Compositions and methods for treating galactosemia

Abstract

The present disclosure relates to methods of treating galactosemia and clinical manifestations of galactosemia using aldose reductase inhibitors.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of July 27, 2018, application number 201880059100.8, and invention name “Compositions and methods for treating galactosemia”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 538,443, filed on July 28, 2017, which is incorporated herein by reference in its entirety. Background Art

[0004] Galactosemia is a metabolic disorder caused by a reduced ability to metabolize galactose or an inability to metabolize galactose. The disease is usually caused by a deficiency in one or more enzymes involved in the Leloir pathway, including galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and galactose-6-phosphate epimerase (GALE). The deficiency of one or more of these enzymes can lead to the destruction of the Leloir pathway and the accumulation of galactose and certain galactose metabolites (such as galactose-1-phosphate (G1P) and plant galactose). In addition, when galactose accumulates, it can become a substrate for aldose reductase (AR), an enzyme in the polyol pathway of glucose metabolism. AR usually catalyzes the reduction of glucose to sorbitol (the first step in the polyol pathway), but when galactose levels are elevated, AR can also convert galactose to galactitol. Accumulation of galactose and galactose metabolites can cause damage to the liver, central nervous system (eg, brain), kidneys, eyes, and other body systems (Quan-Ma et al., Am J Dis Child., 112(5):477-478, 1966).

[0005] Appropriate screening tests can be used to detect genetic disorders that cause galactosemia (Berry et al., "Classic Galactosemia and Clinical Variant Galactosemia," Gene Reviews, Roberta A. Pagon, ed., University of Washington, Seattle; March 2017). There is currently no treatment for galactosemia, and the disease is mainly managed by dietary restrictions that eliminate dairy products and other foods containing galactose or lactose from the diet. (Welling et al., "International Clinical Guideline for the Management of Classical Galactosemia: Diagnosis, Treatment, and Follow up," J Inherit Metab Dis, 40(2): 171-176, 2017; Lai et al., IUBMB Life, 61(11): 1063-74, 2009). However, even if galactosemia is detected early and controlled by strict dietary restrictions, the level of galactose metabolites will still increase, and most patients will experience long-term complications such as speech difficulties, cognitive impairment, neurological symptoms and ovarian failure (Schadewaldt et al., Arch Physiol Biochem., 120 (5): 228-39, 2014; Berry et al., Mol Genet Metab., 81 (1): 22-30, 2004). However, even under strict dietary control, galactosemia patients are still at high risk of complications due to endogenous (or internal) synthesis of galactose in the body. Endogenous galactose production has shown the highest level in infancy and early childhood, but has been stable in adolescence and adulthood. Endogenous production of galactose results in high levels of galactose metabolites in patients even in the setting of absolute dietary compliance and contributes to the development of long-term complications, including central nervous system complications (cognitive, intellectual, speech, and motor deficits) as well as ocular cataracts (which may lead to partial blindness) and primary ovarian insufficiency (POI) in galactosemic women.

[0006] The most common form of galactosemia, type I galactosemia (OMIM#230400), is caused by mutations in GALT, the second enzyme of the Leloir pathway. GALK mutations cause type II galactosemia (OMIM#230200). Type III galactosemia (OMIM#230350) is caused by mutations in GALE. All three types are autosomal recessive disorders. Further subtypes of galactosemia have been identified based on the degree of functional impairment of the enzyme (biochemical phenotype), genotype, and the potential for developing acute and long-term complications.

[0007] The underlying mechanisms of galactosemia pathology are not fully understood, but endogenous production of galactose and the metabolites produced are considered to be important factors (Welling et al., J Inherit Metab Dis, 40 (2): 171-176, 2017). Currently, the only treatment for galactosemia is dietary restriction of galactose, and lifelong restriction of galactose diet is the current standard of care. Although the diet can reverse the acute clinical symptoms of newborns, it cannot prevent the occurrence of long-term complications. There is no way to treat or prevent any long-term complications.

[0008] Thus, there is a recognized but unmet need for methods of treating and / or managing galactosemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Graph showing weight gain of wild-type rat pups (GALT+), GALT null (null) rat pups, and GALT null rat pups treated with an aldose reductase inhibitor (ARI) (Compound A), with weight (g) plotted on the vertical axis and age (days) plotted on the horizontal axis.

[0010] Figures 2A-2D is a graph showing the effect of aldose reductase inhibitors on cataracts in galactosemic rats. Figure 2A Results of qualitative assessment of cataracts at day 9 presence / severity scores (0-3 scale) are shown in control (wild-type rats treated with Compound A) and GALT-null rats treated with placebo or Compound A. A score of 0 indicates the absence of cataracts; a score of 1 indicates mild cataract size and opacity; a score of 2 indicates moderate cataract size and opacity; and a score of 3 indicates severe cataract size and opacity. Cataracts were assessed on day 22 of life. Figure 2B Shown are quantitative numerical assessments of cataracts in wild-type or GALT-null rats treated with Compound B or placebo at day 22 of life. Figure 2C Figure 2 shows the development of cataracts in wild-type or GALT-null rats treated with Compound B or placebo on day 10 of life. QualitativeEvaluate the results. Figure 2D Shown is a qualitative assessment of cataracts in wild-type or GALT-null rats treated with Compound B or placebo on day 22 of life. Figure 2A The same scoring method is used in Figure 2C and Figure 2D Qualitative analysis in .

[0011] Figures 3A-3C Bar graphs showing the levels of the metabolites galactitol, galactose, and galactose 1-phosphate in the liver, brain, or plasma of control (wild-type rats) and GALT-null rats treated with placebo or Compound B. Figure 3A Displays galactitol levels; Figure 3B indicates galactose level; Figure 3C Galactose-1-phosphate (Gal1P) levels are shown. SUMMARY OF THE INVENTION

[0013] The present disclosure relates to methods for treating galactosemia and treating or preventing complications of galactosemia by administering a therapeutically effective amount of an AR inhibitor to a subject in need thereof. Without wishing to be bound by any particular theory, and as described herein, it is believed that inhibition of AR can reduce or prevent the accumulation of galactitol and the resulting pathology associated with galactosemia.

[0014] In one example, the method for treating or preventing galactosemia (or galactosemia complications) includes applying a therapeutically effective amount of zopolrestat to a subject in need thereof. In one example, the method for treating or preventing galactosemia (or galactosemia complications) includes applying a therapeutically effective amount of epalrestat to a subject in need thereof. In one example, the method for treating or preventing galactosemia (or galactosemia complications) includes applying a therapeutically effective amount of any one of Formulas I-VI to a subject in need thereof. In some aspects, the AR inhibitor administered is not ponarestat, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, fennarestat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210.

[0015] Subjects treated according to the methods disclosed herein may have elevated alditol levels in blood, urine or intraocular fluid, such as elevated levels of galactitol, inositol or sorbitol in blood, urine or intraocular fluid. Subjects treated according to the methods disclosed herein may have complications or clinical manifestations of galactosemia, including cirrhosis, retinal disorders, macular edema, ocular cataracts, ovarian dysfunction, muscle or nerve dysfunction, retinopathy, neuropathy, cognitive dysfunction, motor ataxia, epilepsy, pseudomotor cerebrii, speech dysfunction, impaired nerve conduction or mental retardation. In another embodiment, the present disclosure relates to a method for treating or preventing complications associated with galactosemia in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an AR inhibitor and a pharmaceutically acceptable carrier. The present disclosure relates to a method for reducing the amount or level of galactitol in a subject suffering from galactosemia, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to the subject.

[0016] The present disclosure relates to a method for treating cataracts, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to a subject in need thereof. Preferably, the subject in need thereof suffers from galactosemia.

[0017] The present disclosure relates to a method for treating or preventing cognitive or neurological impairment associated with galactosemia, comprising administering a therapeutically effective amount of an aldose reductase inhibitor to a subject suffering from galactosemia. In an embodiment, the cognitive or neurological impairment associated with galactosemia is speech dysfunction. In an embodiment, the cognitive or neurological impairment associated with galactosemia is motor ataxia. In an embodiment, the cognitive or neurological impairment associated with galactosemia is cognitive dysfunction. In an embodiment, the cognitive or neurological impairment associated with galactosemia is pseudokinetic cerebrum. In an embodiment, the cognitive or neurological impairment associated with galactosemia is epilepsy.

[0018] In another embodiment, the present disclosure relates to a method of treating or preventing galactosemia in a subject in need thereof, comprising administering a therapeutically effective amount of

[0019] (a) a first pharmaceutical composition comprising a compound of Formula I-VI and a pharmaceutically acceptable carrier; and

[0020] (b) A second pharmaceutical composition comprising alponalrestat, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, zenastat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210 and a pharmaceutically acceptable carrier.

[0021] In another embodiment, disclosed herein is the use of an AR inhibitor for inhibiting the production of alditols (eg, galactitol) for treating galactosemia.

[0022] In another embodiment, disclosed herein is the use of an AR inhibitor in the preparation of a medicament for treating galactosemia or a clinical manifestation of galactosemia selected from cataracts and primary ovarian insufficiency (POI).

[0023] The present disclosure also relates to the use of AR inhibitors (eg, zopolrestat, epalrestat, compounds of any one of Formulae I-VI) in treating galactosemia and / or treating and preventing complications associated with galactosemia.

[0024] The present disclosure also relates to AR inhibitors (eg, zopolrestat, epalrestat, compounds of any one of Formulae I-VI) for use in the preparation of medicaments for treating galactosemia and / or treating and preventing complications associated with galactosemia.

[0025] The present disclosure also relates to a pharmaceutical preparation for treating galactosemia and / or treating and preventing complications associated with galactosemia, which contains an AR inhibitor (eg, zopolrestat, epalrestat, a compound of any one of Formulae I-VI) as an active ingredient. DETAILED DESCRIPTION OF THE INVENTION

[0027] Various aspects will now be described more fully below. However, such aspects may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete.

[0028] The present disclosure relates to the use of AR inhibitors for the treatment of galactosemia. The methods described herein are based in part on the inventors' insights into the role of AR activity in the pathophysiology of galactosemia. In normal subjects, AR mainly catalyzes the reduction of glucose to sorbitol (the first step of the polyol pathway of glucose metabolism). However, in subjects with elevated galactose levels, due to Leloir pathway defects (e.g., due to the lack or deficiency of related enzymes) and / or other reasons (e.g., due to excessive consumption of lactose, diabetes, endogenous production of galactose), excess galactose is converted to galactitol by AR. Galactitol produced by such mechanisms accumulates in cells because galactitol is not a substrate for the next enzyme sorbitol dehydrogenase in the polyol pathway. Such accumulation of galactitol causes or contributes to pathophysiological events in galactosemia tissues, such as hyperosmosis, sugar imbalance, oxidative stress, etc. Therefore, the present disclosure relates to a method for treating or preventing galactosemia or complications of galactosemia by administering a therapeutically effective amount of an AR inhibitor to a subject in need thereof. Without wishing to be bound by any particular theory, it is believed that inhibition of AR can reduce or prevent the accumulation of galactitol and the pathology and complications associated with galactosemia. These complications can be mediated in part by increased synthesis of galactitol and / or increased accumulation of galactitol (e.g., due to enzyme deficiency or deficiency of the Leloir pathway, elevated galactose levels, abnormal AR activity, reduced excretion of galactitol from tissues (e.g., due to renal disorders). Inhibition of aldose reductase can reduce the synthesis and accumulation of galactitol in tissues, as well as the pathology and complications associated with galactosemia. Therefore, the present disclosure further relates to the use of galactitol as a biomarker for aldose reductase inhibition, and as a biomarker for monitoring the initiation, progression and performance of galactosemia.

