Aldose reductase inhibitors for treatment of phosphomannomutase 2 deficiency

Abstract

The present disclosure relates to methods of treating PMM2-CDG using an aldose reductase inhibitor.

Description

[0001] This application is a divisional application of an invention patent application with an application date of October 7, 2020, application number 202080070704.X, and invention name “Aldose reductase inhibitors for treating phosphomannomutase 2 deficiency”.

[0002] Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 912,441, filed on October 8, 2019, the entire disclosure of which is incorporated herein by reference. Background Art

[0004] Phosphomannose mutase 2 (PMM2) is an enzyme that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P). M1P is a precursor of GDP-mannose, which is required for the production of dalichol-P-oligosaccharides important for protein glycosylation.

[0005] PMM2 forms obligate homodimers in the cytoplasm and converts mannose-6-phosphate to mannose-1-phosphate. Each PMM2 monomer forms a dimer, which itself is a prerequisite for catalytic activity, although each dimer only requires one functional active site (Andreotti, G. et al., 2015, PLoS ONE 10, e0139882.doi:10.1371 / journal.pone.013988). Glucose-1,6-bisphosphate and mannose-1,6-bisphosphate are endogenous co-activators of PMM2 function, binding and stabilizing PMM2 dimers (Id.).

[0006] PMM2 deficiency is the most common cause of congenital glycosylation disorder (CDG) (Van, SE et al., FEBS Lett. 1995, 377, 318-320, Ferreira, CR et al., J. Inherit. Metab. Dis. 2018, 41, 541-553). PMM2-CDG is a multi-system, multi-organ disease, because a minimum degree of glycosylation is always required in all cells of the body, and different cell types and organs are more or less susceptible to complex hypoglycosylation sequelae. As the residual level of PMM2 enzyme activity increases, the number and severity of affected organ systems decrease. Mutations in the gene encoding PMM2 are the cause of PMM2-CDG (Jaeken, J. et al., J Inherit Metab Dis. 2008, 31, 669-72), and more than 115 mutations in the PMM2 gene have been found to cause PMM2-CDG. All disease-causing mutations appear to reduce the enzymatic activity of PMM2, resulting in insufficient amounts of active mannose to form oligosaccharides for normal protein glycosylation. PMM2-CDG is also known as CDG-1A or Jaeken syndrome. PMM2-CDG shows variable clinical progression and manifestations, and affected individuals usually present with signs and symptoms in infancy. Organs affected by PMM2-CDG include the brain, liver, gastrointestinal tract, heart, and kidneys. About 20% of affected infants die of multiple organ failure before the age of 1 year. The most severe cases of PMM2-CDG are characterized by fetal hydrops, and in most cases, infants with fetal hydrops die of fetal hydrops shortly after birth. Most PMM2-CDG patients who survive in infancy have intellectual disability and developmental delay (Schiff, M. et al., J Med Genet., 2017, 54, 843-851).

[0007] There are currently no effective treatments for PMM2-CDG, and the disease is managed through efforts to reduce disease manifestations (e.g., occupational, physical, and speech therapy). Thus, there is a recognized but unmet need for methods of treating PMM2-CDG. Summary of the invention

[0008] The present disclosure relates to methods of treating PMM2-CDG by administering to a subject in need thereof a therapeutically effective amount of an aldose reductase (AR) inhibitor. Without wishing to be bound by any particular theory, it is believed that inhibition of AR may enhance PMM2 enzyme activity.

[0009] In one, the method for treating PMM2-CDG includes administering a therapeutically effective amount of zopolrestat to a subject in need. In one example, the method for treating PMM2-CDG includes administering a therapeutically effective amount of a compound of any one of formula (I)-(VI) to a subject in need. In some aspects, the AR inhibitor administered is not bonacetate, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, fenacetate, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210. In one example, the method for treating or preventing PMM2-CDG does not include administering epalrestat. In other examples, the method for treating or preventing PMM2-CDG does not include administering epalrestat and α-cyano-4-hydroxycinnamic acid.

[0010] Subjects to be treated according to the methods disclosed herein may have typical pediatric clinical manifestations, such as developmental delay, severe encephalopathy with axial hypotonia, abnormal eye movements, psychomotor block, and / or cerebellar hypoplasia. Subjects treated according to the methods disclosed herein may have hypogonadism, coagulation abnormalities and thrombotic events, retinitis pigmentosa, and / or peripheral neuropathy.

