Aldose reductase inhibitors for treating sorbitol dehydrogenase deficiency

Abstract

To provide methods for genetic and / or metabolic disorders that alter sorbitol metabolism or cause overproduction of sorbitol, such as SDH deficiency, hereditary neuropathy, etc., using aldose reductase inhibitors.SOLUTION: The present disclosure also relates to a method of reducing sorbitol accumulation in a subject having a sorbitol-dehydrogenase (SDH) deficiency, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Patent Application No. 63 / 019,186, filed May 1, 2020, and U.S. Patent Application No. 63 / 019,738, filed May 4, 2020, the entire contents of both of which are incorporated herein by reference. [Background technology]

[0002] background Sorbitol dehydrogenase (SDH) is a member of the medium-chain dehydrogenase / reductase protein family and is the second enzyme in the polyol pathway of glucose metabolism. In this pathway, when the glucose concentration in cells becomes too high, aldose reductase (AR) reduces glucose to sorbitol using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. Sorbitol is then oxidized to fructose by sorbitol dehydrogenase, which also uses nicotinamide adenine dinucleotide (NAD) as a cofactor (Tang et al., (2012), Frontiers in Pharmacology, 3;87). SDH is present in almost all mammalian tissues. It is expressed as

[0003] Sorbitol dehydrogenase (SDH) deficiency and other inherited deficiencies of enzymes involved in sorbitol metabolism or genetic conditions that increase sorbitol levels are characterized by damage to the eyes, central nervous system, and kidneys, among other things. SDH deficiency is a genetic condition characterized by an inability to break down sorbitol into fructose due to an enzyme deficiency. Sorbitol is a highly hydrophilic alcohol and does not readily diffuse across cell membranes, therefore, it accumulates within cells.

[0004] The clinical effects of SDH deficiency are due to the accumulation of sorbitol, which leads to osmotic swelling, altered membrane permeability, and also oxidative stress, thereby damaging tissues. Id. Indeed, excessive sorbitol formation has been linked to damage to the eye, central nervous system, and kidney. Id. For example, intracellular sorbitol accumulation due to elevated aldose reductase activity has been implicated in the development of various secondary complications of diabetes, such as cataracts, retinopathy, nephropathy, and neuropathy. Complications associated with sorbitol accumulation currently have no cure. Thus, there is a recognized unmet need for methods for the treatment and / or management of genetic and / or metabolic disorders that alter sorbitol metabolism or cause the overproduction of sorbitol. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Tang et al., (2012), Frontiers in Pharmacology, 3;87 Summary of the Invention [Means for solving the problem]

[0006] overview The present disclosure relates to a method for treating genetic disorders and / or metabolic disorders that alter sorbitol metabolism or cause excessive production of sorbitol, such as sorbitol dehydrogenase (SDH) deficiency, increased aldose reductase activity, fructokinase deficiency, etc. The method comprises administering a therapeutically effective amount of aldose reductase (AR) inhibitor to a subject in need thereof.Without wishing to be bound by any particular theory, it is believed that the inhibition of AR can reduce the accumulation of sorbitol in tissues such as retina, sciatic nerve, spinal cord, liver and kidney.

[0007] The present disclosure also relates to a method for reducing sorbitol accumulation in a subject having a sorbitol-dehydrogenase (SDH) deficiency, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor.

[0008] In some embodiments, the present disclosure relates to a method of reducing sorbitol accumulation in a subject having a genetic disorder, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor.

[0009] The genetic disorder is any disorder that alters the metabolism of sorbitol or causes the overproduction of sorbitol.

[0010] The present disclosure also relates to methods of treating hereditary neuropathies, such as Charcot-Marie-Tooth disease (CMT), including Charcot-Marie-Tooth neuropathy type 1 (CMT1), a demyelinating peripheral neuropathy, or Charcot-Marie-Tooth neuropathy type 2 (CMT2), an axonal (non-demyelinating) peripheral neuropathy. In some embodiments, the CMT2 is distal hereditary motor neuropathy (dHMN).

[0011] In an example, the method comprises administering to a subject in need thereof a therapeutically effective amount of zopolrestat. In an example, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulas (I)-(VI). In some embodiments, the administered AR inhibitor is ponalrestat, epalrestat, sorbinil, or sol. It is not vinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statil, berberine, or SPR-210. In an example, the method excludes administration of epalrestat.

[0012] In other embodiments, the present disclosure relates to a method of treating sorbitol-dehydrogenase (SDH) deficiency in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an AR inhibitor, such as a compound of any one of Formulas (I)-(VI), and a pharmaceutically acceptable carrier.

[0013] In other embodiments, the present disclosure provides a method of treating sorbitol-dehydrogenase (SDH) deficiency in a subject in need thereof, comprising administering a therapeutically effective amount of (a) a compound of Formula (I)-(VI) and a pharmaceutically acceptable carrier; and (b) alponalrestat, epalrestat, sorbinil or is one or more of sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, or SPR-210 The present invention relates to a method comprising administering

[0014] In other embodiments, the present disclosure relates to the use of AR inhibitors in the treatment of genetic and / or metabolic disorders that alter sorbitol metabolism or cause the overproduction of sorbitol, such as SDH deficiency.

[0015] In other embodiments, the present disclosure relates to the use of an AR inhibitor for the manufacture of a medicament for treating a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency.

[0016] The present disclosure also relates to the use of AR inhibitors (e.g., zopolrestat, epalrestat, compounds of any one of Formulas (I)-(VI)) to treat genetic and / or metabolic disorders that alter sorbitol metabolism or cause overproduction of sorbitol, such as SDH deficiency.

[0017] The present disclosure also relates to an AR inhibitor (e.g., zopolrestat, epalrestat, a compound of any one of Formulas (I) to (VI)) for the manufacture of a medicament for treating a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency.

[0018] The present disclosure also relates to a pharmaceutical formulation containing an AR inhibitor (e.g., zopolrestat, epalrestat, any one of the compounds of formulae (I) to (VI)) as an active ingredient for treating genetic and / or metabolic disorders that alter sorbitol metabolism or cause excessive production of sorbitol, such as SDH deficiency.

[0019] In yet another aspect, the present disclosure relates to the treatment of various other disorders, such as diabetes and diabetes-related complications, in which the excessive formation of sorbitol is directly linked to the development and progression of diabetic complications. Such disorders include, but are not limited to, "sugar" cataracts, hyperglycemia, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc. Although not wishing to be bound by any particular theory, it is believed that high glucose levels in diabetic subjects activate the polyol pathway, where glucose is converted to sorbitol by AR, which is then converted to fructose. Because glucose is reduced faster than sorbitol is oxidized, the net effect is the intracellular accumulation of sorbitol, an osmolyte. [Brief explanation of the drawings]

[0020] [Figure 1] The figure is a histogram showing that fibroblasts from patients with sorbital dehydrogenase deficiency (SORD) have elevated sorbitol levels compared to fibroblasts from healthy volunteers. Treatment of SORD fibroblasts with aldose reductase inhibitors Compound A and Compound B reduces sorbitol levels in SORD fibroblasts. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description Various aspects will now be described more fully hereinafter. However, such aspects may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather, these embodiments are presented so that this disclosure will be thorough and complete.

[0022] The present disclosure relates to the use of AR inhibitors to treat genetic and / or metabolic disorders that alter sorbitol metabolism or cause the overproduction of sorbitol, such as SDH deficiency.

[0023] Where a range of values ​​is presented herein, each intervening value between the upper and lower limits of that range, and any other stated or intervening value in such range, is intended to be encompassed within the scope of the disclosure. For example, if a range of 1 μM to 8 μM is specified, then 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, and 7 μM, as well as ranges greater than or equal to 1 μM and ranges less than or equal to 8 μM, are also intended to be expressly disclosed.

[0024] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound of Formula (I)" includes a single compound, as well as two or more of the same or different compounds. Reference to "an excipient" includes a single excipient and two or more of the same or different excipients, and so forth.

[0025] Unless the context of this disclosure indicates otherwise or is inconsistent with the interpretation below, the word "about" refers to a range of plus or minus 10% of the value; for example, "about 50" refers to 45 to 55, "about 25,000" refers to 22,500 to 27,500, etc. For example, in a list of numerical values ​​such as "about 49, about 50, about 55," "about 50" refers to a range extending to less than half the interval between the preceding and succeeding values, e.g., greater than 49.5 and less than 52.5. Furthermore, the phrases "less than about a value" or "greater than about a value" should be understood in light of the definition of the term "about" provided herein.