[0029] Where a range of values ​​is provided in the present disclosure, it is intended that every intervening value between the upper and lower limits of the range and any other stated value or intervening value in the stated range is encompassed within the present disclosure. For example, if the stated range is 1 μM to 8 μM, it is intended that 2 μM, 3 μM, 4 μM, 5 μM, 6 μM and 7 μM are also expressly disclosed, as well as ranges of values ​​greater than or equal to 1 μM and ranges of values ​​less than or equal to 8 μM.

[0030] Unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "a compound of Formula I" includes a single compound as well as two or more identical or different compounds; reference to "an excipient" includes a single excipient as well as two or more identical or different excipients, etc.

[0031] The word "about" refers to a range of plus or minus 10% of the value, for example, "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc., unless the context of the present disclosure indicates otherwise or is inconsistent with such an interpretation. For example, in a series of numerical values ​​such as "about 49, about 50, about 55", "about 50" refers to a range extending to less than half of the interval between the previous value and the subsequent value, for example, greater than 49.5 to less than 52.5. In addition, the phrase "less than about" value or "greater than about" value should be understood according to the definition of the term "about" provided herein.

[0032] In order to provide a complete, concise and clear description of various embodiments, the present disclosure includes descriptions of various components, component groups, ranges and other elements disclosed more broadly. It is intended that such elements may be combined in various ways to provide additional embodiments of the present 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 sub-range or combination of sub-ranges within the group, may be excluded from the present disclosure or any embodiment of the present disclosure for any reason.

[0033] Various embodiments of the present disclosure are described in further detail in the following numbered paragraphs.

[0034] I. Methods

[0035] In general, the present disclosure relates to a method for treating galactosemia (or galactosemia complications), comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits aldose reductase activity. The method is particularly useful for treating and / or preventing complications associated with galactosemia. The compound can be any suitable compound that inhibits AR activity, such as a small molecule compound (e.g., having a size of 5kDa or less), a biological agent (e.g., an inhibitory RNA for aldose reductase) or a combination thereof. Preferably, the AR inhibitor is a small molecule compound. Suitable small molecule AR inhibitors are known in the art and disclosed herein. Small molecule AR inhibitors include bonacitate, sobinil, sorbinol, mirestat, AND-138, CT-112, zenacitate, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine, SPR-210, zopolrestat, epalrestat, compounds disclosed in US 8,916,563 and US 9,650,383 and compounds disclosed herein. Preferred AR inhibitors for the present invention include zopolrestat, epalrestat, compounds disclosed in US Pat. No. 8,916,563 and US Pat. No. 9,650,383 and compounds disclosed herein. AR inhibitors can be administered in any suitable form of molecule, including pharmaceutically acceptable salts, solvates, prodrugs and compounds containing stable isotopes of one or more atoms, such as deuterium instead of hydrogen.

[0036] In one example, a method for treating galactosemia (or galactosemia complications) comprises administering a therapeutically effective amount of zopolrestat to a subject in need thereof. Accordingly, the present disclosure provides a method for treating galactosemia and preventing galactosemia complications in a patient with galactosemia, and comprises administering a therapeutically effective amount of zopolrestat to a subject in need thereof.

[0037] In one example, a method for treating galactosemia (or galactosemia complications) comprises administering a therapeutically effective amount of epalrestat to a subject in need thereof. Therefore, the present disclosure provides a method for treating galactosemia and preventing galactosemia complications in a patient with galactosemia, and comprises administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0038] In one example, a method for treating galactosemia (or a complication of galactosemia) comprises administering to a subject in need thereof a therapeutically effective amount of an aldose reductase, wherein the aldose reductase inhibitor is not bonacerostat, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, zenacerostat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210.

[0039] In one example, a method for treating galactosemia (or galactosemia complications) comprises administering a therapeutically effective amount of a compound of any one of Formulas I-VI to a subject in need thereof. Therefore, the present disclosure provides a method for treating galactosemia and preventing galactosemia complications in a patient with galactosemia, and comprises administering a therapeutically effective amount of a compound of any one of Formulas I-VI to a subject in need thereof. In some instances, the compound administered is Compound A or the compound administered is Compound B.

[0040] As used herein, the term "treatment" refers to curative or palliative (e.g., controlling or alleviating a disease or disease symptom) therapy. This may include reversing, alleviating, preventing or delaying the symptoms, clinical signs and underlying pathology of galactosemia in a manner that improves or stabilizes the subject's condition. In the context of the present method, the term "prevention" refers to prophylactic treatment of an individual with galactosemia, for example, to prevent complications associated with galactosemia (e.g., symptoms and clinical signs). For example, a family history or susceptibility to diabetes may indicate that the subject is at risk for galactosemia and related complications. Therefore, the method can be used for the treatment of galactosemia, the treatment of complications of galactosemia (e.g., symptoms and clinical signs), and / or the treatment and prevention of complications of galactosemia (e.g., symptoms and clinical signs).

[0041] As used herein, a "therapeutically effective amount" is an amount of a compound sufficient to achieve the desired therapeutic effect under the conditions of administration, such as an amount that reduces or improves the severity and / or duration of galactosemia or one or more of its clinical manifestations (e.g., cataracts or primary ovarian insufficiency (POI)), prevents the progression of a condition or symptom associated with galactosemia, or enhances or otherwise improves the therapeutic effect of another therapy for treating or controlling galactosemia (e.g., hormone therapy in the case of POI or surgery in the case of cataracts). A therapeutically effective amount may be an amount that reduces and preferably normalizes the amount or level of galactose or galactose metabolites, particularly galactitol, in the treated subject. The amount actually administered may be determined by an ordinary skilled clinician based on, for example, the subject's age, weight, sex, general health and tolerance to the drug, the severity of the disease, the selected dosage form, the route of administration, and other factors. Typically, the AR inhibitor is administered in an amount of about 0.5 to about 60 mg / kg body weight per day, for example, about 1.0 to 10 mg / kg.

[0042] In some examples of the practice of the methods disclosed herein, the therapeutically effective amount is an amount 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, such as about 100% (e.g., compared to pre-treatment levels). The therapeutically effective amount can be an amount that reduces intracellular galactitol 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, such as about 100% (e.g., compared to pre-treatment levels). The therapeutically effective amount can be an amount that reduces plasma galactitol concentrations in human subjects with galactosemia to less than 200 μM, particularly less than 100 μM, especially less than 50 μM, and preferably less than 10 μM. Untreated patients with classic galactosemia have elevated plasma galactitol levels (120–500 μmol / l) compared to controls (0.08–0.86 μmol / l) (Jakobs et al., Eur J Pediatr., 154(7 Suppl 2): ​​S50-2, 1995). A therapeutically effective amount may be sufficient to restore physiological features that are reduced in galactosemia, such as decreased vision in subjects with cataracts or decreased estrogen levels in subjects with POI. A therapeutically effective amount of an aldose reductase inhibitor may be an amount sufficient to normalize galactitol levels in tissues (e.g., liver galactitol levels, brain galactitol levels) or blood (plasma).

[0043] A "subject" can be any animal, particularly a mammal, and includes but is in no way limited to humans, domestic animals (such as feline or canine subjects), farm animals (such as but not limited to bovine, equine, caprine, ovine, avian and porcine subjects), wild animals (whether in the wild or in a zoo), research or experimental animals (such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc.), birds (such as chickens, turkeys, songbirds, etc.). Preferably, a "subject" is a human who is susceptible (due to a genetic aberration) or has been diagnosed with galactosemia. Typically, a human subject treated using the methods disclosed herein is newly diagnosed with galactosemia by enzyme or genetic screening and has a deficiency in GALT activity, GALK activity, or GALE activity.

[0044] The present disclosure also relates to preventing or treating at least one clinical feature or complication of galactosemia in a subject. Representative clinical features or complications that may occur in children, adolescents or adults include, for example, liver dysfunction, susceptibility to infection, developmental delay, cataracts, retinopathy, neuropsychological and ovarian problems. For example, the present disclosure is directed to treating at least one feature of a galactosemia subject selected from the group consisting of jaundice (incidence: 74% of subjects), vomiting (47% of subjects), hepatomegaly (43% of subjects), developmental delay (29% of subjects), poor feeding (23% of subjects), lethargy (16% of subjects), diarrhea (12% of subjects), sepsis (10% of subjects), more specifically, E. coli sepsis (76% of sepsis), coagulopathy, ascites, seizures, hepatomegaly, hypotonia, edema, full fontanelles, encephalopathy, bruising or excessive bleeding, primary ovarian insufficiency and premature ovarian failure (POF). In addition, galactosemia patients may have low bone density. Preferably, the clinical feature is lenticular cataract, retinopathy or ovarian dysfunction (e.g., primary ovarian insufficiency (POI) or premature ovarian failure (POF)). See, Berry et al., “Classic Galactosemia and Clinical Variant Galactosemia,” in Gene Reviews, Pagon RA, Adam MP, Ardinger HH et al., eds., University of Washington, Seattle, 2017.

[0045] Patients with galactosemia may experience long-term neurological and cognitive complications, even when the disease is diagnosed early and managed with a galactose-restricted diet. Such complications are variable and include below-average IQ, impaired executive function, tremor, ataxia, dysarthria, apraxia of speech, depression, and anxiety. Thus, additional preferred clinical features of galactosemia that can be treated or prevented using the methods described herein are neurological and cognitive deficits, such as central nervous system deficits, including speech dysfunction (e.g., delayed or impaired speech), motor ataxia, epilepsy, pseudokinetic cerebral and cognitive dysfunction (e.g., low IQ (IQ less than about 85)).

[0046] In a particular aspect, the present disclosure relates to a method for treating clinical features or complications of galactosemia and comprises administering to a subject in need thereof a therapeutically effective amount of zopolrestat.

[0047] In one example, the present disclosure relates to a method for treating clinical features or complications of galactosemia, and comprises administering to a subject in need thereof a therapeutically effective amount of epalrestat.

[0048] In one example, the disclosure relates to a method for treating clinical features or complications of galactosemia, and comprises administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulae I-VI.

[0049] In an embodiment, the clinical feature or complication of galactosemia to be treated or prevented is retinopathy or cataract. Early-onset cataract is a common complication in patients with galactosemia, and in a specific embodiment, the method is a method for treating cataracts. Cataracts can be cystic cataracts occurring at the back of the lens, nuclear cataracts formed in the central region (nucleus) of the lens, and cortical (radial) cataracts affecting the lens cortex. The method can also be used to treat cataracts that have been or are being treated surgically, cataracts that occur after surgical removal of an existing opaque lens, i.e., secondary cataracts, cataracts that occur after retinal detachment and surgery to repair retinal detachment, cataracts associated with eye or head trauma, cataracts associated with tumors, cataracts associated with exposure to radiation, and cataracts associated with sugar toxicity. The method of the present invention can also be used to preventively treat cataracts caused by systemic disorders, such as, but not limited to, galactosemia.

