a subject in need thereof an effective amount of the thienopyridone derivative as described above, or a pharmaceutical composition comprising an effective amount of the thienopyridone derivative as described above and a pharmaceutically acceptable support.

[0016] The present invention also relates to the use of the thienopyridone derivative as described above or a pharmaceutical composition comprising the same in the manufacture of a drug for treating ADPKD. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Shown are the volumes of cysts formed by pIMDCK cells in the presence of 10 μM, 100 μM and 1 mM metformin or 10 μM, 25 μM or 50 μM PXL770 compared to control medium.

[0018] Figure 2 Shown are photographs of cysts formed by pIMDCK cells in the presence of 10 μM, 100 μM and 1 mM metformin or 10 μM, 25 μM or 50 μM PXL770.

[0019] Figure 3Shown are the results of in vitro experiments evaluating the efficacy of various thienopyridones of the present invention compared to similar compounds on cyst enlargement. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition

[0022] As used herein, the following terms, unless expressly stated otherwise, have the following meanings.

[0023] The term "halogen atom" refers to an atom selected from fluorine, chlorine, bromine and iodine atoms.

[0024] The term "alkyl group" refers to a straight or branched saturated chain of 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. Preferably, the alkyl group is a straight or branched saturated chain of 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl groups.

[0025] The term "aryl group" refers to a C6-C18 aromatic group, such as a phenyl or naphthyl group, which may be optionally substituted by one or more atoms or groups selected from halogen atoms, alkyl groups, hydroxyl groups (OH), alkoxy groups, amino groups (NH2), mono- or di-alkylamino groups, carboxyl groups (COOH), alkoxycarbonyl groups, mono- or di-alkylaminocarbonyl groups, formamide (CONH2), cyano groups (CN), alkylsulfonyl groups and trifluoromethyl groups (CF3). More specifically, the aryl group may be substituted by fluorine, chlorine, bromine atoms, hydroxyl groups, methoxy groups, ethoxy groups, amino groups, dimethylamino groups, diethylamino groups, methyl groups, ethyl groups, n-propyl groups, n-butyl groups, isopropyl groups, sec-butyl groups, isobutyl groups, tert-butyl groups, carboxyl groups, methoxycarbonyl groups, ethoxycarbonyl groups, formamide groups, dimethylaminocarbonyl groups, methylaminocarbonyl groups, cyano groups, mesyl groups or trifluoromethyl groups.

[0026] The term "aralkyl group" refers to an alkyl group as defined above whose hydrogen atoms are replaced by aryl groups as defined above. An example of an aralkyl group is a benzyl group.

[0027] The term "alkoxy" group refers to an alkyl group as defined above which is linked to the rest of the molecule via an oxygen atom. Among the alkoxy groups that may be mentioned are the methoxy and ethoxy groups.

[0028] The term "aralkyloxy" group refers to an aralkyl group as defined above which is linked to the rest of the molecule via an oxygen atom. Among the aralkyloxy groups that may be mentioned is the benzyloxy group.

[0029] The term "alkylamino group" means an alkyl group as defined above which is linked to the rest of the molecule via a nitrogen atom. Among the alkylamino groups, mention may be made of the dimethylamino and diethylamino groups.

[0030] The term "alkoxycarbonyl group" refers to an alkoxy group as defined above which is attached to the rest of the molecule via a carbonyl group.

[0031] The term "alkylaminocarbonyl group" refers to an alkylamino group as defined above which is attached to the rest of the molecule via a carbonyl group.

[0032] The term "alkylsulfonyl" refers to an alkyl group as defined above which is linked to the rest of the molecule via a SO2 group. Among the alkylsulfonyl groups, mention may be made of the methylsulfonyl and ethylsulfonyl groups.

[0033] "Solvates" of compounds are understood within the context of the present invention to be adducts of inert solvent molecules onto the compounds which form due to their mutual attractive forces. Solvates are, for example, hydrates or alcoholates.

[0034] The present invention relates to a thienopyridone derivative of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same, for use in treating ADPKD.

[0035]

[0036] in:

[0037] R1 represents a hydrogen atom or a halogen atom,

[0038] R2 represents an indanyl or tetrahydronaphthyl group which may be substituted or unsubstituted by one or more (e.g. 2, 3, 4, 5, 6 or 7) groups selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, amino groups, mono- or di-alkylamino groups, carboxyl groups, alkoxycarbonyl groups, mono- or di-alkylaminocarbonyl groups, formamide, cyano groups, alkylsulfonyl groups and trifluoromethyl groups,

[0039] R3 represents an aryl group which may be substituted or unsubstituted by one or more (e.g. 2, 3, 4 or 5) atoms or groups selected from halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, aralkyloxy groups, amino groups, mono- or di-alkylamino groups, carboxyl groups, alkoxycarbonyl groups, mono- or di-alkylaminocarbonyl groups, formamide, cyano groups, alkylsulfonyl groups and trifluoromethyl groups.