[0026] To provide a complete, concise, and clear description of various embodiments, this disclosure includes descriptions of various components, groups of components, ranges, and other elements of the broader disclosure. It is intended that such elements can be combined in various ways to provide additional embodiments of the disclosure. It is also intended that any disclosed feature (e.g., substituent, analog, compound, structure, component), including individual members of any disclosed group, including any subrange within a group, or combination of subranges, may be excluded from the disclosure, or from any embodiment of the disclosure, for any reason.

[0027] Various embodiments of the present disclosure are further described in detail in the following numbered paragraphs: I. Methods

[0028] Generally, the present disclosure relates to a method for treating genetic disorders and / or metabolic disorders, such as SDH deficiency, that alter sorbitol metabolism or cause excessive production of sorbitol, comprising administering to the subject in need thereof a therapeutically effective amount of the compound that inhibits aldose reductase activity.The compound can be any suitable compound that inhibits AR activity, such as small molecule compound (for example, has a size of 5kDa or less), biological agent (for example, the inhibitory RNA of aldose reductase) or their combination.Preferably, AR inhibitor is a small molecule compound.Suitable small molecule AR inhibitor is known in the art and disclosed herein. Small molecule AR inhibitors include ponalrestat, sorbinil, sorbinol, imirestat, AND-138, CT-112, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, SPR-210, zopolrestat, epalrestat, the compounds disclosed in US8,916,563, US9,650,383, US10,150,779 and the compounds disclosed herein.Preferred AR inhibitors for use in the present invention include zopolrestat, epalrestat, the compounds disclosed in US8,916,563, US9,650,383, US10,150,779 and the compounds disclosed herein. The AR inhibitors may be administered in any suitable molecular form, including pharmaceutically acceptable salts, solvates, prodrugs, and compounds containing stable isotopes of one or more atoms, e.g., deuterium in place of hydrogen.

[0029] In one example, a method of treating a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency, comprises administering a therapeutically effective amount of zopolrestat to a subject in need thereof.

[0030] In one example, a method for treating a genetic and / or metabolic disorder that alters sorbitol metabolism or causes overproduction of sorbitol, such as SDH deficiency, comprises administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0031] In one example, a method for treating a genetic and / or metabolic disorder that alters sorbitol metabolism or causes excessive production of sorbitol, such as SDH deficiency, comprises administering a therapeutically effective amount of an aldose reductase inhibitor to a subject in need thereof, wherein the aldose reductase inhibitor is not ponalrestat, epalrestat, sorbinil or sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, or SPR-210. In certain embodiments, the methods for treating sorbitol-dehydrogenase (SDH) deficiency disclosed herein do not comprise the administration of epalrestat.

[0032] In one example, a method for treating a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency, comprises administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulas (I)-(VI). In certain examples, the administered compound is Compound A, or the administered compound is Compound B, or a physiologically acceptable salt, hydrate, solvate, or prodrug of Compound A or Compound B. [ka]

[0033] As used herein, the term "treating" refers to curative or palliative (e.g., controlling or alleviating a disease or disease symptom) therapy. This can include reversing, reducing, arresting, or delaying the symptoms, clinical signs, and underlying pathology of a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency, so as to improve or stabilize the subject's condition. Thus, the present method can be used to treat a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency, including, for example, treating complications (e.g., symptoms and clinical signs) of sorbitol dehydrogenase (SDH) deficiency and / or treating and preventing complications (e.g., symptoms and clinical signs) of sorbitol dehydrogenase (SDH) deficiency.

[0034] As used herein, a "therapeutically effective amount" is an amount of a compound sufficient to achieve a desired therapeutic effect under the conditions of administration, such as an amount that reduces or ameliorates the severity of a genetic and / or metabolic disorder that alters sorbitol metabolism or causes excessive production of sorbitol, such as SDH deficiency, which prevents the progression of a condition or symptom associated with elevated levels of sorbitol and / or sorbital accumulation in cells, resulting in a reduction in sorbitol levels, or enhances or otherwise ameliorates the therapeutic effect(s) of another therapy for the treatment or management of a genetic and / or metabolic disorder that alters sorbitol metabolism or causes excessive production of sorbitol, such as SDH deficiency. A therapeutically effective amount can be an amount that reduces sorbitol in the subject being treated. The actual amount to be administered can be determined by an ordinarily knowledgeable clinician based on, for example, the subject's age, weight, sex, general health and tolerance to drugs, the severity of the disease, the selected dosage form, the route of administration, and other factors. Typically, the amount of AR inhibitor administered is about 0.5 to about 60 mg per kg of body weight per day, such as about 1.0 to 10 mg / kg.

[0035] In some embodiments of the methods disclosed herein, a therapeutically effective amount is sufficient to reduce intracellular aldose reductase activity by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, for example, about 100% (e.g., compared to pre-treatment levels).A therapeutically effective amount can be an amount that reduces sorbitol levels by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, for example, about 100% (e.g., compared to pre-treatment levels).A therapeutically effective amount can be sufficient to normalize sorbitol levels in subjects with genetic and / or metabolic disorders that alter sorbitol metabolism or cause excessive sorbitol production, such as SDH deficiency.

[0036] A "subject" can be any animal, particularly a mammal, having a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency, and can include, but is in no way limited to, humans, domestic animals such as feline or canine subjects, livestock such as, but not limited to, bovine, equine, caprine, ovine, avian, and porcine subjects, wild animals (whether in the wild or in zoos), research or experimental animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species such as chickens, turkeys, songbirds, etc. Typically, human subjects treated using the methods disclosed herein will be diagnosed, e.g., as newborns, by enzymatic or genetic screening, with a genetic and / or metabolic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol, such as SDH deficiency, and / or have accumulation of sorbitol in their tissues.

[0037] The present disclosure also relates to the prevention or treatment of at least one clinical feature or complication of a genetic and / or metabolic disorder that alters sorbitol metabolism or causes excessive production of sorbitol, such as SDH deficiency, in a subject. Representative clinical features or complications that may manifest in children, adolescents, or adults include, for example, cataracts, neuropathy, retinopathy, cardiomyopathy, nephropathy, microvascular complications, atherosclerosis and other cardiovascular complications, albuminuria, and diabetes.

[0038] In certain aspects, the present disclosure relates to methods of treating clinical features or complications of genetic and / or metabolic disorders that alter sorbitol metabolism or cause the overproduction of sorbitol, such as SDH deficiency, comprising administering a therapeutically effective amount of zopolrestat to a subject in need thereof.

[0039] In one example, the present disclosure relates to a method of treating clinical features or complications of genetic and / or metabolic disorders that alter sorbitol metabolism or cause overproduction of sorbitol, such as SDH deficiency, comprising administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0040] In one example, the present disclosure relates to a method of treating clinical features or complications of genetic and / or metabolic disorders that alter sorbitol metabolism or cause the overproduction of sorbitol, such as SDH deficiency, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulas (I)-(VI).

[0041] In some embodiments, the above-mentioned method is carried out by administering a preparation comprising one or more AR inhibitors.The preparation can be adapted to be administered to the subject in need thereof once a day, twice a day, three times a day or four times a day during the desired treatment period.Usually, the preparation is adapted to be administered long-term for a period of several weeks, several months, several years or several decades.In still other embodiments, the method is carried out by administering the preparation that is adapted to be administered for several weeks.Usually, the method is carried out by administering the preparation that is adapted to be administered for several years or several decades. II. AR inhibitors

[0042] Suitable small molecule AR inhibitor is known in the art and disclosed herein.Small molecule AR inhibitor includes ponalrestat, sorbinil, sorbinol, imirestat, AND-138, CT-112, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, SPR-210, zopolrestat, epalrestat, US8,916,563, US9,650,383, the compound disclosed in WO2012 / 009553 and the compound disclosed herein. The preferred AR inhibitors for use in the present invention are zopolrestat, epalrestat, the compounds disclosed in U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, WO2017 / 038505, U.S. Patent No. 10,150,779, and the compounds disclosed herein.The disclosures of U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, U.S. Patent No. 10,150,779, WO2012 / 009553 and WO2017 / 038505 are incorporated herein by reference in their entirety, and disclose compounds suitable for use in the methods described herein. Compounds of formula (I) and (II)

[0043] In one example, the AR inhibitor is a compound of formula (I) or pharmaceutically acceptable salts, prodrugs, and solvates thereof: [ka]

[0044] (In the formula,

[0045] R 1 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl or (C1-C6)-aminoalkyl,

[0046] X 1 is N or CR 3 and

[0047] X 2 is N or CR 4 and

[0048] X 3 is N or CR 5 and

[0049] X 4 is N or CR 6 where X 1 , X 2 , X 3 or X 4 two or three of the are N,

[0050] Y is a bond, C═O, C═S, C═NH or C═N(C1-C4)-alkyl;

[0051] Z is [ka] and

[0052] A 1 is NR 11 , O, S or CH2;

[0053] A 2 is N or CH,

[0054] A3 is NR 11 , O or S;

[0055] R 3 ~R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl, or R 3 ~R 6 Two of these or R 7 ~R 10 two of which taken together are (C1-C4)-alkylenedioxy;

[0056] R 11 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl) is.