[0050] In an embodiment, the clinical features or complications of galactosemia to be treated or prevented are the long-term neurological and cognitive complications of galactosemia. Patients with galactosemia may experience long-term neurological and cognitive complications, even when the disease is diagnosed early and managed with a galactose-restricted diet. Such complications are variable and include below-average IQ, impaired executive function, tremor, ataxia, dysarthria, apraxia of speech, depression, and anxiety.

[0051] In an embodiment, the clinical feature or complication of galactosemia to be treated or prevented is primary ovarian insufficiency (POI) or premature ovarian failure (POF) or symptoms associated therewith. The method comprises administering a compound of the present disclosure or a composition containing the compound to a subject in need thereof. POI is characterized by ovarian dysfunction (e.g., inability to produce estrogen and other hormones that are critical to reproductive health). Galactosemia is one of the few known causes of POI, and almost all women with galactosemia suffer from or develop POI at some point in their lives. Women with POI are more likely to develop the bone disease osteoporosis or heart problems, and POI may also lead to infertility. See, Fridovich-Keil et al., J Inherit Metab Dis. 34(2):357–366, 2011. Symptoms or features associated with POI include, for example, delayed onset of period, sudden stoppage or disruption in period, breast deformity, hot flashes, affect symptoms (eg, mood swings or irritability), vaginal dryness, and / or inability to sleep.

[0052] In some aspects, the disclosure relates to a method for reducing the amount or level of galactitol in a subject, the method comprising administering a compound of the inhibition of aldose reductase activity of a therapeutically effective amount to a subject in need thereof. The method can be used to reduce galactitol in tissues such as liver, brain, eyes, retina and / or circulatory system (e.g., blood or plasma) and / or urine. Preferably, galactitol levels are normalized. The galactose level in the patient suffering from galactosemia can be raised, and preferably, the method for reducing galactitol will not cause a further increase in galactose levels. The normal amount or level of galactitol is the amount or level present in a healthy subject without dietary restrictions. Such normal amount or level is well known and is shown in Table 1.

[0053] In an embodiment, the clinical feature or complication of galactosemia to be treated or prevented is retinopathy or cataract. Early-onset cataract is a common complication in patients with galactosemia, and in a specific embodiment, the method is a method for treating cataracts. Cataracts can be cystic cataracts occurring at the back of the lens, nuclear cataracts formed in the central region (nucleus) of the lens, and cortical (radial) cataracts affecting the lens cortex. The method can also be used to treat cataracts that have been or are being treated surgically, cataracts that occur after surgical removal of an existing opaque lens, i.e., secondary cataracts, cataracts that occur after retinal detachment and surgery to repair retinal detachment, cataracts associated with eye or head trauma, cataracts associated with tumors, cataracts associated with exposure to radiation, and cataracts associated with sugar toxicity. The method of the present invention can also be used to preventively treat cataracts caused by systemic disorders, such as, but not limited to, galactosemia.

[0054] In one particular aspect, the present disclosure relates to a method for treating or preventing cataracts and comprises administering to a subject in need thereof a therapeutically effective amount of zopolrestat.

[0055] In one example, the present disclosure relates to a method for treating or preventing cataracts, and comprises administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0056] In one example, the present disclosure relates to a method for treating or preventing cataracts, and 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 compound administered is Compound A or the compound administered is Compound B.

[0057] Preferably, the patient in need of therapy for the treatment or prevention of cataracts suffers from galactosemia.

[0058] In an embodiment, the clinical features or complications of galactosemia to be treated or prevented are the long-term neurological and cognitive complications of galactosemia. Patients with galactosemia may experience long-term neurological and cognitive complications, even when the disease has been diagnosed early and managed with a galactose-restricted diet. Such complications are variable and include below-average IQ, impaired executive function, tremor, ataxia, dysarthria, apraxia of speech, depression, and anxiety.

[0059] In a specific aspect, the present disclosure relates to a method for treating or preventing neurological and cognitive deficits associated with galactosemia, and comprises administering a therapeutically effective amount of zopolrestat to a subject with galactosemia. In a specific embodiment, the neurological or cognitive deficit associated with galactosemia is speech dysfunction, such as speech delay or speech disorder. In a specific embodiment, the neurological or cognitive deficit associated with galactosemia is motor ataxia. In a specific embodiment, the neurological or cognitive deficit associated with galactosemia is cognitive dysfunction, such as low IQ. In a specific embodiment, the neurological or cognitive deficit associated with galactosemia is pseudokinetic cerebrum. In a specific embodiment, the neurological or cognitive deficit associated with galactosemia is epilepsy.

[0060] In one example, the present disclosure relates to a method for treating or preventing neurological and cognitive defects associated with galactosemia, and comprises administering a therapeutically effective amount of epalrestat to a subject with galactosemia. In a specific embodiment, the neurological or cognitive defect associated with galactosemia is speech dysfunction, such as speech delay or speech disorder. In a specific embodiment, the neurological or cognitive defect associated with galactosemia is motor ataxia. In a specific embodiment, the neurological or cognitive defect associated with galactosemia is cognitive dysfunction, such as low IQ. In a specific embodiment, the neurological or cognitive defect associated with galactosemia is pseudokinetic cerebrum. In a specific embodiment, the neurological or cognitive defect associated with galactosemia is epilepsy.

[0061] In one example, the present disclosure relates to a method for treating or preventing the nervous system and cognitive defects associated with galactosemia, and includes administering a therapeutically effective amount of a compound of any one of Formulas I-VI to a subject suffering from galactosemia. In certain instances, the compound administered is Compound A or the compound administered is Compound B. In a specific embodiment, the nervous system or cognitive defects associated with galactosemia are speech dysfunction, such as speech delay or speech disorder. In a specific embodiment, the nervous system or cognitive defects associated with galactosemia are motor ataxia. In a specific embodiment, the nervous system or cognitive defects associated with galactosemia are cognitive dysfunction, such as low IQ. In a specific embodiment, the nervous system or cognitive defects associated with galactosemia are pseudokinetic cerebral. In a specific embodiment, the nervous system or cognitive defects associated with galactosemia are epilepsy.

[0062] In an embodiment, the clinical feature or complication of galactosemia to be treated or prevented is primary ovarian insufficiency (POI) or premature ovarian failure (POF) or symptoms associated therewith. The method comprises administering a compound of the present disclosure or a composition containing the compound to a subject in need thereof. POI is characterized by ovarian dysfunction (e.g., inability to produce estrogen and other hormones that are critical to reproductive health). Galactosemia is one of the few known causes of POI, and almost all women with galactosemia suffer from or develop POI at some point in their lives. Women with POI are more likely to develop the bone disease osteoporosis or heart problems, and POI may lead to infertility. See, Fridovich-Keil et al., J Inherit Metab Dis. 34(2):357–366, 2011. Symptoms or features associated with POI include, for example, delayed onset, sudden cessation or interruption of periods, breast deformities, hot flashes, affect symptoms (e.g., mood swings or irritability), vaginal dryness, and / or inability to sleep.

[0063] In one specific aspect, the present disclosure relates to a method for treating or preventing POI or POF and comprises administering a therapeutically effective amount of zopolrestat to a subject having galactosemia.

[0064] In one example, the present disclosure relates to a method for treating or preventing POI or POF, and comprises administering a therapeutically effective amount of epalrestat to a subject having galactosemia.

[0065] In one example, the present disclosure relates to a method for treating or preventing POI or POF, and comprises administering a therapeutically effective amount of a compound of any one of Formulas I-VI to a subject with galactosemia. In certain examples, the compound administered is Compound A or the compound administered is Compound B.

[0066] In some aspects, the disclosure relates to a method for reducing the amount or level of galactitol in a subject, the method comprising administering a compound of aldose reductase activity of a therapeutically effective amount to a subject in need thereof. The method can be used to reduce galactitol in tissues such as liver, brain, eyes, retina, and / or circulatory system (e.g., blood or plasma) and / or urine. Preferably, galactitol levels are normalized. The galactose level in the patient suffering from galactosemia can be increased, and preferably, the method for reducing galactitol will not cause a further increase in galactose levels. The normal amount or level of galactitol is the amount or level of a healthy subject without dietary restrictions. Such normal amount or level is well known and is shown in Table 1.

[0067]

[0068]

[0069] In one specific aspect, the present disclosure relates to a method for reducing, and preferably normalizing, the amount or level of galactitol in a subject suffering from galactosemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of zopolrestat.

[0070] In one example, the present disclosure relates to a method for reducing, and preferably normalizing, the amount or level of galactitol in a subject with galactosemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of epalrestat.

[0071] In one example, the present disclosure relates to a method for reducing the amount or level of galactitol in a subject with galactosemia and preferably normalizing it, the method comprising 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 compound administered is Compound A or the compound administered is Compound B.

[0072] In some embodiments, the aforementioned methods are performed by administering a single dose or a single administration (e.g., in the form of a single injection or deposition) of one or more AR inhibitors. Alternatively, the method is performed by administering a preparation suitable for once a day, twice a day, three times a day, or four times a day to a subject in need thereof for about 2 to about 28 days, or about 7 days to about 10 days, or about 7 to about 15 days, or longer. In some embodiments, the method is performed by administering a preparation suitable for chronic administration. In other embodiments, the method is performed by administering a preparation suitable for administration over the course of weeks, months, years, or decades. In other embodiments, the method is performed by administering a preparation suitable for administration over the course of weeks. In other embodiments, the method is performed by administering a preparation suitable for administration over the course of months. In other embodiments, the method is performed by administering a preparation suitable for administration over the course of years. In other embodiments, the method is performed by administering a preparation suitable for administration over the course of decades.

[0073] II. AR Inhibitors

[0074] Suitable small molecule AR inhibitors are known in the art and disclosed herein. Small molecule AR inhibitors include bonacitate, sobinil, sorbinol, mirestat, AND-138, CT-112, zenastat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine, SPR-210, zopolrestat and epalrestat, US 8,916,563, US 9,650,383, WO2012 / 009553 disclosed compounds and compounds disclosed herein. Preferred AR inhibitors for the present invention are zopolrestat, epalrestat, compounds disclosed in US Pat. No. 8,916,563, US Pat. No. 9,650,383, WO2017 / 038505, and compounds disclosed herein. The disclosures of U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, WO 2012 / 009553, and WO 2017 / 038505 are incorporated herein by reference in their entireties and disclose compounds suitable for use in the methods described herein.

[0075] AR inhibitors of formula I and II

[0076] In one example, the AR inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof,

[0077]

[0078] in,

[0079] R 1 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl or (C1-C6)-aminoalkyl;

[0080] X 1 N or CR 3 ;

[0081] X 2 N or CR 4 ;

[0082] X 3 N or CR 5 ;

[0083] X 4 N or CR 6 ; The condition is X 1 , X 2 , X 3 or X 4 Two or three of them are N;

[0084] Y is a bond, C═O, C═S, C═NH or C═N(C1-C4)-alkyl;

[0085] Z is

[0086]

[0087] A 1 NR 11 , O, S or CH2;

[0088] A 2 N or CH;

[0089] A 3 NR 11 , O or S;

[0090] R 3 To R 10 R is 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 To R 6 Two or R 7 To R 10 Two of the together are (C1-C4)-alkylenedioxy; and

[0091] R 11 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0092] Those skilled in the art will recognize the following designations: Z is

[0093]

[0094] It means that when Z is When, the compound of formula (I) includes

[0095]

[0096] And when Z is hour,

[0097] The compounds of formula (I) include

[0098]

[0099] In certain embodiments, R 1 is hydrogen or (C1-C6)-alkyl. 1 In certain embodiments, R 1 is (C1-C6)-alkyl. In certain embodiments, R 1 It is tert-butyl.