[0040] Examples of pharmaceutically acceptable salts of the compound of formula (I) can be obtained by reacting the compound of formula (I) with various organic and inorganic bases to produce corresponding base addition salts by procedures generally known in the art. Such bases are, for example: alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkali metal carbonates, including potassium carbonate and sodium carbonate; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkaline earth metal carbonates; alkali metal alkoxides, such as potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutamine. Aluminum salts of the compound of formula (I) are also included.

[0041] Therefore, the salt of the compound of formula (I) includes aluminum salts, ammonium salts, calcium salts, copper salts, iron (III) salts, iron (II) salts, lithium salts, magnesium salts, manganese (III) salts, manganese (II) salts, potassium salts, sodium salts and zinc salts, but this is not intended to represent a limitation. Among the above-mentioned salts, preferred are mono-, di- and tri-sodium or potassium salts, most preferably potassium salts.

[0042] Any pharmaceutically acceptable salt of the compound of formula (I), or the compound itself, can be used in the present invention in the form of one of its solvates. The "solvate" of a compound refers to an adduct formed by inert solvent molecules on the compound due to their mutual attraction in the present invention. Therefore, the properties of the solvate depend on the solvent used during the reaction of the base with the compound of formula (I). Examples of solvates include alcohol solvates, such as methanol or ethanol solvates, and hydrates, including mono-, di-, tri- or tetrahydrates, but this is not intended to represent a limitation.

[0043] In a specific embodiment, at least one of the following conditions is met, preferably all of the following conditions are met:

[0044] R1 represents a halogen atom, especially a chlorine atom,

[0045] R2 is unsubstituted or substituted by 1 or 2 substituents containing at least one hydroxyl group,

[0046] R2 is a tetrahydronaphthyl group,

[0047] R3 represents a phenyl group which is unsubstituted or substituted by 1 or 2 substituents,

[0048] The compound of formula (I) is in the form of a salt, preferably a sodium salt or a potassium salt, more preferably a potassium salt,

[0049] The compound of formula (I) is in the form of a solvate, preferably a hydrate, more preferably a monohydrate.

[0050] More preferably, at least one of the following conditions is met, preferably all of the following conditions are met:

[0051] R1 represents a halogen atom, especially a chlorine atom,

[0052] R2 is substituted by 1 or 2 substituents containing at least one hydroxyl group,

[0053] R2 is a tetrahydronaphthyl group,

[0054] R3 represents an unsubstituted phenyl group,

[0055] The compound of formula (I) is in the form of a salt, preferably a sodium salt or a potassium salt, more preferably a potassium salt,

[0056] The compound of formula (I) is in the form of a solvate, preferably a hydrate, more preferably a monohydrate.

[0057] In another embodiment, at least one of the following conditions is met, preferably all of the following conditions are met:

[0058] R1 represents a halogen atom, especially a chlorine atom,

[0059] R2 is substituted by 1 or 2 substituents containing at least one hydroxyl group,

[0060] R2 is an indanyl group,

[0061] R3 represents a phenyl group which is unsubstituted or substituted by 1 or 2 substituents.

[0062] Examples of the thienopyridone derivatives of the present invention are as follows:

[0063] 2-Chloro-4-hydroxy-3-indan-5-yl-5-phenyl-7H-thieno[2,3-b]pyridin-6-one

[0064] 2-Chloro-5-(4-fluorophenyl)-4-hydroxy-3-indan-5-yl-7H-thieno[2,3-b]pyridin-6-one

[0065] 2-Chloro-4-hydroxy-3-indan-5-yl-5-(3-methoxyphenyl)-7H-thieno[2,3-b]pyridin-6-one

[0066] 2-Chloro-4-hydroxy-3-indan-5-yl-5-(4-methoxyphenyl)-7H-thieno[2,3-b]pyridin-6-one

[0067] 3-(2-Chloro-4-hydroxy-3-indan-5-yl-6-oxo-7H-thieno[2,3-b]pyridin-5-yl)benzonitrile

[0068] 2-Chloro-4-hydroxy-3-indan-5-yl-5-(3-methylphenyl)-7H-thieno[2,3-b]pyridin-6-one

[0069] 2-Chloro-5-(4-fluorophenyl)-4-hydroxy-3-(4-hydroxyindan-5-yl)-7H-thieno[2,3-b]pyridin-6-one

[0070] 2-Chloro-5-(3-fluorophenyl)-4-hydroxy-3-(4-hydroxyindan-5-yl)-7H-thieno[2,3-b]pyridin-6-one

[0071] 2-Chloro-4-hydroxy-3-(4-hydroxyindan-5-yl)-5-phenyl-7H-thieno[2,3-b]pyridin-6-one

[0072] 2-Chloro-5-(2-fluorophenyl)-4-hydroxy-3-(4-hydroxyindan-5-yl)-7H-thieno[2,3-b]pyridin-6-one