[0057] Z, [ka] or Z is [ka] The indication that

[0058] Z, [ka] If

[0059] The compound of formula (I) [ka] It encompasses

[0060] Z, [ka] If

[0061] The compound of formula (I) [ka] It will be recognized by those skilled in the art that the term "common" refers to the inclusion of

[0062] In certain embodiments, R 1 is hydrogen or (C1-C6)-alkyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is (C1-C6)-alkyl. In certain embodiments, R 1 is tert-butyl.

[0063] In certain embodiments, R 3 ~R 10 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 3 ~R 10 are independently hydrogen, halogen, or trihaloalkyl.

[0064] In certain embodiments, R 3 ~R 6 is hydrogen.

[0065] In certain embodiments, R 7 ~R 10 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 7 ~R 10 are independently hydrogen, halogen, or trihaloalkyl.

[0066] In certain embodiments, R 7 ~R 10 is hydrogen.

[0067] In certain embodiments, R 8 is hydrogen, halogen, or haloalkyl. In certain embodiments, R8 is hydrogen. In certain embodiments, R 8 is halogen. In certain embodiments, R 8 is haloalkyl.

[0068] In certain embodiments, R 9 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is halogen. In certain embodiments, R 9 is haloalkyl.

[0069] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0070] In certain embodiments, A 1 is NR 11 , S, or CH2. In certain embodiments, A 1 is NR 11 or O. In certain embodiments, A 1 is NR 11 or S. In certain embodiments, A 1 is NR 11 In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0071] In certain embodiments, A 2 is N or CH. In certain embodiments, A 1 is N. In certain embodiments, A 1 is CH.

[0072] In certain embodiments, A3 is O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S.

[0073] In certain embodiments, X 1 and X 4 is nitrogen.

[0074] In certain embodiments, X 1 and X 2 is nitrogen.

[0075] In certain embodiments, X 1 and X 3 is nitrogen.

[0076] In certain embodiments, X 2 and X 3 is nitrogen.

[0077] In certain embodiments, X 2 and X 4 is nitrogen.

[0078] In certain embodiments, X 3 and X 4 is nitrogen.

[0079] In certain embodiments, Z is [ka] is.

[0080] In certain embodiments, Z is [ka] is.

[0081] In certain embodiments, R 1 is hydrogen or (C1-C6)-alkyl,

[0082] X 1 and X 4 is N,

[0083] X 2 is CR 4 and

[0084] X 3 is CR 5 and

[0085] Y is C=O,

[0086] Z is [ka] and

[0087] A 1 is NR 11 , O or S;

[0088] A 2 is N,

[0089] A 3 is O or S,

[0090] R 4 and R 5 is hydrogen,

[0091] R 7 ~R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl,

[0092] R 11 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0093] In certain embodiments, R 1is hydrogen or tert-butyl,

[0094] X 1 and X 4 is N,

[0095] X 2 is CR 4 and

[0096] X 3 is CR 5 and

[0097] Y is C=O,

[0098] Z is [ka] and

[0099] A 1 is NR 11 , O or S;

[0100] A 2 is N,

[0101] A 3 is O or S,

[0102] R 4 and R 5 is hydrogen,

[0103] R 7 ~R 10 are independently hydrogen, halogen, or haloalkyl;

[0104] R 11 is hydrogen, (C1-C4)-alkyl or C(O)O-tert-butyl.

[0105] In certain embodiments, R 1 is hydrogen or tert-butyl,

[0106] X1 and X 4 is N,

[0107] X 2 is CH,

[0108] X 3 is CH,

[0109] Y is C=O,

[0110] Z is [ka] and

[0111] A 1 is NR 11 , O or S;

[0112] A 2 is N,

[0113] A 3 is O or S,

[0114] R 7 , R 8 and R 10 are independently hydrogen, halogen, or haloalkyl;

[0115] R 9 is halogen or haloalkyl,

[0116] R 11 is hydrogen or methyl.

[0117] In certain embodiments, R 1 is hydrogen or tert-butyl,

[0118] X 1 and X 4 is N,

[0119] X 2 is CH,

[0120] X 3 is CH,

[0121] Y is C=O,

[0122] Z is [ka] and

[0123] A 1 is NR 11 , O or S;

[0124] A 2 is N,

[0125] A 3 is O or S,

[0126] R 7 , R 8 and R 10 are independently hydrogen, halogen, or haloalkyl;

[0127] R 9 is chlorine or trifluoromethyl,

[0128] R 11 is hydrogen or methyl.

[0129] In certain embodiments, the AR inhibitor is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: [ka]

[0130] (In the formula, R 1 , R 7 ~R 9 and Y are as described in formula (I), preferably R 1is hydrogen or (C1-C6)-alkyl and Y is C=O). Exemplary compounds of formula (II) are the following and salts thereof: [ka] Includes: Compound of formula (III)

[0131] The AR inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt, prodrug, or solvate thereof:

[0132] [ka]

[0133] (In the formula,

[0134] R 1 is CO2R 2 or CO2 - X + and

[0135] R 2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl or (C1-C6)-aminoalkyl,

[0136] X 1 is H or a halogen,

[0137] X 2 is H or a halogen,

[0138] Y is a bond, C═O, C═S, C═NH or C═N(C1-C4)-alkyl;

[0139] Z is [ka] and

[0140] A 1 is NR 7, O, S or CH2;

[0141] A 2 is N or CH,

[0142] A 3 is NR 7 , O or S;

[0143] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl,

[0144] R 7 is hydrogen, C1-C4 alkyl or C(O)O—(C1-C4)-alkyl,

[0145] X + is the counterion) It can be said that:

[0146] Z,

[0147] [ka] or Z is

[0148] [ka] The indication that Z,

[0149] [ka] then the compound of formula (III) is [ka] and Z is understood to include [ka] then the compound of formula (I) is [ka] It will be appreciated by those skilled in the art that the term "common" refers to the term "common" and is understood to encompass the term "common" as used herein.

[0150] In certain embodiments, R 1 is CO2R 2 or CO2 - X + In certain embodiments, R 1 is CO2R 2 In certain embodiments, R 1 is CO2 - X + is.

[0151] In certain embodiments, R 2 is hydrogen or (C1-C6)-alkyl. In certain embodiments, R 2 is hydrogen or (C1-C4)-alkyl. In certain embodiments, R 2 is hydrogen or (C1-C3)-alkyl. In certain embodiments, R 2 is hydrogen, methyl, or ethyl. In certain embodiments, R 2 is hydrogen or methyl. In certain embodiments, R 2 is methyl or ethyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is (C1-C6)-alkyl. In certain embodiments, R 2 is (C1-C6)-n-alkyl. In certain embodiments, R 2 is (C1-C2)-alkyl. In certain embodiments, R 2is (C1-C3)-alkyl. In certain embodiments, R 2 is (C1-C4)-alkyl. In certain embodiments, R 2 is tert-butyl.

[0152] In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl.

[0153] In certain embodiments, R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen, or trihaloalkyl.

[0154] In certain embodiments, R 3 ~R 6 is hydrogen. In certain embodiments, R 3 , R 5 and R 6 is hydrogen.

[0155] In certain embodiments, R 4 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is haloalkyl. In certain embodiments, R 4 is CF3.

[0156] In certain embodiments, R 3 ~R 6 is hydrogen. In certain embodiments, R 3 , R5 , R 6 is hydrogen and R 4 is halogen or haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is CF. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is F. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is Cl.

[0157] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0158] In certain embodiments, A 1 is NR 7 , O, S, or CH2. In certain embodiments, A 1 is NR 7 , O or S. In certain embodiments, A 1 is NR 7 , S, or CH2. In certain embodiments, A 1 is NR 7 or O. In certain embodiments, A 1 is NR 7or S. In certain embodiments, A 1 is NR 7 In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0159] In certain embodiments, A 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 is CH.