[0100] In certain embodiments, R 3 To R 10 is independently hydrogen, halogen or haloalkyl. 3 To R 10 are independently hydrogen, halogen or trihaloalkyl.

[0101] In certain embodiments, R 3 To R 6 For hydrogen.

[0102] In certain embodiments, R 7 To R 10 is independently hydrogen, halogen or haloalkyl. 7 To R 10 are independently hydrogen, halogen or trihaloalkyl.

[0103] In certain embodiments, R 7 and R 10 For hydrogen.

[0104] In certain embodiments, R 8 is hydrogen, halogen or haloalkyl. 8 In certain embodiments, R 8 In certain embodiments, R 8 It is a halogenated alkyl group.

[0105] In certain embodiments, R 9 is hydrogen, halogen or haloalkyl. 9 In certain embodiments, R 9 In certain embodiments, R 9 It is a halogenated alkyl group.

[0106] 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.

[0107] In certain embodiments, A 1 NR 11 , S or CH2. In certain embodiments, A 1 NR 11 Or O. In certain embodiments, A 1 NR 11 Or S. In certain embodiments, A 1NR 11 In certain embodiments, A 1 is 0. In certain embodiments, A 1 For S.

[0108] In certain embodiments, A 2 is N or CH. In certain embodiments, A 1 is N. In certain embodiments, A 1 For CH.

[0109] In certain embodiments, A 3 is O or S. In certain embodiments, A 3 is 0. In certain embodiments, A 3 For S.

[0110] In certain embodiments, X 1 and X 4 For nitrogen.

[0111] In certain embodiments, X 1 and X 2 For nitrogen.

[0112] In certain embodiments, X 1 and X 3 For nitrogen.

[0113] In certain embodiments, X 2 and X 3 For nitrogen.

[0114] In certain embodiments, X 2 and X 4 For nitrogen.

[0115] In certain embodiments, X 3 and X 4 For nitrogen.

[0116] In certain embodiments, Z is

[0117]

[0118] In certain embodiments, Z is

[0119]

[0120] In certain embodiments, R 1 is hydrogen or (C1-C6)-alkyl;

[0121] X 1 and X 4 is N;

[0122] X 2 CR4 ;

[0123] X 3 CR 5 ;

[0124] Y is C═O;

[0125] Z is

[0126]

[0127] A 1 NR 11 , O or S;

[0128] A 2 is N;

[0129] A 3 O or S;

[0130] R 4 and R 5 is hydrogen;

[0131] R 7 To 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; and

[0132] R 11 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0133] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0134] X 1 and X 4 is N;

[0135] X 2 CR 4 ;

[0136] X 3 CR 5 ;

[0137] Y is C═O;

[0138] Z is

[0139]

[0140] A 1 NR 11 , O or S;

[0141] A 2 is N;

[0142] A 3 O or S;

[0143] R 4 and R 5 is hydrogen;

[0144] R 7 To R 10 are independently hydrogen, halogen or haloalkyl; and R 11 is hydrogen, (C1-C4)-alkyl or C(O)O-tert-butyl. 1 is hydrogen or tert-butyl;

[0145] X 1 and X 4 is N;

[0146] X 2 for CH;

[0147] X 3 for CH;

[0148] Y is C═O;

[0149] Z is

[0150]

[0151] A 1 NR 11 , O or S;

[0152] A 2 is N;

[0153] A 3 O or S;

[0154] R 7 , R 8 and R 10 are independently hydrogen, halogen or haloalkyl;

[0155] R 9 is halogen or haloalkyl; and

[0156] R 11 It is hydrogen or methyl.

[0157] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0158] X 1 and X 4 is N;

[0159] X 2for CH;

[0160] X 3 for CH;

[0161] Y is C═O;

[0162] Z is

[0163]

[0164] A 1 NR 11 , O or S;

[0165] A 2 is N;

[0166] A 3 O or S;

[0167] R 7 , R 8 and R 10 are independently hydrogen, halogen or haloalkyl;

[0168] R 9 is chloro or trifluoromethyl; and

[0169] R 11 It is hydrogen or methyl.

[0170] In certain embodiments, the AR inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

[0171]

[0172] Where R 1 , R 7 -R 9 and Y are as described in Formula I, and preferably wherein R 1 is hydrogen or (C1-C6)-alkyl and Y is C=O. Exemplary compounds of Formula II include the following and salts thereof:

[0173]

[0174] Compound of formula III

[0175] The AR inhibitor may be a compound of formula (III) or a pharmaceutically acceptable salt, prodrug or solvate thereof,

[0176]

[0177] in,

[0178] R 1 For CO2R 2 or CO2- X + ;

[0179] R 2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl or (C1-C6)-aminoalkyl;

[0180] X 1 is H or halogen;

[0181] X 2 is H or halogen;

[0182] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

[0183] Z is

[0184] A 1 NR 7 , O, S or CH2;

[0185] A 2 N or CH;

[0186] A 3 NR 7 , O or S;

[0187] R 3 To 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;

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

[0189] X + For the counter ion.

[0190] Those skilled in the art will recognize that the following designations

[0191] Z is Or Z is It means that when Z is

[0192] When the compound of formula (III) is understood to include And when Z is When the compound of formula (I) is understood to include and

[0193] In certain embodiments, R 1 For CO2R 2 or CO2 - X + In certain embodiments, R 1 For CO2R 2 In certain embodiments, R 1 For CO2 - X + .

[0194] In certain embodiments, R 2 is hydrogen or (C1-C6)-alkyl. 2 is hydrogen or (C1-C4)-alkyl. 2 is hydrogen or (C1-C3)-alkyl. 2 is hydrogen, methyl or ethyl. In certain embodiments, R 2 is hydrogen or methyl. In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 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 2 is (C1-C3)-alkyl. In certain embodiments, R 2 is (C1-C4)-alkyl. In certain embodiments, R 2 It is tert-butyl.

[0195] In certain embodiments, R 3 To 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.

[0196] In certain embodiments, R 3 To R 6 is independently hydrogen, halogen or haloalkyl. 3 To R 6 are independently hydrogen, halogen or trihaloalkyl.

[0197] In certain embodiments, R3 and R 6 In certain embodiments, R 3 , R 5 and R 6 For hydrogen.

[0198] In certain embodiments, R 4 is hydrogen, halogen or haloalkyl. 4 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 It is CF3.

[0199] In certain embodiments, R 3 To R 6 In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen or haloalkyl. 3 , R 5 , R 6 is hydrogen and R 4 In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is CF3. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 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 For Cl.

[0200] 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.

[0201] In certain embodiments, A 1 NR 7, O, S or CH2. In certain embodiments, A 1 NR 7 , O or S. In certain embodiments, A 1 NR 7 , S or CH2. In certain embodiments, A 1 NR 7 Or O. In certain embodiments, A 1 NR 7 Or S. In certain embodiments, A 1 NR 7 In certain embodiments, A 1 is 0. In certain embodiments, A 1 For S.

[0202] In certain embodiments, A 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 For CH.

[0203] In certain embodiments, A 3 NR 7 , O or S. In certain embodiments, A 3 is 0. In certain embodiments, A 3 is S. In certain embodiments, A 3 NR 7 .

[0204] In certain embodiments, X 1 and X 2 For hydrogen.

[0205] In certain embodiments, X 1 and X 2 In certain embodiments, X 1 and X 2 For Cl.

[0206] In certain embodiments, X 1 and X 2 In certain embodiments, X 1 is hydrogen and X 2 In certain embodiments, X 1 is Cl and X 2 For hydrogen.

[0207] In certain embodiments, Z is

[0208] In certain embodiments, Z is

[0209] In certain embodiments, R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl. 7 In certain embodiments, R 7 is a C1-C4 alkyl group. 7 is a C1-C3 alkyl group. 7 is a C1-C2 alkyl group. 7 is a C1-C4 n-alkyl group. 7 is a C1-C3 n-alkyl group. 7 is C(O)O-(C1-C4)-alkyl. 7 is C(O)O-(C1-C3)-alkyl. 7 is C(O)O-(C1-C2)-alkyl. 7 is C(O)O-(C1-C4)-n-alkyl. 7 It is C(O)O-(C1-C3)-n-alkyl.

[0210] In certain embodiments, R 1 For CO2R 2 ;

[0211] R 2 is H or (C1-C6)-alkyl;

[0212] X 1 is H;

[0213] X 2 is H;

[0214] Y is C=O;

[0215] Z is

[0216] A 1 NR 7 , O or S;

[0217] A 2 is N;

[0218] A 3 O or S;

[0219] R 3 To R 6are 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; and

[0220] R 7 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0221] In certain embodiments, R 1 For CO2R 2 ;

[0222] R 2 is H or tert-butyl;

[0223] X 1 is H;

[0224] X 2 is H;

[0225] Y is C=O;

[0226] Z is

[0227] A 1 NR 7 , O or S;

[0228] A 2 is N;

[0229] A 3 O or S;

[0230] R 6 To R 6 are independently hydrogen, halogen, or haloalkyl; and

[0231] R 7 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0232] In certain embodiments, R 1 For CO2R 2 ;

[0233] R 2 is H or tert-butyl;

[0234] X 1 is H;

[0235] X 2 is H;

[0236] Y is C=O;

[0237] Z is

[0238] A 1 NR 7 , O or S;

[0239] A 2 is N;

[0240] A 3 O or S;

[0241] R 3 , R 5 and R 6 is hydrogen;

[0242] R 4 is hydrogen, halogen or haloalkyl; and

[0243] R 7 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0244] In certain embodiments, R 1 For CO2R 2 ;

[0245] R 2 is H or (C1-C6)-alkyl;

[0246] X 1 is a halogen;

[0247] X 2 is a halogen;

[0248] Y is C=O;

[0249] Z is

[0250] A 1 NR 7 , O or S;

[0251] A 2 is N;

[0252] A 3 O or S;

[0253] R 3 To 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; and

[0254] R 7It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0255] In certain embodiments, R 1 For CO2R 2 ;

[0256] R 2 is H or tert-butyl;

[0257] X 1 is a halogen;

[0258] X 2 is a halogen;

[0259] Y is C=O;

[0260] Z is

[0261] A 1 NR 7 , O or S;

[0262] A 2 is N;

[0263] A 3 O or S;

[0264] R 3 To R 6 are independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl. 1 For CO2R 2 ;

[0265] R 2 is H or tert-butyl;

[0266] X 1 is Cl;

[0267] X 2 is Cl;

[0268] Y is C=O;

[0269] Z is A 1 NR 7 , O or S;

[0270] A 2 is N;

[0271] A 3 O or S;

[0272] R 3 To R 6are independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl. 1 For CO2R 2 ;

[0273] R 2 is H or tert-butyl;

[0274] X 1 is Cl;

[0275] X 2 is Cl;

[0276] Y is C=O;

[0277] Z is A 1 NR 7 , O or S;

[0278] A 2 is N;

[0279] A 3 O or S;

[0280] R 3 , R 5 and R 6 is hydrogen;

[0281] R 4 is hydrogen, halogen or haloalkyl; and

[0282] R 7 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0283] In certain embodiments, the compound of formula (III) is selected from:

[0284] In certain embodiments, the compound of formula (I) is or a pharmaceutically acceptable salt thereof.