[0011] In other embodiments, the present disclosure relates to a method of treating PMM2-CDG in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an AR inhibitor, such as a compound of any one of Formulas (I)-(VI), and a pharmaceutically acceptable carrier. The present disclosure relates to a method of increasing PMM2 enzyme activity in a subject suffering from PMM2-CDG, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor, such as a compound of any one of Formulas (I)-(VI).

[0012] In other embodiments, the present disclosure relates to methods of treating PMM2-CDG in a subject in need thereof, comprising administering a therapeutically effective amount of

[0013] (a) a compound of formula (I)-(VI) and a pharmaceutically acceptable carrier; and

[0014] (b) one or more of apalrestat, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, zenastat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210.

[0015] In other embodiments, the disclosure relates to the use of AR inhibitors to increase PMM2 enzyme activity to treat PMM2-CDG.

[0016] In other embodiments, the disclosure relates to the use of an AR inhibitor in the preparation of a medicament for treating PMM2-CDG.

[0017] The present disclosure also relates to the use of AR inhibitors (eg, zopolrestat, epalrestat, a compound of any one of Formulae (I)-(VI)) for treating PMM2-CDG.

[0018] The present disclosure also relates to the use of an AR inhibitor (eg, zopolrestat, epalrestat, a compound of any one of formula (I)-(VI)) in the preparation of a pharmaceutical composition for treating PMM2-CDG.

[0019] The present disclosure also relates to a pharmaceutical preparation for treating PMM2-CDG, which contains an AR inhibitor (eg, zopolrestat, epalrestat, a compound of any one of formula (I)-(VI)) as an active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This indicates that compound B inhibits aldose reductase in vitro.

[0021] Figure 2 Activation of PMM2 activity in PMM2-CDG patient-derived fibroblasts treated with compound B is demonstrated. DETAILED DESCRIPTION OF THE INVENTION

[0023] Various aspects will now be described more fully below. However, these aspects may be implemented in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided to make this disclosure thorough and complete.

[0024] The present disclosure relates to the use of AR inhibitors for treating PMM2-CDG.

[0025] Where a range of values ​​is provided in the present disclosure, it is intended that each intervening value between the upper and lower limits of that range and any other specified or intervening value in that specified range is included in the present disclosure. For example, if a range of 1M to 8M is stated, it is intended that 2M, 3M, 4M, 5M, 6M, and 7M are also specifically disclosed, as well as ranges of values ​​greater than or equal to 1M and ranges of values ​​less than or equal to 8M.

[0026] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound of Formula (I)" includes a single compound as well as two or more identical or different compounds; reference to "an excipient" includes a single excipient as well as two or more identical or different excipients, etc.

[0027] The word "about" refers to a range of plus or minus 10% of the value, for example, "about 50" refers to 45 to 55, "about 25000" refers to 22500 to 27500, etc., unless the context of the present disclosure is inconsistent with such an interpretation. For example, in a numerical list, 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 next 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.

[0028] In order to provide a complete, concise and clear description of various embodiments, the present disclosure includes descriptions of various components, groups of components, scopes and other elements disclosed more widely. These elements can be combined differently to provide additional embodiments of the present disclosure. It is also intended that for any reason, any disclosed feature (e.g., substituent, analog, compound, structure, component), including a single member of any disclosed group, including any subrange or combination of subranges within the group, can be excluded from the present disclosure or any embodiment of the present disclosure.

[0029] Various embodiments of the present disclosure are described in further detail in the following numbered paragraphs.

[0030] I. Methods

[0031] In general, the present disclosure relates to a method for treating PMM2-CDG, comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits aldose reductase activity. 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 ponastat, sobinil, sorbinol, mirestat, AND-138, CT-112, zenastat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine, SPR-210, zopolrestat, epalrestat, compounds disclosed in US8916563, US9650383, US10150779, and compounds disclosed herein. α-cyano-4-hydroxycinnamic acid is also an AR inhibitor. Preferred AR inhibitors for use in the present invention include zopolrestat, epalrestat, compounds disclosed in U.S. Pat. No. 8,916,563, U.S. Pat. No. 9,650,383, U.S. Pat. No. 10,150,779, and compounds disclosed herein. AR inhibitors can be administered in any suitable molecular form, including pharmaceutically acceptable salts, solvates, prodrugs, and compounds containing stable isotopic forms of one or more atoms (e.g., deuterium instead of hydrogen).

[0032] In one example, a method for treating PMM2-CDG comprises administering a therapeutically effective amount of zopolrestat to a subject in need thereof.