[0160] In certain embodiments, A 3 is NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S. In certain embodiments, A 3 is NR 7 is.

[0161] In certain embodiments, X 1 and X 2 is hydrogen.

[0162] In certain embodiments, X 1 and X 2 is a halogen. In certain embodiments, X 1 and X 2 is Cl.

[0163] In certain embodiments, X 1 and X 2 are independently hydrogen or halogen. In certain embodiments, X 1 is hydrogen and X 2 is Cl. In certain embodiments, X 1 is Cl and X 2 is hydrogen.

[0164] In certain embodiments, Z is [ka] is.

[0165] In certain embodiments, Z is [ka] is.

[0166] In certain embodiments, R 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C4 alkyl. In certain embodiments, R 7 is C1-C3 alkyl. In certain embodiments, R 7 is C1-C2 alkyl. In certain embodiments, R 7 is C1-C4n-alkyl. In certain embodiments, R 7 is C1-C3n-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C4)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C2)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C4)-n-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-n-alkyl.

[0167] In certain embodiments, R 1 is CO2R 2 and

[0168] R 2 is H or (C1-C6)-alkyl,

[0169] X 1is H,

[0170] X 2 is H,

[0171] Y is C=O,

[0172] Z is [ka] and

[0173] A 1 is NR 7 , O or S;

[0174] A 2 is N,

[0175] A 3 is O or S,

[0176] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl,

[0177] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0178] In certain embodiments, R 1 is CO2R 2 and

[0179] R 2 is H or tert-butyl,

[0180] X 1 is H,

[0181] X2 is H,

[0182] Y is C=O,

[0183] Z is [ka] and

[0184] A 1 is NR 7 , O or S;

[0185] A 2 is N,

[0186] A 3 is O or S,

[0187] R 6 ~R 6 are independently hydrogen, halogen, or haloalkyl;

[0188] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0189] In certain embodiments, R 1 is CO2R 2 and

[0190] R 2 is H or tert-butyl,

[0191] X 1 is H,

[0192] X 2 is H,

[0193] Y is C=O,

[0194] Z is [ka] and

[0195] A 1 is NR 7 , O or S;

[0196] A 2 is N,

[0197] A 3 is O or S,

[0198] R 3 , R 5 and R 6 is hydrogen,

[0199] R 4 is hydrogen, halogen or haloalkyl;

[0200] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0201] In certain embodiments, R 1 is CO2R 2 and

[0202] R 2 is H or (C1-C6)-alkyl,

[0203] X 1 is a halogen,

[0204] X 2 is a halogen,

[0205] Y is C=O,

[0206] Z is [ka] and

[0207] A 1 is NR 7, O or S;

[0208] A 2 is N,

[0209] A 3 is O or S,

[0210] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl,

[0211] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0212] In certain embodiments, R 1 is CO2R 2 and

[0213] R 2 is H or tert-butyl,

[0214] X 1 is a halogen,

[0215] X 2 is a halogen,

[0216] Y is C=O,

[0217] Z is [ka] and

[0218] A 1 is NR 7 , O or S;

[0219] A 2 is N,

[0220] A 3 is O or S,

[0221] R 3 ~R 6 are independently hydrogen, halogen, or haloalkyl;

[0222] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0223] In certain embodiments, R 1 is CO2R 2 and

[0224] R 2 is H or tert-butyl,

[0225] X 1 is Cl,

[0226] X 2 is Cl,

[0227] Y is C=O,

[0228] Z is [ka] and

[0229] A 1 is NR 7 , O or S;

[0230] A 2 is N,

[0231] A 3 is O or S,

[0232] R 3 ~R 6are independently hydrogen, halogen, or haloalkyl;

[0233] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0234] In certain embodiments, R 1 is CO2R 2 and

[0235] R 2 is H or tert-butyl,

[0236] X 1 is Cl,

[0237] X 2 is Cl,

[0238] Y is C=O,

[0239] Z is [ka] and

[0240] A 1 is NR 7 , O or S;

[0241] A 2 is N,

[0242] A 3 is O or S,

[0243] R 3 , R 5 and R 6 is hydrogen,

[0244] R 4 is hydrogen, halogen or haloalkyl;

[0245] R 7is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0246] In certain embodiments, the compound of formula (III) is [ka] is selected from the group consisting of:

[0247] In certain embodiments, the compound of formula (III) is [ka] or a pharmaceutically acceptable salt thereof.

[0248] In certain embodiments, the compound of formula (III) is [ka] or a pharmaceutically acceptable salt thereof. Compounds of formula (IV), (V) and (VI)

[0249] The AR inhibitor is a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof:

[0250] [ka]

[0251] (In the formula,

[0252] X 1 is H or a halogen,

[0253] X 2 is H or a halogen,

[0254] Y is a bond, C═O, C═S, C═NH or C═N(C1-C4)-alkyl;

[0255] Z 1 and Z2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0256] [ka] Forming

[0257] During the ceremony,

[0258] X is a substituted or unsubstituted C2-C5 alkylene;

[0259] Z is [ka] and

[0260] A 1 is NR 7 , O, S or CH2;

[0261] A 2 is N or CH,

[0262] A 3 is NR 7 , O or S;

[0263] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl,

[0264] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl) It can be said that:

[0265] Suitable substituents on the C2-C5 alkylene include one or more of alkyl, alkoxy, aryl, aryloxy, halo, haloalkyl, haloalkoxy, and haloalkylthio. A preferred substituted C2-C5 alkylene is substituted ethylene. A more preferred substituted C2-C5 alkylene is -C(CH3)2C(CH3)2-.

[0266] Z,

[0267] [ka] or Z is [ka] The indication that Z is [ka] then the compound of formula (IV) is [ka] and

[0268] Z, [ka] then the compound of formula (IV) is [ka] and [ka]

[0269] (In the formula,

[0270] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z1 and Z 2 together with the boron atoms to which they are bonded,

[0271] [ka] Forming

[0272] During the ceremony,

[0273] X is a substituted or unsubstituted C2-C5 alkylene. It will be appreciated by those skilled in the art that the term "common" refers to the term "common" as used herein.

[0274] In certain embodiments, R of formula (IV) 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl.

[0275] In certain embodiments, R of formula (IV) 3 ~R 6 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen, or trihaloalkyl.

[0276] In certain embodiments, R of formula (IV) 3 ~R 6 is hydrogen. In certain embodiments, R 3 , R 5 and R 6 is hydrogen.

[0277] In certain embodiments, R of formula (IV) 4 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 4is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is haloalkyl. In certain embodiments, R 4 is CF3.

[0278] In certain embodiments, R of formula (IV) 3 ~R 6 is hydrogen. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen or haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is haloalkyl. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is CF. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is F. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is Cl.

[0279] In certain embodiments, Y in formula (IV) is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0280] In certain embodiments, A of formula (IV) 1 is NR 7 , O, S, or CH2. In certain embodiments, A 1 is NR 7 , O or S. In certain embodiments, A 1 is NR 7 , S, or CH2. In certain embodiments, A 1 is NR 7 or O. In certain embodiments, A 1 is NR 7 or S. In certain embodiments, A 1 is NR 7 In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0281] In certain embodiments, A of formula (IV) 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 is CH.

[0282] In certain embodiments, A of formula (IV) 3 is NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A in formula (IV) 3 is S. In certain embodiments, A 3 is NR 7 is.

[0283] In certain embodiments, X in formula (IV) 1 and X 2 is hydrogen.

[0284] In certain embodiments, X in formula (IV) 1 and X 2 is a halogen. In certain embodiments, X 1 and X 2 is Cl.

[0285] In certain embodiments, X in formula (IV) 1 and X 2 is independently hydrogen or halogen. 1 is hydrogen and X 2 is Cl. In certain embodiments, X 1 is Cl and X 2 is hydrogen.

[0286] In certain embodiments, Z in formula (IV) is [ka] is.

[0287] In certain embodiments, Z in formula (IV) is [ka] is.

[0288] In certain embodiments, R of formula (IV) 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C4 alkyl. In certain embodiments, R 7 is C1-C3 alkyl. In certain embodiments, R 7 is C1-C2 alkyl. In certain embodiments, R 7 is C1-C4n-alkyl. In certain embodiments, R 7 is C1-C3n-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C4)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C2)-alkyl. In certain embodiments, R7 is C(O)O—(C1-C4)-n-alkyl. In certain embodiments, R 7 is C(O)O—(C1-C3)-n-alkyl.