[0285] In certain embodiments, the compound of formula (I) is or a pharmaceutically acceptable salt thereof.

[0286] Compounds of formula IV, V and VI

[0287] The AR inhibitor may be a compound of formula (IV) or a pharmaceutically acceptable salt and solvate thereof,

[0288]

[0289] in,

[0290] X 1 is H or halogen;

[0291] X 2 is H or halogen;

[0292] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

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

[0294]

[0295] in,

[0296] X is a substituted or unsubstituted C2-C5 alkylene group;

[0297] Z is

[0298] A 1 NR 7 , O, S or CH2;

[0299] A 2 N or CH;

[0300] A 3 NR 7 , O or S;

[0301] R 3 To 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; and

[0302] R 7 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0303] Suitable substituents on the C2-C5 alkylene group include one or more alkyl, alkoxy, aryl, aryloxy, halogen, haloalkyl, haloalkoxy, haloalkylthio. Preferred substituted C2-C5 alkylene groups are substituted ethylene groups. More preferred substituted C2-C5 alkylene groups are -C(CH3)2C(CH3)2-.

[0304] Those skilled in the art will recognize that the following designations

[0305] Z is Or Z is It means that when Z is When the compound of formula (IV) is understood to include and

[0306] When Z is When the compound of formula (IV) is understood to include and

[0307] in,

[0308] Z 1 and Z 2 are independently selected from hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 Together with the boron atoms to which they are bonded, they form

[0309]

[0310] in,

[0311] X is a substituted or unsubstituted C2-C5 alkylene group.

[0312] In certain embodiments, R of formula (IV) 3 To 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.

[0313] In certain embodiments, R of formula (IV) 3 To R 6 is independently hydrogen, halogen or haloalkyl. 3 To R 6 are independently hydrogen, halogen or trihaloalkyl.

[0314] In certain embodiments, R of formula (IV) 3 and R 6 In certain embodiments, R 3 , R 5 and R 6 For hydrogen.

[0315] In certain embodiments, R of formula (IV) 4 is hydrogen, halogen or haloalkyl. 4 In certain embodiments, R 4In certain embodiments, R 4 In certain embodiments, R 4 It is CF3.

[0316] In certain embodiments, R of formula (IV) 3 To R 6 In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen or haloalkyl. 3 , R 5 , R 6 is hydrogen and R 4 In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is CF3. In certain embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 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 For Cl.

[0317] In certain embodiments, Y of 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.

[0318] In certain embodiments, A of formula (IV) 1 NR 7 , O, S or CH2. In certain embodiments, A 1 NR 7 , O or S. In certain embodiments, A 1 NR 7 , S or CH2. In certain embodiments, A 1 NR 7 Or O. In certain embodiments, A 1 NR 7Or S. In certain embodiments, A 1 NR 7 In certain embodiments, A 1 is 0. In certain embodiments, A 1 For S.

[0319] In certain embodiments, A of formula (IV) 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 For CH.

[0320] In certain embodiments, A of formula (IV) 3 NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A of formula (IV) 3 is S. In certain embodiments, A 3 NR 7 .

[0321] In certain embodiments, X of formula (IV) 1 and X 2 For hydrogen.

[0322] In certain embodiments, X of formula (IV) 1 and X 2 In certain embodiments, X 1 and X 2 For Cl.

[0323] In certain embodiments, X of formula (IV) 1 and X 2 In certain embodiments, X 1 is hydrogen and X 2 In certain embodiments, X 1 is Cl and X 2 For hydrogen.

[0324] In certain embodiments, Z of formula (IV) is

[0325] In certain embodiments, Z of formula (IV) is

[0326] In certain embodiments, R of formula (IV) 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl. 7 In certain embodiments, R 7is a C1-C4 alkyl group. 7 is a C1-C3 alkyl group. 7 is a C1-C2 alkyl group. 7 is a C1-C4 n-alkyl group. 7 is a C1-C3 n-alkyl group. 7 is C(O)O-(C1-C4)-alkyl. 7 is C(O)O-(C1-C3)-alkyl. 7 is C(O)O-(C1-C2)-alkyl. 7 is C(O)O-(C1-C4)-n-alkyl. 7 It is C(O)O-(C1-C3)-n-alkyl.

[0327] In certain embodiments, the compound of formula (IV) is

[0328]

[0329] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0330] in,

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

[0332]

[0333] in,

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

[0335] In certain embodiments, the compound of formula (IV) is

[0336]

[0337] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0338] in,

[0339] Z 1 and Z 2 are independently selected from hydroxy, alkoxy, aryloxy, or Z 1 and Z 2Together with the boron atoms to which they are bonded, they form

[0340]

[0341] in,

[0342] X is a substituted or unsubstituted C2-C5 alkylene group.

[0343] In certain embodiments, the compound of formula (IV) is

[0344]

[0345] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0346] in,

[0347] Z 1 and Z 2 are independently selected from hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 Together with the boron atoms to which they are bonded, they form

[0348]

[0349] in,

[0350] X is a substituted or unsubstituted C2-C5 alkylene group.

[0351] In certain embodiments, the compound of formula (IV) is

[0352]

[0353] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0354] in,

[0355] Z 1 and Z 2 are independently selected from hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 Together with the boron atoms to which they are bonded, they form

[0356]

[0357] in,

[0358] X is a substituted or unsubstituted C2-C5 alkylene group.

[0359] In another aspect, the aldose reductase inhibitor is a compound of formula (V)

[0360]

[0361] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0362] in,

[0363] X 3 N or CR 8 ;

[0364] X 4 N or CR 9 ;

[0365] X 5 N or CR 10 ;

[0366] X 6 N or CR 11 ; The condition is X 3 , X 4 , X 5 or X 6 Two or three of them are N;

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

[0368]

[0369] in,

[0370] X is a substituted or unsubstituted C2-C5 alkylene group;

[0371] Z 3 for

[0372] A 4 NR 16 , O, S or CH2;

[0373] A 5 N or CH;

[0374] A 6 NR 16 , O or S;

[0375] R 8 To R 15 R is 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 To R11 Two or R 12 To R 15 Two of the together are (C1-C4)-alkylenedioxy; and

[0376] R 16 It is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0377] Suitable substituents on the C2-C5 alkylene group include one or more alkyl, alkoxy, aryl, aryloxy, halogen, haloalkyl, haloalkoxy, haloalkylthio. Preferred substituted C2-C5 alkylene groups are substituted ethylene groups. More preferred substituted C2-C5 alkylene groups are -C(CH3)2C(CH3)2-.

[0378] Those skilled in the art will recognize that the following designations

[0379] Z is Or Z is It means that when Z is When the compound of formula (V) is understood to include And when Z is When the compound of formula (V) is understood to include

[0380] In some compounds of Formula V, R 8 To R 15 are independently hydrogen, halogen or haloalkyl, for example, R 8 To R 15 is independently hydrogen, halogen, or trihaloalkyl (eg, -CF3).

[0381] In other compounds of Formula V, R 8 To R 11 For hydrogen.

[0382] In certain embodiments of the compound of Formula V, R 12 To R 15 are independently hydrogen, halogen or haloalkyl, for example, R 12 To R 15 is independently hydrogen, halogen, or trihaloalkyl (eg, -CF3).

[0383] In certain embodiments, R of formula (V) 12 and R 15 For hydrogen.

[0384] In certain embodiments, R of formula (V) 13 is hydrogen, halogen or haloalkyl. 13 In certain embodiments, R 13In certain embodiments, R 13 It is a halogenated alkyl group.

[0385] In certain embodiments, R of formula (V) 14 is hydrogen, halogen or haloalkyl. 14 In certain embodiments, R 14 In certain embodiments, R 14 It is a halogenated alkyl group.

[0386] In certain embodiments, Y of 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.

[0387] In certain embodiments, A of formula (V) 4 NR 16 , S or CH2. In certain embodiments, A 4 NR 16 Or O. In certain embodiments, A 4 NR 16 Or S. In certain embodiments, A 4 NR 16 In certain embodiments, A 4 is 0. In certain embodiments, A 4 For S.

[0388] In certain embodiments, A of formula (V) 5 is N or CH. In certain embodiments, A 4 is N. In certain embodiments, A 4 For CH.

[0389] In certain embodiments, A of formula (V) 6 is O or S. In certain embodiments, A 6 is 0. In certain embodiments, A 6 For S.

[0390] In certain embodiments, X of formula (V) 3 and X 6 For nitrogen.

[0391] In certain embodiments, X of formula (V) 3 and X 4 For nitrogen.

[0392] In certain embodiments, X of formula (V) 3and X 5 For nitrogen.

[0393] In certain embodiments, X of formula (V) 4 and X 5 For nitrogen.

[0394] In certain embodiments, X of formula (V) 4 and X 6 For nitrogen.

[0395] In certain embodiments, X of formula (V) 5 and X 6 In certain embodiments, Z of formula (V) 3 for

[0396] In certain embodiments, Z of formula (V) 3 for

[0397] In some embodiments, the compound of formula (V) is

[0398]

[0399] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0400] in,

[0401] R 14 is hydrogen, halogen, or trihaloalkyl (e.g., -CF3); and

[0402] Z 1 and Z 2 are independently selected from hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 Together with the boron atoms to which they are bonded, they form

[0403]

[0404] in,

[0405] X is a substituted or unsubstituted C2-C5 alkylene group.

[0406] In an embodiment, the compound of formula (V) is

[0407]

[0408] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0409] In one aspect, the aldose reductase inhibitor is a compound of formula (VI)

[0410]

[0411] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0412] in,

[0413] Z 1 and Z 2 are independently selected from hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 Together with the boron atoms to which they are bonded, they form

[0414]

[0415] in,

[0416] X is a substituted or unsubstituted C2-C5 alkylene group.

[0417] In one embodiment, the aldose reductase inhibitor of formula (VI) is

[0418]

[0419] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0420] In one embodiment, the AH inhibitor of formula (VI) is

[0421]

[0422] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0423] The term "alkyl" as used herein, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon group having a straight chain, branched chain, monocyclic or polycyclic portion, or a combination thereof, wherein the group is optionally substituted at one or more carbons of the straight chain, branched chain, monocyclic or polycyclic portion, or a combination thereof, with one or more substituents at each carbon, wherein the one or more substituents are independently C1-C 10 Alkyl. Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0424] As used herein, the term "halogen" or "halo-" refers to chlorine (Cl), fluorine (F), iodine (I), or bromine (Br).