[0033] In one example, a method for treating PMM2-CDG comprises administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0034] In one example, the method for treating PMM2-CDG includes administering a therapeutically effective amount of aldose reductase to a subject in need thereof, wherein the aldose reductase inhibitor is not bonacetate, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, zenastat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210. In a particular embodiment, the method for treating PMM2-CDG disclosed herein does not include administering epalrestat. In a particular embodiment, the method for treating PMM2-CDG disclosed herein does not include administering epalrestat or α-cyano-4-hydroxycinnamic acid.

[0035] In one example, a method for treating PMM2-CDG 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 or a physiologically acceptable salt, hydrate, solvate or prodrug of Compound A or Compound B.

[0036]

[0037] As used herein, the term "treatment" refers to curative or palliative (e.g., controlling or alleviating a disease or disease symptom) therapy. This can include reversing, reducing, preventing, or delaying the symptoms, clinical signs, and underlying pathological manifestations of PMM2-CDG in a manner that improves or stabilizes the subject's condition. Thus, the method can be used to treat PMM2-CDG, treat complications (e.g., symptoms and clinical signs) of PMM2-CDG, and / or treat and prevent complications (e.g., symptoms and clinical signs) of PMM2-CDG.

[0038] 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 reducing or improving the severity of PMM2-CDG, preventing the progression of a condition or symptom associated with PMM2-CDG, or enhancing or otherwise improving the therapeutic effect of another therapy for treating or managing PMM2-CDG. A therapeutically effective amount can be an amount that increases PMM2 enzyme activity in the treated subject. The actual amount administered can be determined by an ordinary 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 amount of the AR inhibitor administered is about 0.5 to about 60 mg / kg body weight per day, such as about 1.0 to 10 mg / kg.

[0039] In some examples of the practice of the methods disclosed herein, the therapeutically effective amount is sufficient to reduce intracellular aldose reductase activity by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, such as about 100% (e.g., compared to pre-treatment levels). The therapeutically effective amount can be an amount that increases PMM2 enzyme 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 may be sufficient to restore PMM2 enzyme levels in subjects with PMM2-CDG.

[0040] A "subject" can be any animal with PMM2-CDG, 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 cattle, horses, goats, sheep, avian and porcine subjects, wild animals (whether in the wild or in a zoo), research or laboratory animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc. Typically, the human subject to be treated using the methods disclosed herein is diagnosed as a newborn with PMM2-CDG by enzymatic or genetic screening and has a defect in PMM2 activity.

[0041] The present disclosure also relates to at least one clinical feature or complication of PMM2-CDG in the prevention or treatment subject.Representative clinical features or complications that may be present in children, adolescents or adults include, for example, alternating esotropia and other abnormal eye movements, axial hypotonia, intellectual disability, ataxia and decreased reflexes.After infancy, symptoms include retinitis pigmentosa, usually stroke-like attacks, sometimes epilepsy.Other features are variable malformations (large, dysplastic / dysplastic ears), abnormal subcutaneous adipose tissue distribution (fat pads, nipple inversion), mild to moderate hepatomegaly, skeletal abnormalities (including atlantoaxial subluxation) and hypogonadism.Pericardial effusion and / or cardiomyopathy occur in some infants.At the other end of the clinical spectrum are patients with very mild phenotypes (no malformations, very mild intellectual disability, ataxia) (Jaeken, J et al., "Glycosylation and its Disorders: General Overview," Elsevier, Reference Module in Biomedical Sciences, 2016).

[0042] In a specific aspect, the present disclosure relates to methods for treating clinical features or complications of PMM2-CDG, and comprises administering to a subject in need thereof a therapeutically effective amount of zopolrestat.

[0043] In one example, the present disclosure relates to a method for treating clinical features or complications of PMM2-CDG, and comprises administering a therapeutically effective amount of epalrestat to a subject in need thereof.

[0044] In one example, the present disclosure relates to a method for treating clinical features or complications of PMM2-CDG, and comprises administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulae (I)-(VI).

[0045] In some embodiments, the above methods are performed by administering a formulation comprising one or more AR inhibitors. The formulation can be suitable for administration to a subject in need thereof once a day, twice a day, three times a day, or four times a day for the desired treatment period.

[0046] Typically, the preparation is suitable for long-term 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. Typically, the method is performed by administering a preparation suitable for administration over the course of years or decades.