[0289] In certain embodiments, the compound of formula (IV) is

[0290] [ka]

[0291] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0292] During the ceremony,

[0293] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0294] [ka] Forming

[0295] During the ceremony,

[0296] X is a substituted or unsubstituted C2 to C5 alkylene.

[0297] In certain embodiments, the compound of formula (IV) is

[0298] [ka]

[0299] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0300] During the ceremony,

[0301] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0302] [ka] Forming

[0303] During the ceremony,

[0304] X is a substituted or unsubstituted C2 to C5 alkylene.

[0305] In certain embodiments, the compound of formula (IV) is

[0306] [ka]

[0307] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0308] During the ceremony,

[0309] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0310] [ka] Forming

[0311] During the ceremony,

[0312] X is a substituted or unsubstituted C2 to C5 alkylene.

[0313] In certain embodiments, the compound of formula (IV) is

[0314] [ka]

[0315] [ka]

[0316] [ka]

[0317] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0318] During the ceremony,

[0319] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0320] [ka] Forming

[0321] During the ceremony,

[0322] X is a substituted or unsubstituted C2 to C5 alkylene.

[0323] In another embodiment, the aldose reductase inhibitor is a compound of formula (V)

[0324] [ka]

[0325] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0326] During the ceremony,

[0327] X 3 is N or CR 8 and

[0328] X 4 is N or CR 9 and

[0329] X 5 is N or CR 10 and

[0330] X 6 is N or CR 11 where X 3 , X 4 , X 5 or X 6 two or three of the are N,

[0331] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0332] [ka] Forming

[0333] During the ceremony,

[0334] X is a substituted or unsubstituted C2-C5 alkylene;

[0335] Z 3 teeth, [ka] and

[0336] A 4 is NR 16 , O, S or CH2;

[0337] A 5 is N or CH,

[0338] A 6 is NR 16 , O or S;

[0339] R 8 ~R 15 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl, or R 8 ~R 11 Two of these or R 12 ~R 15 two of which together are (C1-C4)-alkylenedioxy;

[0340] R 16 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0341] Suitable substituents on the C2-C5 alkylene include one or more of alkyl, alkoxy, aryl, aryloxy, halo, haloalkyl, haloalkoxy, and haloalkylthio. A preferred substituted C2-C5 alkylene is substituted ethylene. A more preferred substituted C2-C5 alkylene is -C(CH3)2C(CH3)2-.

[0342] Z,

[0343] [ka] or Z is [ka] The indication that Z is [ka] then the compound of formula (V) is [ka] and Z is understood to encompass [ka] then the compound of formula (V) is [ka] It will be appreciated by those skilled in the art that the term "common" refers to the term "common" as used herein.

[0344] In some compounds of formula (V), R 8 ~R 15 are independently hydrogen, halogen or haloalkyl, e.g., R 8 ~R 15 is independently hydrogen, halogen, or trihaloalkyl (e.g., —CF 3 ).

[0345] In other compounds of formula (V), R 8 ~R 11 is hydrogen.

[0346] In certain embodiments of compounds of Formula (V), R 12 ~R 15 are independently hydrogen, halogen or haloalkyl, e.g., R 12 ~R 15 is independently hydrogen, halogen, or trihaloalkyl (e.g., —CF 3 ).

[0347] In certain embodiments, R of formula (V) 12 ~R 15is hydrogen.

[0348] In certain embodiments, R of formula (V) 13 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 13 is hydrogen. In certain embodiments, R 13 is halogen. In certain embodiments, R 13 is haloalkyl.

[0349] In certain embodiments, R of formula (V) 14 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is halogen. In certain embodiments, R 14 is haloalkyl.

[0350] In certain embodiments, Y in formula (V) is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0351] In certain embodiments, A of formula (V) 4 is NR 16 , S, or CH2. In certain embodiments, A 4 is NR 16 or O. In certain embodiments, A 4 is NR 16 or S. In certain embodiments, A 4 is NR 16 In certain embodiments, A 4 is O. In certain embodiments, A 4 is S.

[0352] In certain embodiments, A of formula (V) 5is N or CH. In certain embodiments, A 4 is N. In certain embodiments, A 4 is CH.

[0353] In certain embodiments, A of formula (V) 6 is O or S. In certain embodiments, A 6 is O. In certain embodiments, A 6 is S.

[0354] In certain embodiments, X in formula (V) 3 and X 6 is nitrogen.

[0355] In certain embodiments, X in formula (V) 3 and X 4 is nitrogen.

[0356] In certain embodiments, X in formula (V) 3 and X 5 is nitrogen.

[0357] In certain embodiments, X in formula (V) 4 and X 5 is nitrogen.

[0358] In certain embodiments, X in formula (V) 4 and X 6 is nitrogen.

[0359] In certain embodiments, X in formula (V) 5 and X 6 is nitrogen.

[0360] In certain embodiments, Z of formula (V) 3 teeth, [ka] is.

[0361] In certain embodiments, Z of formula (V)3 teeth, [ka] is.

[0362] In some embodiments, formula (V) is:

[0363] [ka]

[0364] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0365] During the ceremony,

[0366] R 14 is hydrogen, halogen, or trihaloalkyl (e.g., —CF),

[0367] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0368] [ka] Forming

[0369] X is a substituted or unsubstituted C2 to C5 alkylene.

[0370] In an embodiment, the compound of formula (V) is

[0371] [ka]

[0372] [ka]

[0373] [ka]

[0374] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0375] In one embodiment, the aldose reductase inhibitor is a compound of formula (VI)

[0376] [ka]

[0377] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0378] During the ceremony,

[0379] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atoms to which they are bonded,

[0380] [ka] Forming

[0381] During the ceremony,

[0382] X is a substituted or unsubstituted C2 to C5 alkylene.

[0383] In embodiments, the aldose reductase inhibitor of formula (VI) is [ka] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0384] In embodiments, the AH inhibitor of formula (VI) is [ka] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0385] The term "alkyl," as used herein, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon radical having straight-chain, branched-chain, monocyclic or polycyclic moieties, or combinations thereof, which radical is optionally substituted on one or more carbons of the straight-chain, branched-chain, monocyclic or polycyclic moiety, or combinations thereof, with one or more substituents for each carbon, and the one or more substituents are independently selected from the group consisting of C1 to C6. 10 Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0386] The term "halogen" or "halo-", as used herein, means chlorine (Cl), fluorine (F), iodine (I) or bromine (Br).

[0387] As used herein, the term "acyl" is used broadly to denote an RCO-type radical, where R represents an organic radical which may be a substituted or unsubstituted, saturated or unsaturated, alkyl, aralkyl, aryl, alicyclic or heterocyclic radical, or, as otherwise defined, the term "acyl" is used broadly to denote the monovalent radical which remains when the OH group of a carboxylic acid radical is removed from a molecule of carboxylic acid.

[0388] The term "alkoxy" is used to represent a group of formula -OR, where R is an alkyl group, optionally containing substituents such as halogens. Preferably, the term "alkoxy" is used to represent an alkoxy having an alkyl group of 1 to 6 carbon atoms. Most preferably, the term "alkoxy" is used to represent an alkoxy having an alkyl group of 1 to 3 carbon atoms, such as methoxy or ethoxy.

[0389] The term "cycloalkyl group" is used herein to identify a cycloalkyl group having from 3 to 6 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0390] The term "solvate" as used herein means a compound or a pharmaceutically acceptable salt thereof in which molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent is physiologically tolerable at the administered dosage. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate."