[0425] As used herein, the term "acyl" is used in a broad sense to refer to a group of the RCO-type, wherein R represents an organic group, which may be a substituted or unsubstituted, saturated or unsaturated alkyl, aralkyl, aryl, alicyclic or heterocyclic group; or, in a different definition, the term "acyl" is used to broadly refer to the monovalent group that remains when the OH group of the carboxyl group is removed from a carboxylic acid molecule.

[0426] The term "alkoxy" is used to denote a radical of the formula: -OR, wherein R is an alkyl group, which optionally contains substituents, such as halogen. Preferably, the term "alkoxy" is used to denote an alkoxy group of an alkyl group having 1 to 6 carbon atoms. Most preferably, the term "alkoxy" is used to denote an alkoxy group of an alkyl group having 1 to 3 carbon atoms, such as methoxy or ethoxy.

[0427] The term "cycloalkyl" is used herein to denote a cycloalkyl group having 3 to 6 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0428] As used herein, the term "solvate" refers to a compound or a pharmaceutically acceptable salt thereof, in which molecules of a suitable solvent are incorporated into the crystal lattice. Suitable solvents are physiologically tolerable at the doses administered. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate."

[0429] "Prodrug" refers to an agent that is converted into a parent drug in vivo. Prodrugs are generally useful because, in some cases, they are easier to administer than the parent drug. They are bioavailable, for example, by oral administration, while the parent drug is less bioavailable or non-bioavailable. Prodrugs also have improved solubility in pharmaceutical compositions than the parent drug. For example, a compound carries a protective group that is separated by hydrolysis in a body fluid, such as in the blood, thereby releasing the active compound, or is oxidized or reduced in a body fluid to release the compound. The term "prodrug" can be applied to functional groups such as the following, for example; an acid functional group of a compound of formula I. Prodrugs can consist of structures in which the acid group is masked as, for example, an ester or an amide. Other examples of prodrugs are discussed herein. See also Alexander et al., (J. Med. Chem. 1988, 31, 318), which are incorporated by reference. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including bio-hydrolyzable parts, such as bio-hydrolyzable amides, bio-hydrolyzable esters, bio-hydrolyzable carbamates, bio-hydrolyzable carbonates, and bio-hydrolyzable phosphate analogs. Prodrugs are also described in, for example, The Practice of Medicinal Chemistry (Camille Wermuth, 1999, Academic Press; It is incorporated herein by reference in its entirety). In certain embodiments, the prodrug of a compound with a carboxyl functional group is a lower alkyl ester of a carboxylic acid. Carboxylic acid esters are conveniently formed by any carboxylic acid moiety present on the esterification molecule. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th edition (Donald J. Abraham, 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard, 1985, Harwood Academic Publishers Gmfh; It is each incorporated herein by reference in its entirety). The biohydrolyzable portion of the compound of Formula I (a) does not interfere with the biological activity of the compound, but may impart beneficial properties to the compound in vivo, such as uptake, duration of action, or onset of action; or (b) may be biologically inert, but is converted into a biologically active compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, 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 polyetheramines.

[0430] The term "salt" includes salts derived from any suitable organic and inorganic counterions known in the art, and includes, for example, hydrochlorides or hydrobromides or basic or acidic salts of the aforementioned amino acids. The 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-2sulfonic acid and the like; and salts derived from inorganic or organic bases, including, for example, sodium, potassium, calcium, ammonium or tetrafluoroborate. Exemplary pharmaceutically acceptable salts are found, for example, in Berge et al., (J. Pharm. Sci. 1977, 66 (1), 1; and U.S. Pat. Nos. 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, wherein the ratio of compound:acid is 2:1, respectively. Exemplary hemi-salts are those 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 those derived from diprotic inorganic acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemi-succinate.

[0431] The term "acid" encompasses all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids, for example 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 acid, which is optionally substituted by halogen or hydroxyl, or C6-C 12 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 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 include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and phenylstearic acid. Other acids include gluconic acid, saccharoheptanoic acid and lactobionic acid.

[0432] III. Composition

[0433] Compound can be applied in the form of suitable composition, such as pharmaceutical composition. Pharmaceutical composition is physiologically acceptable, and generally includes active compound and carrier. The term "carrier" refers to a diluent, adjuvant, excipient or vehicle applied together with the compound. Non-limiting examples of such pharmaceutical carriers include liquids, such as water and oil, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical carrier can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, etc. In addition, auxiliary agents, stabilizers, thickeners, lubricants and colorants can be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences (Alfonso Gennaro, ed., Krieger Publishing Company (1997); Remington's: The Science and Practice of Pharmacy, 21st ed. (Lippincot, Williams & Wilkins (2005); Modern Pharmaceutics, vol. 121 (Gilbert Banker and Christopher Rhodes, CRC Press (2002); each of which is incorporated herein by reference in its entirety). In particular, the carrier may be suitable for ocular application, such as application to the eye to treat eye diseases, such as cataracts. In another embodiment, the carrier may comprise a suppository for vaginal administration, such as for the treatment of premature ovarian failure (POI).

[0434] The composition can be in a physiologically and / or pharmaceutically acceptable desired form, such as a tablet, capsule, solution, emulsion, suspension, gel, sol or colloid. If desired, the carrier can include a buffer, such as an alkaline buffer, such as an ammonium buffer, an acidic buffer, such as acetate, citrate, lactate, acetate, etc., or a zwitterionic buffer, such as glycine, alanine, valine, leucine, isoleucine and phenylalanine, Kreb's-Ringer buffer, TRIS, MES, ADA, ACES, PIPES, MOPSO, choline chloride, MOPS, BES, TES, HEPES, DIPSO, MOBS, TAPSO, acetylaminoglycine, TEA, POPSO, HEPPSO, EPS, HEPPS, Tricine, TRIZMA, glycinamide, glycosylglycine, HEPBS, Bicine, TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS and CABS.

[0435] 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, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids (e.g., triglycerides, vegetable oils, liposomes) and combinations thereof. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin; by dispersing in a carrier such as a liquid polyol or lipid to maintain the desired particle size; by using a surfactant such as hydroxypropyl cellulose; or a combination of such methods. If desired, a tension modifier such as a sugar, sodium chloride, or a combination thereof can be included. In some embodiments, the composition is isotonic.

[0436] The composition may also include other ingredients such as acceptable surfactants, cosolvents, emollients, agents for adjusting pH and osmotic pressure, and / or antioxidants to prevent oxidation of one or more components.

[0437] The composition can be prepared for administration by any suitable route, such as ocular (including periocular and intravitreal administration), oral, parenteral, intranasal, anal, vaginal, topical, subcutaneous, intravenous, intraarterial, intrathecal and intraperitoneal administration. As shown in the working examples disclosed herein, oral administration of aldose reductase inhibitors effectively reduces and normalizes galactitol levels in blood and tissues (including brain). Therefore, although intrathecal administration is an option and can be selected by a clinician (for example, when the aldose reductase inhibitor is not a central nervous system penetrant), it is generally preferred that the aldose reductase inhibitor is not administered intrathecally. For ocular administration, the composition can be formulated into, for example, drops, solutions, suspensions, emulsions, ointments, sustained release formulations, lozenges, elixirs, syrups, wafers, powders, or combinations thereof. See, Gaudana et al., AAPS J., 12 (3): 348–360, 2010. Oral compositions can be mixed directly with food in the diet. Preferred carriers for oral administration include inert diluents, edible carriers, or combinations thereof. Examples of pharmaceutically acceptable carriers may include, for example, water or saline solutions, 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 formulation. Specific examples of surfactants include polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylated sorbitan esters; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives such as methacrylates, anionic surfactants such as alkaline 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 dodecylbenzene sulfonate or sodium dioctyl sulfosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants such as formula N Water-soluble quaternary ammonium salts of R'R"R'"R""Y", wherein the R groups are identical or different optionally hydroxylated hydrocarbon groups, and Y" is an anion of a strong acid, such as a halide, sulfate and sulfonate anion; hexadecyltrimethylammonium bromide is one of the cationic surfactants that can be used, amine salts of the formula NR'R'R", wherein the R groups are identical or different optionally hydroxylated hydrocarbon groups; octadecylamine hydrochloride is one of the cationic surfactants that can be used, nonionic surfactants, such as optionally polyoxyethylated dehydrated sorbitan esters, in particular polysorbate 80, or polyoxyethylated alkyl ethers; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0438] If desired, the oral composition may include one or more binders, excipients, disintegrants, lubricants, flavoring agents, and combinations thereof. In certain embodiments, the composition may include one or more of the following: binders, such as gum tragacanth, gum arabic, corn starch, gelatin, or a combination thereof; excipients, such as dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, or a combination thereof; disintegrants, such as corn starch, potato starch, alginic acid, or a combination thereof; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose, saccharin, or a combination thereof; flavoring agents, such as peppermint, wintergreen oil, cherry flavoring, orange flavoring, etc., or a combination thereof containing two or more of the foregoing substances.

[0439] Other preparations suitable for other modes of administration include suppositories. In addition, suitable solvents can be used to prepare sterile injection solutions. Generally, dispersions are prepared by incorporating various sterile amino acid components into sterile vehicles, which contain basic dispersion media and / or other ingredients. Suitable formulations for any desired mode of administration are well known in the art (generally, see, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990).

[0440] A typical pharmaceutically acceptable composition may contain an AR inhibitor and / or a pharmaceutically acceptable salt thereof in a concentration range of about 0.01 to about 2 wt%, such as 0.01 to about 1 wt% or about 0.05 to about 0.5 wt%. The composition may be formulated into a solution, a suspension, an ointment or a capsule, etc. The pharmaceutical composition may be prepared as an aqueous solution and may contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity adjusting ingredients, etc. Other equivalent modes of administration may be found in U.S. Pat. No. 4,939,140.

[0441] When administered to a subject, the AR inhibitor and the pharmaceutically acceptable carrier may be sterile. Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, ethylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, etc. If necessary, the composition of the present invention may also contain a small amount of a wetting agent or emulsifier, or a pH buffer.

[0442] The pharmaceutical preparations disclosed herein are prepared by methods known in pharmacy. Optionally, one or more auxiliary ingredients (e.g., buffers, flavoring agents, surfactants, etc.) are also 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.

[0443] In some embodiments, the composition is in unit dosage form, such as a tablet, capsule, or single-dose vial. The appropriate unit dosage, i.e., the therapeutically effective amount, can be determined during clinical trials that are appropriately designed for each condition in which the administration of the selected compound is indicated, and will of course vary depending on the desired clinical endpoint.

[0444] Any compound and / or composition of the present disclosure may be provided in a kit comprising the compound and / or composition. Thus, in one embodiment, the compound and / or composition of the present disclosure is provided in a kit that includes a carrier and optionally instructions for using the kit for therapeutic or preventive end use in the same or separate packaging.

[0445] IV. Combination Therapy

[0446] The methods described herein include administering an AR inhibitor and one or more additional therapeutic agents. The additional therapeutic agent may be administered before, simultaneously with, or after the AR inhibitor, but in a manner that provides an overlap in the pharmacological activity of the AR inhibitor and the additional therapeutic agent. The additional therapeutic agent may be, for example, a second aldose reductase inhibitor, an antioxidant, or both.