[0073] 2-Chloro-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-5-phenyl-7H-thieno[2,3-b]pyridin-6-one

[0074] 3-(2-Chloro-4-hydroxy-6-oxo-3-tetrahydronaphthalen-6-yl-7H-thieno[2,3-b]pyridin-5-yl)benzonitrile

[0075] 2-Chloro-3-(5-oxotetralin-6-yl)-5-phenyl-thieno[2,3-b]-4,6-dihydroxypyridine trisodium

[0076] 2-Chloro-4-hydroxy-5-phenyl-3-tetrahydronaphthalen-6-yl-7H-thieno[2,3-b]pyridin-6-one

[0077] 2-Chloro-5-(4-fluorophenyl)-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-7H-thieno[2,3-b]pyridin-6-one

[0078] Disodium 2-chloro-3-(5-oxotetralin-6-yl)-6-oxo-5-phenyl-7H-thieno[2,3-b]-4-hydroxypyridine

[0079] 2-Chloro-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-5-(3-methylphenyl)-7H-thieno[2,3-b]pyridin-6-one

[0080] 2-Chloro-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-5-(4-methylphenyl)-7H-thieno[2,3-b]pyridin-6-one

[0081] 2-Chloro-5-(3-fluorophenyl)-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-7H-thieno[2,3-b]pyridin-6-one

[0082] Sodium 2-chloro-3-(5-hydroxytetrahydronaphthalen-6-yl)-6-oxo-5-phenyl-7H-thieno[2,3-b]-4-hydroxypyridine

[0083] Potassium 2-chloro-3-(5-hydroxytetralin-6-yl)-6-oxo-5-phenyl-7H-thieno[2,3-b]-4-hydroxypyridine.

[0084] The compounds of formula (I) can generally be prepared as disclosed in WO 2014 / 001554.

[0085] Examples of such compounds include:

[0086] PXL770, which is 2-chloro-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-5-phenyl

[0087] -7H-thieno[2,3-b]pyridin-6-one monohydrate potassium salt, corresponding to the structure of the following formula (Ia):

[0088]

[0089] ·2-Chloro-5-(3-fluorophenyl)-4-hydroxy-3-(4-hydroxyindan-5-yl)-7H-thieno

[0090] [2,3-b]pyridin-6-one having formula (Ib):

[0091]

[0092] 2-Chloro-4-hydroxy-3-(4-hydroxyindan-5-yl)-5-phenyl-7H-thieno[2,3-b]pyridin-6-one, having the formula (Ic):

[0093]

[0094] PXL770 can be prepared according to a method comprising the following steps:

[0095] (A) reacting a compound of formula (II) with potassium carbonate in a solution comprising water and a solvent selected from n-butyl acetate and isopropanol:

[0096]

[0097] (B) forming a precipitate; and

[0098] (C) recovering the precipitate obtained in step (B), preferably by filtration.

[0099] The compound of formula (II) and its preparation method have been disclosed in patent application WO 2014 / 001554.

[0100] Alternatively, the compound of formula (II) can be obtained by an improved method comprising the following steps:

[0101] (a) reacting 6-acetyl-5-hydroxytetralin with an electrophilic benzyl source, preferably benzyl bromide, in the presence of a base;

[0102] (b) reacting the compound obtained in step (a) with ethyl cyanoacetate in the presence of hexamethyldisilazane and acetic acid;

[0103] (c) reacting the compound obtained in step (b) with sulfur in the presence of a base;

[0104] (d) optionally forming a salt, preferably a hydrochloride, of the compound obtained in step (c);

[0105] (e) reacting the compound obtained in step (c) or (d) with an electrophilic chlorine source, preferably N-chlorosuccinimide;

[0106] (f) reacting the compound obtained in step (e) with phenylacetyl chloride;

[0107] (g) reacting the compound obtained in step (f) with a base;

[0108] (h) reacting the compound obtained in step (g) with boron tribromide or boron trichloride, preferably boron trichloride; and

[0109] (i) optionally recovering the compound obtained in step (h).

[0110] Typically, step (B) may comprise a sub-step (b1) of heating the mixture obtained in step (A), preferably at a temperature close to the reflux of the mixture, followed by a sub-step (b2) of cooling the resulting mixture, for example at a temperature between -15° C. and 35° C. The expression “close to the reflux of the mixture” typically refers to a temperature between 90% and 100% of the boiling point of the solvent system (e.g., water / isopropanol or water / n-butyl acetate) in step (A).

[0111] A distillation step may be carried out between the heating sub-step and sub-step (b2), preferably under reduced pressure.

[0112] Step (B) allows for the formation of a crystalline precipitate, which formation may be facilitated or triggered by the addition of seeds to step (b2).

[0113] In a preferred embodiment, the precipitate is recovered by filtration in step (C). It may then be washed successively with one or more solvents, preferably water, n-butyl acetate and / or tert-butyl methyl ether.