[0391] A "prodrug" refers to an agent that is converted into the parent drug in vivo. In some situations, prodrugs are often useful because they are easier to administer than the parent drug. A prodrug may be bioavailable, for example, by oral administration, while the parent drug is either less bioavailable or not bioavailable at all. A prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. For example, the compound may have a protecting group that is hydrolyzed in biological fluids, such as the bloodstream, to release the active compound, or that is oxidized or reduced in biological fluids to release the compound. The term "prodrug" may apply to functional groups, such as the acid functional group of a compound of Formula (I). A prodrug may also be constructed in which the acid group is masked, for example, as an ester or amide. Further examples of prodrugs are discussed herein. See also Alexander et al. (J. Med. Chem. 1988, 31, 318), incorporated by reference. Examples of prodrugs include derivatives and metabolites of compounds containing biohydrolyzable moieties, such as, but not limited to, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable phosphate analogs. Prodrugs are also described, for example, in The Practice of Medicinal Chemistry (Camille Wermuth, ed., 1999, Academic Press), which is incorporated herein by reference in its entirety. In certain embodiments, prodrugs of compounds with carboxyl functional groups are lower alkyl esters of carboxylic acids. Carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present in the molecule. Prodrugs are typically prepared according to the methods described in Burger's Medicinal Chemistry and Drug Discovery 6 th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh) (each of which is incorporated herein by reference in its entirety). The biohydrolyzable portion of the compound of Formula I (a) does not impair the biological activity of the compound but can confer advantageous in vivo properties to the compound, such as uptake, duration of action, or onset of action, or (b) may be biologically inactive but is converted to a bioactive compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkylacylaminoalkyl esters, and choline esters. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

[0392] The term "salt" includes salts derived from any suitable organic and inorganic counterions known in the art, such as hydrochloride or hydrobromide salts of the above-mentioned amino acids, or alkaline or acid salts.This term is intended to include salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2 ​​sulfonic acid and other acids, and salts derived from inorganic or organic bases, including, for example, sodium, potassium, calcium, ammonium or tetrafluoroborate.Exemplary pharmaceutically acceptable salts are described, for example, in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1); and U.S. Patent No. 6,570,013. and 4,939,140 (each of which is incorporated herein by reference in its entirety). Pharmaceutically acceptable salts are also intended to encompass hemi-salts in which the compound:acid ratio is 2:1, respectively. Exemplary hemi-salts are salts derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemi-salts are salts derived from diprotic mineral acids, such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemi-maleates, hemifumarates, and hemi-succinates.

[0393] The term "acid" contemplates all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids, such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic, and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, and fatty acids. Preferred acids are linear or branched, saturated, or unsaturated C1-C 20 Aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C6-C12 Aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples are butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid, and lactobionic acid. include. III. Composition

[0394] The compound can be administered in the form of a suitable composition, such as a pharmaceutical composition. Pharmaceutical compositions are physiologically acceptable and typically contain an active compound and a carrier. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical carriers can also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Additionally, auxiliary agents, stabilizers, thickeners, lubricants, and coloring agents can be used. Other examples of suitable pharmaceutical carriers can be found in Remington's Pharmaceutical Sciences (Alfonso Gennaro ed., Krieger Publishing Company (1997)); Remington's: The Science and Practice of Pharmacy, 21 stEd. (Lippincot, Williams & Wilkins (2005)); Modern Pharmaceutics, vol. 121 (Gilbert Banker and Christopher Rhodes, CRC Press (2002)) (each of which in its entirety) (which is incorporated herein by reference).

[0395] The composition can be in any desired form, such as a physiologically and / or pharmaceutically acceptable tablet, capsule, solution, emulsion, suspension, gel, sol, or colloid. If desired, the carrier can include a buffer, such as an alkaline buffer, e.g., an ammonium buffer, an acidic buffer, e.g., an ethanoate, a citrate, a lactate, an acetate, or a zwitterionic buffer such as glycine, alanine, valine, leucine, isoleucine, and phenylalanine, Krebs-Ringer buffer, TRIS, MES, ADA, ACES, PIPES, MOPSO, cholamine chloride, MOPS, BES, TES, HEPES, DIPSO, MOBS, TAPSO, acetamidoglycine, TEA, POPSO, HEPPSO, EPS, HEPPS, tricine, TRIZMA, glycinamide, glycyl-glycine, HEPBS, bicine, TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS, and CABS.

[0396] In embodiments where the composition is in liquid form, the carrier can be a solvent or dispersion medium, including, but not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipid (e.g., triglyceride, vegetable oil, liposome), and combinations thereof. The appropriate fluidity can be maintained by, for example, using a coating agent such as lecithin, by maintaining the required particle size by dispersing in a carrier such as liquid polyol or lipid, by using a surfactant such as hydroxypropyl cellulose, or by a combination of these methods. If desired, a tonicity adjuster can be included, for example, sugar, sodium chloride, or a combination thereof. In some embodiments, the composition is isotonic.

[0397] The compositions may also include additional ingredients such as acceptable surfactants, cosolvents, emollients, agents to adjust pH and osmolality, and / or antioxidants to inhibit oxidation of one or more components.

[0398] The compositions can be prepared for administration by any suitable route, such as ocular (including periocular and intravitreal), oral, parenteral, intranasal, anal, vaginal, topical, subcutaneous, intravenous, intraarterial, intrathecal, and intraperitoneal. Thus, although intrathecal administration is an option and may be selected by the clinician (e.g., if the aldose reductase inhibitor is not a central nervous system penetrant), it is generally preferred that the aldose reductase inhibitor not be administered intrathecally. Oral compositions may be taken directly with food. Preferred carriers for oral administration include inert diluents, edible carriers, or combinations thereof. Examples of pharmaceutically acceptable carriers include, for example, water or saline solution, polymers such as polyethylene glycol, carbohydrates and their derivatives, oils, fatty acids, or alcohols. Surfactants, such as detergents, are also suitable for use in the formulations.Specific examples of surfactants are polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, polyoxyethylenated esters of mannitol, glycerol, sorbitol, or sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates; anionic surfactants, such as alkali stearates, in particular sodium stearate, potassium stearate, or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, in particular those derived from coconut oil; cationic surfactants, such as water-soluble quaternary ammonium salts of the formula NR'R''R'''R''''Y'', where the R radicals may be the same or different, if necessary. and Y" is an anion of a strong acid such as a halide, sulfate, or sulfonate; cetyltrimethylammonium bromide is one cationic surfactant that can be used), amine salts of the formula NR'R'R" (where the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one cationic surfactant that can be used), nonionic surfactants such as, optionally, polyoxyethylenated esters of sorbitan, in particular polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as substituted lauryl compounds of betaine.

[0399] If desired, oral compositions can comprise one or more binders, excipients, disintegrants, lubricants, flavoring agents and their combinations.In certain embodiments, compositions can comprise one or more of the following binders, such as gum tragacanth, acacia, corn starch, gelatin or their combinations; excipients, such as dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate or their combinations; disintegrants, such as corn starch, potato starch, alginic acid or their combinations; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose, saccharin or their combinations; flavoring agents, such as peppermint, wintergreen oil, cherry flavor, orange flavoring, or their combinations, or contain two or more of the above-mentioned.

[0400] Additional formulations suitable for other modes of administration include suppositories. Additionally, sterile solutions for injection can be prepared using appropriate solvents. Generally, dispersions are prepared by incorporating various sterilized amino acid components into a sterile vehicle containing the basic dispersion medium and / or other ingredients. Methods of formulation suitable for any desired mode of administration are well known in the art (generally, see Remington's Pharmaceutical Sciences, 18 th Ed. Mack Printing Company, 1990).

[0401] A typical pharmaceutically acceptable composition may contain an AR inhibitor and / or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 2% by weight, such as 0.01 to about 1% by weight or about 0.05 to about 0.5% by weight. The composition may be formulated as a solution, suspension, ointment, capsule, or the like. The pharmaceutical composition may be prepared as an aqueous solution and may contain additional components such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-modifying ingredients, and the like. Other equivalent modes of administration may be found in U.S. Pat. No. 4,939,140.

[0402] When administered to subject, AR inhibitor and pharmaceutically acceptable carrier can be sterilized.Suitable pharmaceutical carrier can also comprise excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk powder, glycerol, propylene glycol, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, etc.Composition of the present invention can also contain a small amount of wetting agent, or emulsifying agent, or pH buffering agent if desired.

[0403] The pharmaceutical preparations of the present disclosure are prepared by methods well known in the art of pharmacy.If necessary, one or more accessory ingredients (e.g., buffers, flavoring agents, surfactants, etc.) may also be added.The choice of carrier is determined by the solubility and chemical properties of the compound, the selected route of administration, and standard pharmaceutical practice.

[0404] In some embodiments, the composition is in unit dosage form, such as a tablet, capsule, or single-dose vial. The appropriate unit dose, i.e., the therapeutically effective amount, may be determined during appropriately designed clinical trials for each condition for which administration of the selected compound is indicated, and will, of course, vary depending on the desired clinical endpoint.

[0405] Any of the compounds and / or compositions of the present disclosure may be supplied in a kit comprising the compounds and / or compositions. Thus, in one embodiment, the compounds and / or compositions of the present disclosure are supplied in a kit, in the same package or in separate packages, including a carrier and, optionally, instructions for using the kit for therapeutic or prophylactic end use. IV. Combination Therapy

[0406] The method described herein comprises administering AR inhibitor and one additional therapeutic agent.The additional therapeutic agent can be administered before, simultaneously with, or after the AR inhibitor, but in a way that achieves the overlap of the pharmacological activity of AR inhibitor and additional therapeutic agent.The additional therapeutic agent can be, for example, a second aldose reductase inhibitor, an antioxidant, or both.