[0447] For example, the second aldose reductase can be, for example, those described in U.S. Pat. Nos. 5,677,342; 5,155,259; 4,939,140; US Pat. No. 2006 / 0293265; and Roy et al., (Diabetes Research and Clinical Practice, 10, Issue 1, 91 -97, 1990; and compounds described in 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 sobinil, 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 bonarestat, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, zenastat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210.

[0448] Other therapeutic agents that may be administered include, for example, corticosteroids such as prednisone, methylprednisolone, dexamethasone, or triamcinalone acetinide, or non-corticosteroid anti-inflammatory compounds such as ibuprofen or flubiproben. Similarly, vitamins and minerals such as zinc and micronutrients may be co-administered. In addition, inhibitors of protein tyrosine kinase pathways, including natural protein tyrosine kinase inhibitors such as quercetin, lavendustin A, erbstatin, and herbimycin A may be administered. A), and synthetic protein tyrosine kinase inhibitors, such as tyrphostin (e.g., AG490, AG17, AG213 (RG50864), AG18, AG82, AG494, AG825, AG879, AG1112, AG1296, AG1478, AG126, RG13022, RG14620, and AG555), dihydroxy and dimethoxybenzylidenemalononitrile, analogs of lavender A (e.g., AG814 and AG957), quinazolines (e.g., AG1478), 4,5-diphenylaminophthalimide, and thiazolidinediones can be co-administered with genistein or its analogs, prodrugs, or pharmaceutically acceptable salts (see Levitzki 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 listed in Mazurek et al., U.S. Pat. No. 5,637,703. Selenoindole (2-thioindole) and related disulfide selenides, such as those described in Dobrusin et al., U.S. Pat. No. 5,464,961, are useful protein tyrosine kinase inhibitors. Neutralizing proteins to growth factors, such as monoclonal antibodies specific for a given growth factor, such as VEGF (e.g., see 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 various compounds that may be co-administered include inhibitors of protein kinase C (see, e.g., U.S. Pat. Nos. 5,719,175 and 5,710,145), cytokine modulators, endothelial cell-specific proliferation inhibitors, such as thrombospondin, endothelial cell-specific inhibitory growth factors, such as TNFα, antiproliferative peptides, such as SPARC and prolferin-like peptides, glutamate receptor antagonists, aminoguanidine, angiotensin converting enzyme inhibitors, such as angiotensin II, calcium channel blockers, gamma-inositol agonist, ST638, somatostatin analogs, such as SMS201-995, monosialoganglioside GM1, ticlopidine, neurotrophic growth factor, methyl 2,5-dihydroxycinnamate, angiogenesis inhibitors, such as recombinant EPO, sulfonylurea oral hypoglycemic agents, such as gliclazide (non-insulin-dependent diabetes), ST638 (Asahi et al., FEBS Letters 309:10-14 (1992)), thalidomide, nicardipine hydrochloride, aspirin, picatinol, staurosporine, doxorubicin, epistatin, (+)-aeroplysinin-1, phenazosins, halomethyl ketones, antilipidemic agents such as etofibrate, chlorpromazine, spironol 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)).

[0449] V. Diagnostic Applications

[0450] The present disclosure further relates to diagnosing or prognosing the risk of developing galactosemia in a subject by measuring one or more biomarkers associated with galactosemia. In one embodiment, the biomarker associated with galactosemia is a galactitol level elevated in a biological sample obtained from a subject. Diagnosis can be performed, for example, by detecting elevated levels of sugar metabolites (e.g., galactose metabolites (e.g., galactitol) and / or glucose metabolites (e.g., sorbitol)) in a biological sample (e.g., aqueous humor or vitreous humor, blood tissue, cerebrospinal fluid, urine, etc.).

[0451] Tables 1 and 2 show the concentrations of galactose and its metabolites in plasma (or whole blood), erythrocytes, and / or urine samples from subjects with classic galactosemia (GALT deficiency) or severe GALK deficiency.

[0452] The present disclosure further relates to a method for combined diagnosis and intervention of galactosemia, wherein the diagnosis of galactosemia is performed as previously described by detecting one or more biomarkers in a sample obtained from a subject. Based on the diagnosis result, if the subject is determined to have galactosemia or is considered to be at risk of developing galactosemia, a composition comprising an aldose reductase inhibitor (ARI) is administered to the subject. Preferably, the ARI comprises a compound of the present disclosure or a composition comprising a compound of the present disclosure.

[0453] In certain embodiments, the present disclosure provides a method for treating galactosemia, comprising diagnosing galactosemia in a subject by detecting elevated plasma galactitol concentrations (e.g., >10 μM galactitol) and / or elevated urine galactitol levels (e.g., >100 mmol galactitol / mol creatine); and administering a therapeutically effective amount of a composition that inhibits aldose reductase activity to a galactosemia subject in need thereof. In another embodiment, the diagnostic step may further include genetic testing, for example, detecting mutations in one or more enzymes (e.g., GALT, GALK, GALE, etc.) involved in the Leloir pathway. In yet another embodiment, the diagnostic step may additionally include performing an enzymatic assay, for example, an assay of GALT, GALK, and / or GALE activity using a detectable substrate, the product of which may be detected using conventional methods, such as HPLC or mass spectrometry (Ko et al., Clinical Chemistry 56:5 764–771, 2010).

[0454] 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 galactosemia. In another embodiment, the present disclosure relates to 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 galactosemia, the method comprising the following steps: (a) identifying a subject in need of such treatment; (b) providing a compound of Formula I-VI or a pharmaceutically acceptable salt, hydrate, solvate, prodrug thereof; and (c) administering the compound of Formula I-VI in a therapeutically effective amount to treat, inhibit and / or prevent a disease state or condition in a subject in need of such treatment.

[0455] 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 galactosemia, the method comprising the steps of: (a) identifying a subject in need of such treatment; (ii) providing a composition comprising a compound of Formula I-VI, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or tautomer thereof; and (iii) administering the composition in a therapeutically effective amount to treat, inhibit, and / or prevent a disease state or condition in a subject in need of such treatment.

[0456] In the aforementioned embodiments, the compound or composition is preferably administered orally. Example

[0457] The structures, materials, compositions and methods described herein are intended to be representative examples of the present disclosure, and it should be understood that the scope of the present disclosure is not limited to the scope of the examples. Those skilled in the art will recognize that the present disclosure can be practiced by modifying the disclosed structures, materials, compositions and methods, and such modifications are considered to be within the scope of the present disclosure.

[0458] Rats with impaired GALT activity (GALT-deficient) due to genetic modification are used as a model of galactosemia. This rat model reflects classical human galactosemia in some important aspects. Rats develop physical characteristics including cataracts, growth abnormalities, and neurological / cognitive abnormalities after exposure to galactose, which reflect the abnormalities in human patients and can be quantified. Rats also have biochemical features that reflect the human disease, including elevated levels of galactose and galactose metabolites (including galactitol and Gal1) in blood and tissues.

[0459] Rats will be fed a diet containing one or more aldose reductase inhibitors (ARIs), and AR inhibitory effects will be measured at tissue levels and in vivo levels. For example, the galactitol levels in the eyes of rats lacking GALT can be measured before and after treatment with ARIs disclosed herein. Alternatively or additionally, conventional methods will be used to measure the effect of ARIs in reducing the frequency and severity of galactosemia and / or improving the results of the disease (e.g., improved vision, movement or memory ability).

[0460] Example 1

[0461] A study was conducted to test the effects of an aldose reductase inhibitor (ARI) (Compound A or Compound B) in a rat model of classical galactosemia (GALT-null rats). The effects of aldose reductase inhibitor treatment on key aspects of galactosemia, including growth, cataract formation, metabolite levels (galactose and galactitol) in the liver and brain, and circulation of GALT-null rats exposed to breast milk were analyzed.

[0462]

[0463] method

[0464] Genetic Model: Rats were generated from a heterozygous cross (representing a heterozygous M3 GALT-deficient strain of classic galactosemia). Wild-type (WT, + / +) and heterozygous rats (+ / M3) express normal levels of GALT, whereas M3 homozygotes (M3 / M3) do not express detectable levels of GALT and display abnormally high levels of galactose and galactitol in the liver and brain.

[0465] Application of Drugs and Placebo: The vehicle used to administer drugs to newborn pups was Gerber's Good Start Birth-12 Months Soy Formula prepared according to the manufacturer's instructions (157.5 mg powder was added to 1 ml of deionized water and mixed thoroughly before use). Liquid formula was prepared freshly from the powder daily and stored at 4°C until use. Liquid formula alone (without drug powder added) was used as a placebo control.

[0466] Aldose reductase inhibitors (Compound A or Compound B) suspended in Gerber's formula were orally administered at approximately 12 hour intervals (BID) at a dose of 1 mg inhibitor / gram of pup body weight (=1000 mg / kg). Prior to use, the drugs were stored in foil-wrapped bottles or tubes at -20°C. Prior to each feeding, an aliquot of the drug was resuspended in the formula, mixed thoroughly, and pipetted into separate tubes to feed the pups (volume calculated based on the weight of each pup measured that morning). Immediately prior to feeding, placebo and drug tubes of all formulations were warmed to 37°C.

[0467] Placebo and drug were artificially fed to the pups using a syringe and cannula. The pups receiving drug were also fed a small additional volume of Gerber's formula, which had been used to clean the tube and syringe immediately after drug administration. To stimulate feeding, the pups were removed from their mothers (to prevent suckling) and kept in a nest in a humidified incubator at 35-37°C for about 2 hours before each feeding. Separate syringes were used for placebo and drug. During feeding, the pups were wrapped in wool, which lasted about 2-5 minutes each time.

[0468] Tracking Growth: Growth was tracked by weighing each pup daily (in grams).

[0469] Tracking / Quantification of Cataracts: In the first part of the study, cataracts were visually scored by a blinded rater on a 3-point scale, where zero was no cataract present (absent), 1 was mild cataract present, 2 was moderate cataract present, and 3 was severe cataract present. In the second part of the study, eyes were dissected after euthanasia, photographed by a digital camera, and cataracts were quantified by software.

[0470] Determination of genotype: Pup GALT genotype (M3 / M3 vs. M3 / + vs. + / +) was determined by Transnetyx using DNA isolated from tail snips collected from all pups between 5-8 days after birth. The genotype of a representative pup was confirmed by GALT enzyme activity measured in liver samples collected from euthanized pups. In all samples tested, the observed GALT activity was consistent with the GALT genotype.

[0471] Euthanize pups: Pups were euthanized by CO2 inhalation according to standard procedures.

[0472] Enzyme assays: As previously described (Sanders et al., Dis Model Mech., 3(9-10):628-38, 2010), galactose-1-P uridyltransferase (GALT) and galactokinase (GALK) assays were performed using lysates prepared from frozen samples of liver. The GALK assay was performed as a control for sample integrity. The lysate was prepared by homogenizing a small piece (10-50 mg) of liver in 100 μl of lysis buffer consisting of a complete EDTA-free micro protease inhibitor cocktail tablet (Roche, REF04 693 159 001) dissolved in 10 ml of 100 mM glycine (pH 8.7). The lysate was centrifuged at 16,110X g for 5 minutes at 4°C, and the resulting supernatant was passed through a MICROBIO-SPIN P-6 column (Bio-Rad, Inc.) to remove small molecules. The protein concentration of each sample was determined using the BIO-RAD DC protein assay with BSA as a standard. GALT and GALK assays were run using 4 μg of total protein per reaction. Substrate and product were quantified by HPLC as previously described (Ross, 2004).