[0114] The compound of formula (Ia) is thus obtained in solid form, for example in powder form, namely PXL770, which has the following XRPD (X-ray powder diffraction) peaks measured by a diffractometer using Cu K (α) radiation:

[0115]

[0116] In the following description, the term "thienopyridone derivative" refers to the compound of formula (I), or one of its pharmaceutically acceptable salts and / or solvates.

[0117] One object of the present invention is a method for treating autosomal dominant polycystic kidney disease (ADPKD), which comprises administering to a subject in need thereof an effective amount of a thienopyridone derivative or a pharmaceutical composition comprising an effective amount of a thienopyridone derivative and a pharmaceutically acceptable support.

[0118] The present invention also relates to the use of the thienopyridone derivative or a composition containing the thienopyridone derivative in the manufacture of a drug for treating autosomal dominant polycystic kidney disease (ADPKD).

[0119] The pharmaceutical compositions used according to the invention can be prepared by any conventional method. The thienopyridone derivatives can be converted into a suitable dosage form together with at least one solid, liquid and / or semi-liquid excipient or adjuvant and, if necessary, in combination with one or more other active ingredients.

[0120] The term "pharmaceutically acceptable support" refers to a carrier, adjuvant or excipient that is acceptable to subjects from a pharmacological / toxicological point of view, and to a pharmaceutical chemist from a physical / chemical point of view with respect to composition, formulation, stability, subject acceptance and bioavailability.

[0121] The term "carrier", "adjuvant" or "excipient" refers to any substance added to a pharmaceutical composition as a carrier, adjuvant and / or diluent to deliver a therapeutic agent to a subject, which is not a therapeutic agent itself, but is added to improve the handling or storage properties of the therapeutic agent, or to enable or facilitate the formation of dosage units of the composition into discrete products. The pharmaceutical composition of the present invention, alone or in combination, may contain one or more agents or media selected from dispersants, solubilizers, stabilizers, preservatives, etc.

[0122] The term "treatment" refers to the treatment, prevention and prophylaxis of autosomal dominant polycystic kidney disease (ADPKD). The term "treatment" as disclosed herein refers to the prevention of a disease or at least one symptom thereof. This also means improving, preventing at least one measurable physical parameter associated with the disease being treated, which parameter is perceptible or unperceptible in the subject. The term "treatment" also refers to inhibiting or slowing the progression of the disease in the body, stabilizing physiologically perceptible symptoms, such as stabilizing physical parameters, or both. The term "treatment" also refers to delaying the onset of a disease or condition. In some specific embodiments, the compounds of the present invention are administered as a preventive measure. In this context, "prevention" refers to reducing the risk of at least one symptom associated with the disease.

[0123] The term "treatment" may include preventing or limiting cyst growth with a thienopyridone derivative or a pharmaceutical composition comprising it. "Treatment" as used herein also encompasses reducing cyst volume. Thus, the term "treatment" includes treatment of symptoms associated with ADPKD.

[0124] The treatment involves administering the thienopyridone derivative or pharmaceutical composition of the present invention to a subject suffering from the declared disorder to cure, delay or slow the progression, thereby improving the patient's condition.

[0125] In the context of the present invention, the term "subject" refers to mammals, more particularly humans. The subject to be treated of the present invention can be appropriately selected based on several criteria associated with the disease. In the case of ADPKD, the treatment is more particularly suitable for patients with at least one mutation in PKD1 and / or PKD2 genes or patients at risk of ADPKD. "AdPKD risk" patients include patients with three or more unilateral or bilateral renal cysts, patients with two or more cysts in each kidney at the age of 40-59 years old and 60 years old or more and patients with four or more cysts in each kidney as detected by ultrasonography. Alternatively, patients aged 30 or less and with at least ten renal cysts are generally considered to have an ADPKD risk by magnetic resonance imaging.

[0126] The pharmaceutical composition may be administered in the form of dosage units, each dosage unit containing a predetermined effective amount of an active ingredient.

[0127] The pharmaceutical composition can be suitable for administration by any desired suitable method, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such compositions can be prepared by, for example, combining the active ingredient with an excipient or adjuvant using all methods known in the pharmaceutical art. Preferably, the pharmaceutical composition of the present invention is suitable for oral administration.

[0128] Pharmaceutical compositions suitable for oral administration can be administered as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or emulsions, such as oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0129] Thus, for example, in the case of oral administration in tablet or capsule form, the active ingredient components may be combined with an oral non-toxic and pharmaceutically acceptable inert excipient. Powders are prepared by pulverizing the compound to a suitable fine size and mixing it with a similarly pulverized pharmaceutical excipient, such as an edible carbohydrate, such as starch or mannitol. Flavoring agents, preservatives, dispersants and dyes may also be present.

[0130] Capsules can be produced by preparing a powder mixture as described above and filling a shaped gelatin shell with it. Before the filling operation, glidants and lubricants such as highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture. Disintegrants or solubilizers such as agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the drug after the capsule is taken.