[0407] For example, second aldose reductases can be synthesized using the methods described, for example, in U.S. Patent Nos. 5,677,342; 5,155,259; 4,939,140; US2006 / 0293265; and Roy et al., (Diabetes Research and Clinical Practice, 10, Issue 1, 91-97, 1990); and the references cited therein, each of which is incorporated herein by reference in its entirety. Aldose reductase inhibitors include, for example, zopolrestat, epalrestat, ranirestat, berberine, and sorbinil, as described, for example, in U.S. Pat. Nos. 4,939,140; 6,159,976; and 6,570,013. Preferably, the second aldose reductase inhibitor is selected from ponalrestat, epalrestat, sorbinil or sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alkonyl, statyl, berberine, or SPR-210.

[0408] Other therapeutic agents that may be administered include, for example, corticosteroids, such as prednisone, methylprednisolone, dexamethasone, or triamcinalone acetonide, or non-corticosteroid anti-inflammatory compounds, such as ibuprofen or flubiproben. Similarly, vitamins and Minerals, such as zinc, and micronutrients may be co-administered. Additionally, inhibitors of the protein tyrosine kinase pathway, including natural protein tyrosine kinase inhibitors such as quercetin, lavendustin A, erbstatin, and herbimycin A, and synthetic protein tyrosine kinase inhibitors such as tyrphostins (e.g., AG490, AG17, AG213 (RG50864), AG18, AG82, AG494, AG825, AG879, AG1112, AG1296, AG1478, AG126, RG13022, RG14620, and AG555), dihydroxybenzylidene malononitrile and dimethoxybenzylidene malononitrile, analogs of lavendustin A (e.g., AG814 and AG957), quinazolines (e.g., AG1478), 4,5-dianilinophthalimides, and thiazolidinediones, may be co-administered with genistein or its analogs, prodrugs, or pharmaceutically acceptable salts (Levitzki et al., 2001). (See, for example, U.S. Pat. No. 5,637,703 to Mazurek et al., Science 267: 1782-1788 (1995); and Cunningham et al., Anti-Cancer Drug Design 7: 365-384 (1992)). In this regard, potentially useful derivatives of genistein include those described in U.S. Pat. No. 5,637,703 to Mazurek et al. Selenoindoles (2-thioindoles) and related disulfide selenium compounds, such as those described in U.S. Pat. No. 5,464,961 to Dobrusin et al., are useful protein tyrosine kinase inhibitors. Neutralizing proteins against a given growth factor, such as monoclonal antibodies specific for VEGF (see, e.g., Aiello et al., PNAS USA 92: 10457-10461 (1995)) or phosphotyrosine (Dhar et al., Mol. Pharmacol. 37: 519-525 (1990)), can be co-administered. Other compounds that may be used include inhibitors of protein kinase C (see, e.g., U.S. Pat. Nos. 5,719,175 and 5,710,145), cytokine modulators, inhibitors of endothelial cell-specific proliferation such as thrombospondin, endothelial cell-specific inhibitory growth factors such as TNFα, antiproliferative peptides such as SPARC and proliferin-like peptides, glutamate receptor antagonists, amino acid agonists, and the like. Guanidine, angiotensin converting enzyme inhibitors, e.g., angiotensin II, calcium channel blockers, γ-tectorigenin, ST638, somatostatin analogs, e.g., SMS201-995, monosialoganglioside GM1, ticlopidine, neurotrophic growth factors, methyl-2,5-dihydroxycinnamate, angiogenesis inhibitors, e.g., recombinant EPO, sulfonylurea oral hypoglycemic agents, e.g., gliclazide (non-insulin dependent diabetes mellitus), ST638 (Asahi et al., FEBS Letter 309: 10-14 (1992)), thalidomide, nicardipine hydrochloride, aspirin, piceatannol, staurosporine, adriamycin, epidelstatin, (+)-aeroprisinin-1, phenazocine, halomethyl ketones, antidyslipidemic agents such as etofibrate, chlorpromazine, spingosine, and retinoic acid and its analogs (Burke et al., Drugs of the Future 17 (2): 119-131 (1992); and Tomlinson et al., Pharmac. Ther. 54: 151-194 (1992)).

[0409] The present disclosure further provides the use of a compound of Formula (I)-(VI), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in a method for treating a disease state and / or condition caused by or associated with sorbitol dehydrogenase (SDH) deficiency. In another embodiment, the present disclosure relates to the use of a compound of Formula (I)-(VI), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in a method for treating a disease state and / or condition caused by or associated with sorbitol dehydrogenase (SDH) deficiency, the method comprising the steps of: (a) identifying a subject in need of such treatment; (b) providing a compound of Formula (I)-(VI), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; and (c) administering a therapeutically effective amount of said compound of Formula (I)-(VI) to treat, inhibit, and / or prevent the disease state or condition in the subject in need of such treatment.

[0410] In another embodiment, the present disclosure relates to the use of a compound of Formulas (I)-(VI), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in a method of treating a disease state and / or condition caused by or associated with sorbitol-dehydrogenase (SDH) deficiency, comprising the steps of: (a) identifying a subject in need of such treatment; (ii) providing a composition comprising a compound of Formulas (I)-(VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof; and (iii) administering a therapeutically effective amount of the composition to treat, inhibit, and / or prevent the disease state or condition in the subject in need of such treatment.

[0411] In the above-described embodiments, the compound or composition is preferably administered orally.

[0412] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [Example]

[0413] Aldose reductase inhibitors reduce sorbitol levels in human fibroblasts from patients via sorbitol dehydrogenase activity

[0414] Fibroblasts were obtained from skin biopsies of normal human volunteers or patients with confirmed sorbitol dehydrogenase deficiency (biallelic c.757delG). Fibroblasts were cultured in triplicate in Dulbecco's modified Eagle's medium (ThermoFisher) supplemented with 10% fetal bovine serum, penicillin, and streptomycin (Gibco). Cells were grown in a humidified incubator at 37°C with 5% CO2. Asynchronous cell cultures were grown to approximately 80% confluence and then treated with vehicle, Compound A (100 μM), or Compound B (10 μM) for 72 hours. Medium containing vehicle, Compound A, or Compound B was changed every 24 hours.

[0415] Sorbitol and protein were determined from human fibroblast lysates. For protein measurement, fibroblasts were harvested, lysed in RIPA buffer (ThermoFisher) containing protease inhibitors (Roche), and sonicated for 5 minutes using a Bioruptor sonicator (Diagenode). Protein quantification was performed using a Coomassie assay. For sorbitol determination, UPLC-tandem mass spectrometry (MS / MS) (Waters Acquity UPLC and TQD mass spectrometer) was used. Fibroblasts were harvested, lysed in RIPA buffer (ThermoFisher), and sonicated for 5 minutes using a Bioruptor sonicator (Diagenode). Cell lysates were centrifuged at 13,000 g for 10 minutes at 4°C, and the supernatant was collected for protein quantification and sorbitol measurement. For sorbitol measurement, the lysate was subjected to protein precipitation with acetonitrile (1:5), diluted 10-fold with acetonitrile / water (50:50), and cleaned with an Oasis HLB cartridge (10 mg / ml) before injection (3 μl) into the UPLC system. The UPLC conditions were as follows: column: BHE amid 1.7 μm (2.1 × 100 mm), 88°C; eluent A: 90% acetonitrile / 5% water / 5% isopropanol; eluent B: 80% acetonitrile / 20% water; gradient elution from 100% A at 0 min to 100% B in 3.6 min; flow rate: 0.45 mL / min. The retention time of sorbitol was 2.7 min. The linearity of the method was 0.25–50 mg / ml. -1 The MS / MS conditions were as follows: interface, electrospray interface in negative ion mode; multiple reaction monitoring acquisition, m / z 180.0 → 88.9 (CV24, CE15). The detection limit (signal-to-noise ratio = 3) was 0.03 mg / L. -1 Sorbitol levels were normalized to protein concentration.