[0047] II. AR Inhibitors

[0048] 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, fenacitate, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine, SPR-210, zopolrestat, epalrestat, US8916563, US9650383, WO2012 / 009553 disclosed compounds and compounds disclosed herein. Preferred AR inhibitors for the present invention are zopolrestat, epalrestat, compounds disclosed in US Pat. No. 8916563, US Pat. No. 9650383, WO2017 / 038505, US Pat. No. 10150779 and compounds disclosed herein. The disclosures of U.S. Pat. No. 8,916,563, U.S. Pat. No. 9,650,383, U.S. Pat. No. 10,150,779, WO2012 / 009553, and WO2017 / 038505 are incorporated herein by reference and disclose compounds suitable for use in the methods described herein.

[0049] Compounds of formula (I) and (II)

[0050] In one example, the AR inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or solvate thereof,

[0051]

[0052] in,

[0053] R 1 is H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-hydroxyalkyl or (C 1 -C 6 )-aminoalkyl;

[0054] X 1 Is N or CR 3 ;

[0055] X 2 Is N or CR 4 ;

[0056] X 3 Is N or CR 5 ;

[0057] X 4 Is N or CR 6 ; The condition is X 1 , X 2 , X 3 or X 4 Two or three of them are N;

[0058] Y is a bond, C=O, C=S, C=NH or C=N(C 1 -C 4 )-alkyl;

[0059] Z is

[0060]

[0061] A 1 YesNR 11 , O, S or CH 2 ;

[0062] A 2 is N or CH;

[0063] A 3 NR 11 , O or S;

[0064] R 3 To R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl; or R 3 To R 6 Two or R 7 To R 10 The two together are (C 1-C 4 )-alkylenedioxy; and

[0065] R 11 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 )-alkyl.

[0066] Those skilled in the art will recognize that the designation of Z is

[0067]

[0068] It means that when Z is

[0069]

[0070] The compounds of formula (I) include

[0071]

[0072] And when Z is

[0073]

[0074] The compounds of formula (I) include

[0075]

[0076] In certain embodiments, R 1 is hydrogen or (C 1 -C 6 In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 Yes (C 1 -C 6 In certain embodiments, R 1 It is tert-butyl.

[0077] In certain embodiments, R 3 To R 10 is independently hydrogen, halogen or haloalkyl. 3 To R 10 are independently hydrogen, halogen or trihaloalkyl.

[0078] In certain embodiments, R 3 To R 6 It's hydrogen.

[0079] In certain embodiments, R 7 To R 10 is independently hydrogen, halogen or haloalkyl.7 To R 10 are independently hydrogen, halogen or trihaloalkyl.

[0080] In certain embodiments, R 7 and R 10 It's hydrogen.

[0081] In certain embodiments, R 8 is hydrogen, halogen or haloalkyl. 8 is hydrogen. In certain embodiments, R 8 In certain embodiments, R 8 It is a haloalkyl group.

[0082] In certain embodiments, R 9 is hydrogen, halogen or haloalkyl. 9 is hydrogen. In certain embodiments, R 9 In certain embodiments, R 9 It is a haloalkyl group.

[0083] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(C 1 -C 4 )-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(C 1 -C 4 )-alkyl.

[0084] In certain embodiments, A 1 YesNR 11 , S or CH 2 In certain embodiments, A 1 YesNR 11 Or O. In certain embodiments, A 1 YesNR 11 In certain embodiments, A 1 YesNR 11 In certain embodiments, A 1 is O. In certain embodiments, A 1 It’s S.

[0085] In certain embodiments, A 2 is N or CH. In certain embodiments, A 1 is N. In certain embodiments, A 1 It is CH.

[0086] In certain embodiments, A 3is O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 It’s S.

[0087] In certain embodiments, X 1 and X 4 It's nitrogen.

[0088] In certain embodiments, X 1 and X 2 It's nitrogen.

[0089] In certain embodiments, X 1 and X 3 It's nitrogen.

[0090] In certain embodiments, X 2 and X 3 It's nitrogen.

[0091] In certain embodiments, X 2 and X 4 It's nitrogen.

[0092] In certain embodiments, X 3 and X 4 It's nitrogen.

[0093] In certain embodiments, Z is

[0094]

[0095] In certain embodiments, Z is

[0096]

[0097] In certain embodiments, R 1 is hydrogen or (C 1 -C 6 )-alkyl;

[0098] X 1 and X 4 is N;

[0099] X 2 Yes CR 4 ;

[0100] X 3 Yes CR 5 ;

[0101] Y is C=O;

[0102] Z is

[0103]

[0104] A1 YesNR 11 , O or S;

[0105] A 2 is N;

[0106] A 3 is O or S;

[0107] R 4 and R 5 It is hydrogen;

[0108] R 7 To R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl; and

[0109] R 11 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 )-alkyl.