[0131] In addition, if desired or necessary, suitable binders, lubricants and disintegrating agents and dyes can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrating agents include but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum, etc. Tablets are prepared, for example, as described below: prepare a powder mixture, granulate the mixture or dry press, add lubricants and disintegrating agents, and compress the entire mixture to produce tablets. Powder mixture is prepared as follows: the compound crushed in a suitable manner is mixed with a diluent or alkali as described above, and optionally mixed with a binder such as carboxymethyl cellulose, alginate, gelatin or polyvinyl pyrrolidone, a dissolution delay agent such as paraffin, an absorption promoter such as a quaternary salt, and / or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, gum arabic, or a cellulose or polymer material solution and pressing it through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet press to produce unevenly shaped blocks, which are broken to form particles. The particles can be lubricated by adding stearic acid, stearate, talcum powder or mineral oil to prevent sticking to the tablet casting mold. Then the lubricated mixture is pressed to produce tablets. The compound of the present invention can also be combined with a free-flowing inert excipient, and then the granulation or dry pressing step is not performed, and the tablet is directly pressed to produce a tablet. There can be a transparent or opaque protective layer consisting of a shellac sealing layer, a sugar or polymer material layer and a wax gloss layer. Dyestuffs can be added to these coatings to allow for differentiation between different dosage units.

[0132] Pharmaceutical compositions suitable for oral administration may also be formulated by spray-drying of solid or liquid dispersions.

[0133] Oral liquids, such as solutions, syrups and elixirs, can be prepared in dosage unit form so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with suitable flavoring agents, while elixirs are prepared using non-toxic alcoholic media. Suspensions can be prepared by dispersing the compound in a non-toxic medium. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, etc. can also be added.

[0134] If desired, dosage unit formulations for oral administration can be encapsulated in microcapsules. The formulations can also be prepared in a manner to prolong or delay the release, for example, by coating or embedding particulate materials in polymers, waxes, etc.

[0135] The thienopyridone derivatives used according to the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholine.

[0136] "Effective amount" refers to the amount of the compound as defined above that prevents, eliminates or reduces the harmful effects of the disease being treated in humans. It should be understood that those skilled in the art can adjust the dosage according to the patient, pathology, mode of administration, etc. For example, the thienopyridone derivative can be administered once or twice a day, and the daily dose for human patients is 0.5 mg to 300 mg, preferably 20 mg to 1000 mg, and more preferably 60 mg to 500 mg. It can be administered as a long-term drug for 4, 5, 6 or 7 days a week.

[0137] In a particular embodiment of the present invention, the thienopyridone derivative is administered in a dosage unit comprising 0.5 mg to 1500 mg, preferably 20 mg to 1000 mg, more preferably 60 mg to 500 mg of the thienopyridone derivative.

[0138] The present invention will be described in more detail in the following examples, which are not intended to limit the scope of the present invention, which is defined by the claims. DETAILED DESCRIPTION

[0139] Embodiment 1: Synthesis of PXL770

[0140] Analytical methods

[0141] XRPD

[0142] X-ray powder diffraction (XRPD) analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu (Kα radiation) X-ray tube and a Pixcel detector system. Samples were analyzed in transmission mode and sandwiched between low-density polyethylene films. XRPD patterns were classified, manipulated, and indexed using HighScore Plus 2.2c software.

[0143] TG / DTA

[0144] Thermogravimetric (TG) analysis was performed on a Perkin Elmer Diamond Thermogravimetric / Differential Temperature Analyzer (TG / DTA). The calibration standards were indium and tin. The samples were placed in an aluminum sample pan, inserted into a TG furnace and accurately weighed. The samples were heated from 30°C to 300°C at a rate of 10°C / min in a nitrogen stream. The furnace temperature was equilibrated at 30°C before analyzing the samples.

[0145] 1a) Synthesis of 1-(5-benzyloxytetralin-6-yl)ethanone (1)

[0146]

[0147] 6-Acetyl-5-hydroxytetralin (100 g, 1 eq.) was dissolved in acetonitrile (300 mL). After adding K2CO3 (1.1 eq.) and benzyl bromide (1.05 eq.), the suspension was heated (76°C). After 48 hours, benzyl bromide (0.1 eq.) was added. After a total of 74 hours, the solid was filtered off and washed with acetonitrile (200 mL), and the combined filtrate was evaporated.

[0148] Compound 1 was obtained as a syrup: m = 148.6 g, quantitative yield, purity 96.6% a / a.

[0149] 1b) Synthesis of ethyl 2-amino-4-(5-benzyloxytetralin-6-yl)thiophene-3-carboxylate (2)

[0150]

[0151] Acetic acid (70 mL) was heated to T = 65°C. HMDS (1.5 eq.) was added over 10 minutes. Then, a solution of compound 1 (69.5 g, 1 eq.) and ethyl cyanoacetate (1.5 eq.) in acetic acid (140 mL) was added. The resulting mixture was stirred at T = 65°C for 24 hours.