[0416] result

[0417] Research results demonstrate that human fibroblasts from patients with SDH deficiency exhibit dramatically elevated levels of sorbitol. Such elevated sorbitol levels in fibroblasts and other cell types result in osmotic swelling, altered membrane permeability, and oxidative stress, leading to cell and tissue damage, including hereditary neuropathies associated with SDH deficiency, such as Charcot-Marie-Tooth disease (CMT1, and particularly CMT2), and distal hereditary motor neuropathy (dHMN), a form of CMT2 that primarily affects motor neurons. Research results demonstrate that treating fibroblasts from patients with SDH deficiency with an inhibitor of aldose reductase activity reduces cellular sorbitol levels. See Figure. Compared to vehicle controls, treatment with Compound A reduced sorbitol levels by 78%, and treatment with Compound B reduced sorbitol levels by 75%. Data demonstrate that aldose reductase inhibitors can be used to treat genetic and metabolic disorders that alter sorbitol metabolism or cause elevated levels of sorbitol, such as SDH deficiency, and associated clinical features and complications, including neuropathies such as CMT2 and dHMN.

[0418] Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, suitable methods and materials are described in the preceding paragraphs.Furthermore, the materials and methods are merely exemplary and are not intended to be limiting.All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated herein by reference.All foreign published patents and patent applications cited herein are incorporated herein by reference.All published references, documents, manuscripts, and scientific literature cited herein are incorporated herein by reference.All identifiers and accession numbers for scientific databases (e.g., PUBMED, NCBI, GENBANK, EBI) referenced herein are incorporated herein by reference. The present invention provides, for example, the following items. (Item 1) An aldose reductase inhibitor for use in the treatment of genetic and / or metabolic disorders that alter sorbitol metabolism or cause the overproduction of sorbitol, such as SDH deficiency. (Item 2) 2. The aldose reductase inhibitor according to item 1, wherein the treatment reduces sorbitol accumulation. (Item 3) 3. The aldose reductase inhibitor according to item 1 or 2, wherein the disorder is a genetic disorder that alters sorbitol metabolism or causes the overproduction of sorbitol. (Item 4) 3. The aldose reductase inhibitor according to item 1 or 2, wherein the disorder is hereditary SDH deficiency. (Item 5) 5. The aldose reductase inhibitor according to any one of items 1 to 4, wherein the disorder comprises a clinical feature or complication selected from the group consisting of cataract, neuropathy, retinopathy, cardiomyopathy, nephropathy, microvascular complications, atherosclerosis and other cardiovascular complications, albuminuria and diabetes. (Item 6) 6. The aldose reductase inhibitor according to any one of items 1 to 5, wherein the disorder is a hereditary neuropathy. (Item 7) 7. The aldose reductase inhibitor according to item 6, wherein the hereditary neuropathy is associated with SDH deficiency. (Item 8) 8. The aldose reductase inhibitor according to item 6 or 7, wherein the hereditary neuropathy is Charcot-Marie-Tooth disease (CMT). (Item 9) 8. The aldose reductase inhibitor according to item 6 or 7, wherein the CMT is CMT-2. (Item 10) 10. The aldose reductase inhibitor according to item 9, wherein the CMT-2 is distal hereditary motor neuropathy (dHMN). (Item 11) 11. The aldose reductase inhibitor according to any one of items 1 to 10, wherein the aldose reductase inhibitor is a compound of any one of formulae (I) to (VI) or a salt thereof: (Item 12) 11. The aldose reductase inhibitor according to any one of items 1 to 10, wherein the aldose reductase inhibitor is zopolrestat or a salt thereof, or epalrestat or a salt thereof. (Item 13) 11. The aldose reductase inhibitor according to any one of items 1 to 10, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof: (Item 14) The aldose reductase inhibitor is [ka] Item 14. The aldose reductase inhibitor according to item 13, selected from: (Item 15) 11. The aldose reductase inhibitor according to any one of items 1 to 10, wherein the aldose reductase inhibitor is a compound of formula (III). (Item 16) The aldose reductase inhibitor is [ka] 16. The aldose reductase inhibitor according to item 15, selected from: (Item 17) 17. The aldose reductase inhibitor according to any one of items 1 to 16, wherein the disease or disorder is in a human. (Item 18) 18. The aldose reductase inhibitor of item 17, wherein the human has diabetes. (Item 19) The aldose reductase inhibitor according to Item 18, wherein the human has complications of diabetes. (Item 20) The aldose reductase inhibitor according to any one of the preceding items, wherein the aldose reductase inhibitor is compound A or a salt thereof. (Item 21) The aldose reductase inhibitor according to any one of the preceding items, wherein the aldose reductase inhibitor is compound B or a salt thereof. (Item 22) A method for treating a genetic and / or metabolic disorder in a subject that alters sorbitol metabolism or causes overproduction of sorbitol, such as SDH deficiency, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor. (Item 23) 23. The method of claim 22, wherein the effective amount of the aldose reductase inhibitor is sufficient to reduce sorbitol accumulation in the subject. (Item 24) 24. The method of claim 22 or 23, wherein the genetic disorder is a disorder that alters sorbitol metabolism or causes the overproduction of sorbitol. (Item 25) 24. The method of item 22 or 23, wherein the disorder is an inherited SDH deficiency. (Item 26) 26. The method of any one of items 22 to 25, wherein the disorder comprises a clinical feature or complication selected from the group consisting of cataract, neuropathy, retinopathy, cardiomyopathy, nephropathy, microvascular complications, atherosclerosis and other cardiovascular complications, albuminuria, and diabetes. (Item 27) 23. The method of claim 22, wherein the disorder is a hereditary neuropathy. (Item 28) 28. The method of claim 27, wherein the hereditary neuropathy is associated with or caused by SDH deficiency. (Item 29) 29. The method of item 27 or 28, wherein the hereditary neuropathy is Charcot-Marie-Tooth disease (CMT). (Item 30) 29. The method according to item 27 or 28, wherein the Charcot-Marie-Tooth neuropathy type 2 (CMT-2). (Item 31) 31. The method of claim 30, wherein the CMT-2 is distal hereditary motor neuropathy (dHMN). (Item 32) 32. The method according to any one of items 22 to 31, wherein the aldose reductase inhibitor is a compound of any one of formulae (I) to (VI) or a salt thereof: (Item 33) 32. The method according to any one of items 22 to 31, wherein the aldose reductase inhibitor is zopolrestat or a salt thereof, or epalrestat or a salt thereof. (Item 34) 32. The method according to any one of items 22 to 31, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof: (Item 35) The aldose reductase inhibitor is [ka] Item 35. The method according to item 34, wherein the compound is selected from the group consisting of methyl, methylamino ... (Item 36) 32. The method according to any one of items 22 to 31, wherein the aldose reductase inhibitor is a compound of formula (III). (Item 37) The aldose reductase inhibitor is [ka] Item 37. The method according to item 36, wherein the compound is selected from the group consisting of methyl, methylamino ... (Item 38) 138. The method according to any one of items 22 to 137, wherein the subject is a human. (Item 39) 39. The method of item 38, wherein the subject in need thereof has diabetes. (Item 40) 40. The method of item 39, wherein the subject in need thereof has a diabetic complication. (Item 41) 41. The method according to any one of items 22 to 40, wherein the aldose reductase inhibitor is compound A or a salt thereof. (Item 42) 41. The method according to any one of items 22 to 40, wherein the aldose reductase inhibitor is compound B or a salt thereof. (Item 43) Use of aldose reductase inhibitors (ARIs) to treat sorbitol dehydrogenase (SDH) deficiency. (Item 44) Use of aldose reductase inhibitors (ARIs) to treat genetic disorders that alter sorbitol metabolism or cause overproduction of sorbitol. (Item 45) Use of aldose reductase inhibitors (ARIs) to treat hereditary neuropathies. (Item 46) An aldose reductase inhibitor (ARI) for use in the manufacture of a medicament for the treatment of sorbitol dehydrogenase (SDH) deficiency. (Item 47) An aldose reductase inhibitor (ARI) for use in the manufacture of a medicament for treating a genetic disorder that alters the metabolism of sorbitol or causes the overproduction of sorbitol. (Item 48) An aldose reductase inhibitor (ARI) for use in the manufacture of a medicament for the treatment of hereditary neuropathy. (Item 49) A pharmaceutical composition for treating sorbitol dehydrogenase (SDH) deficiency, comprising administering an aldose reductase inhibitor (ARI) as an active ingredient. (Item 50) A pharmaceutical composition for treating a genetic disorder that alters the metabolism of sorbitol or causes the overproduction of sorbitol, comprising administering an aldose reductase inhibitor (ARI) as an active ingredient. (Item 51) A pharmaceutical composition for treating hereditary neuropathy, comprising administering an aldose reductase inhibitor (ARI) as an active ingredient.

Claims

[Claim 1] The invention described in this specification.

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