[0473] Metabolites: Lysates for metabolite analysis were prepared as follows: 50-100 mg of previously frozen liver or brain blocks were homogenized by grinding in 125 μl of ice-cold HPLC-grade water using a Teflon micropestle and a handheld micropestle motor (Kimble Chase Life Science and Research Products LLC) for 30 seconds. Metabolites were separated and quantified by HPLC (see, e.g., Daenzer et al., Dis. Model Mech. 2016, 9(11): 1375-1382). Galactitol, inositol, and glucose were quantified using the same HPLC conditions described for quantifying galactose as (Daenzer, 2016). Metabolite levels were standardized to the total peak area detected by the relevant column and the elution run on the sample, minus the peak that best distinguished the homozygous M3 / M3 sample compared to the control. Specifically, metabolites separated on the MA1 column (galactitol, inositol, galactose, and glucose) were normalized to the total peak area minus galactose and galactitol, and metabolites separated on the PA10 column (galactose-1P) were normalized to the total peak area minus galactose and galactose-1P.

[0474] result

[0475] Lifespan Observations: Although the consistency of the medicated formula was slightly "thicker" than the formula alone, pups consumed both without apparent objection.

[0476] Growth: Pups were weighed each morning and the mass recorded in grams. The mass of pups still gaining weight was recorded in Figure 1 As shown, the weight of homozygous GALT null pups tended to lag behind their wild-type and heterozygous GALT+ littermates, but the difference was small. Other studies have demonstrated that after the third week of life, this lag becomes more pronounced and statistically significant.

[0477] Figure 1 The data presented indicate that drug treatment can reduce or prevent growth lag in homozygotes.

[0478] Cataracts: Cataracts are the most obvious and visible phenotype associated with the GALT-null state in the rat model. Rats open their eyes on day 14 of life with bilateral cataracts present. Notably, classical galactosemic infants exposed to dietary galactose (e.g., breast milk) also develop bilateral cataracts. In the GALT-null rat model without intervention, cataracts were observed in all M3 / M3 homozygous pups, but not in any M3 / + or + / + pups. In the initial studies, GALT-null rats treated with Compound A or placebo were qualitatively assessed for cataracts on day 9 of life. The qualitative assessment is based on a scale of 0-3, where 0 indicates no cataracts and 3 indicates severe cataracts. As Figure 2A As shown in Figure 2, GALT-null rats treated with placebo developed severe cataracts on day 9 of life. In contrast, GALT-null rats treated with Compound A had no cataracts. A follow-up study was conducted in which rats were treated with either 1,000 mg / kg BID or 250 mg / kg BID of Compound A, and the eyes were digitally photographed and cataracts quantified. In both studies, Compound A reduced cataracts.

[0479] Additional studies were performed using Compound B and cataracts were assessed on day 22 of life. Qualitative assessment on a 0-3 scale showed that in this study, GALT-null rats treated with placebo developed cataracts with a mean severity of 1.5, whereas wild-type rats and GALT-null rats treated with Compound B had no cataracts ( Figure 2D ). Digital quantitative analysis yielded the same results, with GALT-null rats treated with Compound B having scores identical to those of wild-type rats, but GALT-null rats treated with placebo showed higher cataract scores ( Figure 2B ).

[0480] Since GALT-null rats have cataracts when they open their eyes on day 14 of life, it is possible that treating newborn rats with an aldose reductase inhibitor could prevent the formation of postnatal cataracts and / or reduce cataracts that form in utero. Further studies using compound B provided evidence that an aldose reductase inhibitor could reduce cataracts that have already formed. In this study, cataracts were assessed on days 10 and 22 of life. Figure 2C and Figure 2D As shown, GALT-null rats treated with placebo had cataracts on days 10 and 22. However, GALT-null rats treated with Compound B had cataracts on day 10 but not on day 22. The data demonstrate that treatment with an aldose reductase inhibitor can reduce and resolve cataracts.

[0481] Metabolites: Galactose and galactitol metabolites were resolved and quantified in liver and brain samples of euthanized pups by HPLC. In GALT-deficient rats, treatment with Compound A reduced liver galactitol levels by 87% at day 9 and by 57% at days 15-18 compared to placebo. In GALT-deficient rats, treatment with Compound A reduced brain galactitol levels by 40% at day 9 and by 57% at days 15-18 compared to placebo. Additional studies were conducted in rats treated with Compound B, and galactose and galactitol levels were measured on day 10 of life. The results of this study showed that galactitol levels were elevated in the liver, brain, and plasma of GALT-deficient rats compared to wild-type rats. Treatment with Compound B reduced galactitol levels in GALT-deficient rats to normal or near-normal levels ( Figure 3A ). Galactose and Gal1P levels were also elevated in GALT-deficient rats relative to wild-type rats. Treatment with Compound B did not further increase galactose or Gal1P levels in GALT-deficient rats ( Figure 3B and Figure 3C ). The data demonstrate that an aldose reductase inhibitor can reduce and normalize galactitol levels in diseased animals without further increasing galactose and Gal1P levels.

[0482] Conclusion and discussion

[0483] This study examined the effects of aldose reductase inhibitor exposure (Compound A or Compound B) on growth, cataract formation, and galactitol accumulation in GALT-deficient rat pups. As expected, dairy-exposed GALT-deficient animals had significantly increased accumulation of galactose and galactitol in the liver and brain relative to GALT+ heterozygous or wild-type animals. Treatment with an aldose reductase inhibitor significantly reduced galactitol in the brain, liver, and blood (plasma). Treatment with an aldose reductase inhibitor also had a significant effect on cataracts and demonstrated that an aldose reductase inhibitor could reduce existing cataracts to the point where they were no longer present. These data demonstrate that an aldose reductase inhibitor can be administered to effectively treat galactosemia.

[0484] Example 2

[0485] In this study, the long-term cognitive and neurological deficits associated with galactosemia will be studied in GALT-deficient rats and normal control rats treated with placebo or aldose reductase inhibitors. The aldose reductase inhibitor will be used substantially as described in Example 1, and the central nervous system results of rats will be evaluated using a rotarod test to assess balance, motor control and learning, and a novel object recognition test will be used to assess cognition and memory. Compared with wild-type rats, GALT-deficient rats show altered responses in these tests. The data will show that treatment with an aldose reductase inhibitor reduces cognitive and neurological deficits in GALT-deficient rats, and some or all of the responses of GALT-deficient rats will be normalized to the responses observed in wild-type rats.

[0486] Example 3

[0487] A newborn was diagnosed with classic galactosemia by neonatal testing and presented with elevated blood galactose and galactitol levels. The child was immediately placed on a galactose and lactose restricted diet. Therapy with an aldose reductase inhibitor (such as compound A or compound B) was started at a dose selected by the clinician to normalize blood galactose and / or galactitol levels. Treatment resulted in a decrease in blood galactitol levels and eventual return to normal. The child continued treatment indefinitely, and regular checks confirmed that blood galactitol levels remained normal. The dose was adjusted as needed to maintain normal blood galactitol levels. As the child aged, he did not show growth delay, speech delay, learning impairment, motor ataxia, or precocious cataracts.

[0488] Example 4

[0489] An adult patient with galactosemia presents with motor ataxia, spasticity and poor balance. Therapy with an aldose reductase inhibitor (such as compound A or compound B) is started at a dose selected by a clinician to normalize blood galactose and / or galactitol levels. Treatment results in a decrease in blood galactitol levels and eventual return to normal. With the normalization of galactitol levels, the patient exhibits reduced motor ataxia and spasticity, as well as improved balance. The dose is adjusted as needed to maintain normal blood galactose levels, as well as improvements in the patient's motor control and balance.

[0490] Unless defined otherwise, 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.

[0491] Although methods and materials similar or equivalent to those described herein can be used in the practice or test of the present disclosure, suitable methods and materials are described in the preceding paragraphs. In addition, materials, methods and embodiments are only illustrative and are not intended to be restrictive. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated herein by reference. All disclosed foreign patents and patent applications cited herein are incorporated herein by reference. All disclosed references, files, manuscripts, scientific literature cited herein are incorporated herein by reference. All identifiers and accession numbers related to the scientific databases (e.g., PUBMED, NCBI, GENBANK, EBI) cited herein are incorporated herein by reference.

Claims

1. A method for treating galactosemia or preventing complications associated with galactosemia, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor.

2. A method of reducing the amount or level of galactitol in a subject suffering from galactosemia, comprising administering to said subject a therapeutically effective amount of an aldose reductase inhibitor.

3. A method for treating cataracts comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor.

4. The method of claim 3, wherein the subject in need thereof suffers from galactosemia.

5. A method for treating or preventing cognitive or neurological impairment associated with galactosemia, comprising administering to a subject suffering from galactosemia a therapeutically effective amount of an aldose reductase inhibitor.

6. The method of claim 5, wherein the cognitive or neurological impairment associated with galactosemia is speech dysfunction.

7. The method of claim 5, wherein the cognitive or neurological deficit associated with galactosemia is motor ataxia.

8. The method of claim 5, wherein the cognitive or neurological impairment associated with galactosemia is cognitive dysfunction.

9. The method of claim 5, wherein the cognitive or neurological deficit associated with galactosemia is pseudokinetic cerebral infarction.

10. The method of claim 5, wherein the cognitive or neurological deficit associated with galactosemia is epilepsy.

11. The method of any one of claims 1-10, wherein the aldose reductase inhibitor is a compound of any one of Formulae I-VI or a salt thereof.

12. The method of any one of claims 1-10, wherein the aldose reductase inhibitor is zopolrestat or a salt thereof, or epalrestat or a salt thereof.

13. The method of any one of claims 1 to 10, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof.

14. The method of claim 13, wherein the aldose reductase inhibitor is selected from the following or a salt thereof 15. The method of any one of claims 1-10, wherein the aldose reductase inhibitor is a compound of formula III.

16. The method of claim 15, wherein the aldose reductase inhibitor is selected from the group consisting of: E 17. The method of any one of E 1-16, wherein the subject is a human.

18. The method of any one of claims 1-17, wherein the galactosemia is manifested in the subject as elevated alditol levels in the blood, urine, or intraocular fluid.

19. The method of claim 18, wherein the alditol is galactitol, inositol or sorbitol.

20. The method of any one of claims 1-19, wherein the galactosemia manifests in the subject as increased liver cirrhosis, retinal disorders, macular edema, ocular cataracts, ovarian dysfunction, muscle or nerve dysfunction, retinopathy, neuropathy, impaired nerve conduction, or mental retardation.

21. The method of any one of claims 1-20, wherein the galactosemia is type I galactosemia (GALT deficiency).

22. The method of any one of claims 1-20, wherein the galactosemia is type II galactosemia (GALK deficiency).

23. The method of any one of claims 1-10, wherein the galactosemia is type III galactosemia (GALE deficiency).

24. The method of any one of the preceding claims, wherein the aldose reductase inhibitor is Compound A or a salt thereof.

25. The method of any one of the preceding claims, wherein the aldose reductase inhibitor is Compound B or a salt thereof.

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