[0152] After cooling to room temperature, NaOH aqueous solution (1 M, 140 mL) and TBME (210 mL) were added. The layers were separated. The organic layer was washed with NaOH aqueous solution (1 M, 4×140 mL) until the pH of the aqueous phase was basic (pH=13). The organic layer was washed with HCl aqueous solution (1 M, 140 mL) and H2O (2×140 mL).

[0153] EtOH (240 mL), NaHCO3 (1.3 eq.) and sulfur (1.0 atomic equivalent) were added. After heating to reflux for 180 min, the reaction mixture was concentrated to 210 mL and co-evaporated with TBME (3×140 mL). After cooling to room temperature, the suspension was filtered and the solids were washed with TBME (70 mL). The combined filtrate was concentrated to 210 mL and distilled water was added dropwise at room temperature. A solution of 1.1 eq. of heptane was added. A precipitate was observed after inoculation. Heptane (350 mL) was added dropwise at room temperature. After stirring for 14 hours, the suspension was filtered. After washing with heptane (3×70 mL) and drying, compound 2 was recovered as a solid. m=83.2 g, yield 71%, purity 93.7% a / a.

[0154] 1c) 4-(5-Benzyloxytetralin-6-yl)-5-chloro-2-[(2-phenylacetyl)amino]thiophene-3-carboxylic acid ethyl Synthesis of ester (3)

[0155]

[0156] Compound 2 (17.69 g, 1 eq.) was dissolved in dichloromethane (140 mL). The resulting solution was cooled with ice / water. N-chlorosuccinimide (1.05 eq.) was added under stirring. The mixture turned black within a few minutes. After 1 hour, phenylacetyl chloride (1.25 eq.) was added.

[0157] After 1 hour at 0°C and 2 hours at room temperature, the mixture was evaporated to about 35 mL, EtOH (2×70 mL) was added, and evaporated again. The mixture was diluted with EtOH (35 mL) and cooled with ice / water. The product precipitated. The solid was filtered off and washed with cold EtOH (3×18 mL).

[0158] Compound 3 was obtained as a solid: m=20.99 g, yield 94.2%, purity 99.3% a / a.

[0159] 1d) 3-(5-Benzyloxytetralin-6-yl)-2-chloro-4-hydroxy-5-phenyl-7H-thieno Synthesis of [2,3-b]pyridin-6-one (4)

[0160]

[0161] Compound 3 (19.88 g, 1 eq.) was dissolved in methyltetrahydrofuran (120 mL), and the reaction mixture was cooled to a temperature between -16°C and -10°C (NaCl / ice). Potassium tert-butoxide (5 eq.) was added in four portions. The reaction mixture was then warmed to room temperature and stirred at room temperature for 65 minutes. 2N HCl (5 eq.) was added dropwise at T = 0-5°C (water / ice), and the resulting mixture was stirred vigorously. NaCl was added to obtain a 2.5-nitro-1H-pyrrolidone (1.5 eq.). (水溶液)(11%, 1×50 mL) and water (2×50 mL) were used to wash the organic phase. The organic phase was concentrated to a ~50% solution. Methyltetrahydrofuran (80 mL) was added and the resulting solution was concentrated to a ~50% solution. TBME (100 mL) was added and the resulting solution was concentrated to a ~50% solution (this step was repeated 3 times). Then, TBME (25 mL), seeds of compound 4 and n-heptane (20 mL) were added and the resulting solution was stirred at room temperature overnight. The mixture was concentrated to about 50 mL, filtered, rinsed with mother liquor, washed with n-heptane (2×40 mL) and dried. Compound 4 was obtained as a granular solid. Yield 88%, purity 99.5% a / a.

[0162] 1e) 2-Chloro-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-5-phenyl-7H-thieno[2,3-b]pyridine-6-yl Synthesis of Ketone (I)

[0163]

[0164] Compound 4 (15 g, 1 eq.) was dissolved in 75 mL of dichloromethane and cooled to T = -10 ° C / -15 ° C (with ice / NaCl). BCl3 (1.5 eq., solution: 1 mol / L dichloromethane solution) was added dropwise and the resulting mixture was stirred at room temperature for 15 hours. The resulting mixture was cooled with ice / water, and water (75 mL) was added. The resulting mixture was stirred vigorously and the organic phase was extracted with water / MeOH (9: 1 v / v, 5 × 45 mL). The organic phase was concentrated, solvent exchanged with toluene (3 × 90 mL) and diluted with toluene to a final volume of 90 mL toluene. The resulting mixture was heated to reflux and 15 mL of methanol was added. A light brown solution with a few particles was obtained. Seed crystals were added at T = 40 ° C, warmed to T = 52 ° C and cooled to room temperature. The resulting mixture was stirred overnight and then cooled with ice / NaCl (T = -10 ° C / -15 ° C) for 100 minutes. The precipitated product was filtered off, washed with toluene / heptane 1:2 v / v (15 mL) and heptane (15 mL) and dried to obtain crystals of compound (I): yield 87%, purity 99.0% a / a.

[0165] 1f) 2-Chloro-4-hydroxy-3-(5-hydroxytetrahydronaphthalen-6-yl)-5-phenyl-7H-thieno[2,3-b]pyridine-6-yl Synthesis of the monohydrated potassium salt of ketone (Ia)

[0166] Compound (I) is suspended in a water / isopropanol mixture (1 / 1, 5 parts of each solvent), and then 0.50 to 0.55 eq of potassium carbonate is added. The pH at the end of the addition of potassium carbonate is about 12 (pH test paper). After stirring at 50°C for 3 hours, the suspension thickens and the pH is about 8 (pH test paper). The temperature is raised to 80°C until a solution is obtained (10-15 minutes). If necessary, clarification can be performed at this point in the process. 7 parts of water are added, and the reaction mixture is then cooled to 40°C (a turbid solution is observed). The solvent is distilled under reduced pressure at 40°C (from 180 mbar to 40 mbar) until 7 parts of solvent remain in the reactor. Crystallization of potassium salt monohydrate can occur at this time. 4.2 parts of water are added, and the mixture is seeded with compound (I) (1 to 2% of seeds). The suspension is then cooled from 40°C to 5°C (5°C / hour) within 7 hours and maintained at 5°C for several hours. The suspension is filtered. The filter cake is washed twice with 1.42 parts of water. The collected solid was dried under vacuum at 40°C to give compound (Ia) in minimum 80% yield at the desired chemical purity (ie 98%+).

[0167] Embodiment 2: Characterization of PXL770

[0168] a) X-ray powder diffraction (XRPD) data of compound (Ia) showed that it was composed of crystalline material. The XRPD description of compound (Ia) is shown in Table 1.

[0169] Table 1

[0170]

[0171]

[0172] b) TG / DTA analysis showed an initial weight loss of 1.1% from 30-100°C, followed by a larger weight loss of 3% from 117-160°C due to the loss of bound water. The second weight loss was accompanied by a large endotherm, and the combined weight loss of 4% was close to the theoretical weight loss of the monohydrate (3.75% w / w). The compound decomposed above 240°C.

[0173] Example 3 : In vitro experiments

[0174] method:

[0175] plMDCK cells were cultured at 37°C, 21% O2 and 5% CO2 in modified MEM medium containing "Earl's balanced salt solution", 2mM L-glutamine, 10% heat shock inactivated FCS, 50IU / ml penicillin and 50μg / ml streptomycin. For cyst formation, plMDCK cells were trypsinized and dissolved in type I collagen suspension and then transferred to 24-well plates. Four wells were used for each condition and single experiment. Next, cell culture medium containing 10μM forskolin (control; Ctrl) or 10μM forskolin + a given concentration of metformin or 10μM forskolin + a given concentration of PXL770 was added. The experiment was performed for 5 days. Afterwards, pictures were taken at 4 different areas (0, 3, 6, and 9 o'clock) in each well using a Zeiss Primo Vert microscope with a Zeiss Axiocam 105 color camera (both Zeiss Microscopy GmbH, Jena, Germany). The diameter of the cysts was then measured in a blinded manner using ImageJ (V.1.48). Assuming the cysts were spherical, the formula 4 / 3πr 3 Calculate the volume. Calculate the mean value of all cysts for each condition and experiment. The control cyst volume was set as 100%. The results are shown in Figure 1 shown.

[0176] Photos of the cysts were also taken and Figure 2 Shown (scale bar: 100 μm).

[0177] result:

[0178] like Figure 1 and 2 As shown, PXL770 significantly inhibited cyst growth at a dose lower than that of metformin.

[0179] Example 4 : Comparative experiment

[0180] In this example, various thienopyridone compounds were compared in an in vitro experiment, namely:

[0181] PXL770: Potassium 2-chloro-3-(5-hydroxytetralin-6-yl)-6-oxo-5-phenyl-7H-thieno[2,3-b]-4-hydroxypyridine

[0182] PXL700: 2-Chloro-4-hydroxy-3-indan-5-yl-5-(3-pyridyl)-7H-thieno[2,3-b]pyridin-6-one

[0183] PXL702: 2-Chloro-4-hydroxy-3-(4-hydroxyindan-5-yl)-5-phenyl-7H-thieno[2,3-b]pyridin-6-one

[0184] PXL695: 2-Chloro-5-(3-fluorophenyl)-3-(4-hydroxyindan-5-yl)-7H-thieno[2,3-b]pyridin-6-one,

[0185] PXL037:

[0186]

[0187] To investigate the effects of these compounds, an in vitro 3D cyst enlargement assay using polycystic kidney disease (PKD) patient-derived primary cells embedded in a 3D culture matrix (referred to as the huPKD model) was employed. Cyst enlargement can be visualized and quantified by high-content microscopy.

[0188] method

[0189] 3D huPKD cyst enlargement assays have been performed using huPKD05 cells.

[0190] 3D culture and compound exposure: huPKD05 cells (PKD1 mutation: c.5622G>Ap.Trp1874*) were mixed with PrimCyst gel (OcellO BV). 15 μL of the cell-gel mixture was pipetted into a 384-well plate (Greiner μClear, Greiner Bio-One BV) using a CyBio Felix 96 / 250 automatic liquid dispenser (Analyik Jena AG). The gel-cell mixture was plated at a final cell density of 450 cysts per well. After the gel was polymerized at 37°C for 30 minutes, 33 μL of culture medium (without serum) was added to each well. The cells were grown in the gel for 24 hours, and then the cells were exposed to desmopressin (ddAVP) (Tocris), which stimulates cyst enlargement, and the following molecules PXL770, PXL037, PXL700, PXL695, PXL702 for a total of 48 hours.

[0191] Table 1: Overview of exposure conditions

[0192]

[0193] Sample processing: After 48 hours, the culture was fixed with 4% formaldehyde (Sigma Aldrich), permeabilized with 0.2% Triton-X100 (Sigma Aldrich) and stained with 0.25 μM rhodamine-phalloidin (Sigma Aldrich) and 0.1% Hoechst 33258 (Sigma Aldrich) in 1×PBS (Sigma Aldrich) for 2 days at 4°C in the dark. After fixation and staining, the plates were washed with 1×PBS, sealed with Greiner SilverSeal (Greiner Bio-One BV) and stored at 4°C before imaging.

[0194] Imaging and image analysis: Imaging was performed using a Molecular Devices ImageXpressMicro XLS (Molecular Devices) with a 4× NIKON objective. For each well, approximately 35 images were made in the z direction for both channels, capturing the entire z plane in each image. TM Image analysis was performed using OcellO software (OcellO BV). Cysts were segmented using detection of Hoechst-stained nuclei and rhodamine-phalloidin-stained cellular f-actin. Cyst area was determined by calculating the pixel (px) area of ​​each object in each focal plane. The average value for each well was taken and normalized between solvent control (0%) and stimulant only (100%). Statistics were performed using GraphPad Prism and plotted in GraphPad Prism 6 (GraphPad Software, La Jolla, CA).

[0195] result

[0196] The results of the above experiments are shown in Figure 3 .

[0197] Control conditions: A significance window was established between desmopressin (ddAVP) stimulation and no stimulation (solvent control, DMSO). Figure 1 )(ddAVP only compared with DMSO, p<0.0001)

[0198] PXL770, PXL695, PXL700, PXL702, and PXL037:

[0199] PXL770, PXL695, PXL700, PXL702 and PXL037 were tested at 4 concentrations: 10, 5, 2.5, 0.5 μM in the presence of ddAVP (2.5 μM).

[0200] PXL770 dose-dependently reduced cyst area, an effect that was significant at 5 and 10 μM compared to ddAVP alone, with PXL770 achieving a 50% reduction at both 5 and 10 μM (p<0.01 and p<0.05, respectively, compared to ddAVP alone). Figure 3 Not shown, but note that PXL770 provided a 75% reduction in cyst area at 25 μM (p<0.0001 compared to ddAVP alone).

[0201] PXL695 and PXL702 reduced cyst area in a dose-dependent manner.

[0202] In contrast, PXL037 and PXL700 showed no significant effect compared to ddAVP alone.

[0203] in conclusion

[0204] PXL770, PXL037, PXL770, PXL695, and PXL702 were evaluated in the huPKD cyst enlargement assay to investigate their efficacy in inhibiting desmopressin (ddAVP)-induced cyst enlargement.

[0205] PXL770 dose-dependently reduced cyst enlargement. 5 and 10 μM of PXL770 inhibited almost 50% of the induced enlargement.

[0206] Similar potency and efficacy were achieved with PXL695 and PXL702.

[0207] PXL037 and PXL700 had no effect on cyst area up to 10 μM.

Claims

1. Use of a compound of the following formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating autosomal dominant polycystic kidney disease ADPKD, 2. Use of a compound of the following formula (Ia) in the preparation of a medicament for treating autosomal dominant polycystic kidney disease ADPKD, 3. Use of a compound selected from the following formula (Ib), (Ic) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating autosomal dominant polycystic kidney disease ADPKD, 4. The use according to any one of claims 1 to 3, wherein the medicament is in the form of a dosage unit comprising 0.5 mg to 1500 mg of the compound.

5. The use according to any one of claims 1 to 3, wherein the medicament is for preventing or limiting cyst growth or reducing cyst volume in a subject suffering from ADPKD.

6. The use according to any one of claims 1 to 3, wherein the medicament is for oral administration.

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