[0110] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0111] X 1 and X 4 is N;

[0112] X 2 Yes CR 4 ;

[0113] X 3 Yes CR 5 ;

[0114] Y is C=O;

[0115] Z is

[0116]

[0117] A 1 YesNR 11 , O or S;

[0118] A 2 is N;

[0119] A 3 is O or S;

[0120] R 4 and R 5 It is hydrogen;

[0121] R 7 To R 10 are independently hydrogen, halogen or haloalkyl; and R 11 is hydrogen, (C 1 -C 4 In certain embodiments, R 1 is hydrogen or tert-butyl;

[0122] X 1 and X 4 is N;

[0123] X 2 It is CH;

[0124] X 3 It is CH;

[0125] Y is C=O;

[0126] Z is

[0127]

[0128] A 1 YesNR 11 , O or S;

[0129] A 2 is N;

[0130] A 3 is O or S;

[0131] R 7 , R 8 and R 10 are independently hydrogen, halogen or haloalkyl;

[0132] R 9 is halogen or haloalkyl; and

[0133] R 11 is hydrogen or methyl.

[0134] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0135] X 1 and X 4 is N;

[0136] X 2 It is CH;

[0137] X 3 It is CH;

[0138] Y is C=O;

[0139] Z is

[0140]

[0141] A 1 YesNR 11 , O or S;

[0142] A 2 is N;

[0143] A 3 is O or S;

[0144] R 7 , R 8 and R 10 are independently hydrogen, halogen or haloalkyl;

[0145] R 9 is chloro or trifluoromethyl; and

[0146] R 11 is hydrogen or methyl.

[0147] In certain embodiments, the AR inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

[0148]

[0149] Where R 1 , R 7 -R 9 and Y are as described in formula (I), and preferably wherein R 1 is hydrogen or (C 1 -C 6 )-alkyl and Y is C=O. Exemplary compounds of formula (II) include the following compounds and salts thereof:

[0150]

[0151] Compound of formula (III)

[0152] The AR inhibitor may be a compound of formula (III) or a pharmaceutically acceptable salt, prodrug or solvate thereof,

[0153]

[0154] in,

[0155] R 1 It is CO2 R 2 or CO 2 - X + ;

[0156] R 2 H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-hydroxyalkyl or (C 1 -C 6 )-aminoalkyl;

[0157] X 1 is H or halogen;

[0158] X 2 is H or halogen;

[0159] Y is a bond, C=O, C=S, C=NH or C=N(C 1 -C 4 )-alkyl;

[0160] Z is

[0161] A 1 YesNR 7 , O, S or CH 2 ;

[0162] A 2 is N or CH;

[0163] A 3 NR 7 , O or S;

[0164] R 3 To R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl;

[0165] R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C4 )-alkyl; and

[0166] X + It is a counter ion.

[0167] Those skilled in the art will recognize that

[0168] Z is It means that when Z is

[0169] When the compound of formula (III) is understood to include And when Z is Formula, the compounds of formula (I) are understood to include

[0170] In certain embodiments, R 1 It is CO 2 R 2 or CO 2 - X + In certain embodiments, R 1 It is CO 2 R 2 In certain embodiments, R 1 It is CO 2 - X + .

[0171] In certain embodiments, R 2 is hydrogen or (C 1 -C 6 In certain embodiments, R 2 is hydrogen or (C 1 -C 4 In certain embodiments, R 2 is hydrogen or (C 1 -C 3 In certain embodiments, R 2 is hydrogen, methyl or ethyl. In certain embodiments, R 2 is hydrogen or methyl. In certain embodiments, R 2 is methyl or ethyl. In certain embodiments, R 2 In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 Yes (C 1 -C 6 In certain embodiments, R 2 Yes (C 1 -C 6In certain embodiments, R 2 Yes (C 1 -C 2 In certain embodiments, R 2 Yes (C 1 -C 3 In certain embodiments, R 2 Yes (C 1 -C 4 In certain embodiments, R 2 It is tert-butyl.

[0172] In certain embodiments, R 3 To R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl.

[0173] In certain embodiments, R 3 To R 6 is independently hydrogen, halogen or haloalkyl. 3 To R 6 are independently hydrogen, halogen or trihaloalkyl.

[0174] In certain embodiments, R 3 and R 6 is hydrogen. In certain embodiments, R 3 , R 5 and R 6 It's hydrogen.

[0175] In certain embodiments, R 4 is hydrogen, halogen or haloalkyl. 4 is hydrogen. In certain embodiments, R 4 In certain embodiments, R 4 is a haloalkyl group. In certain embodiments, R 4 It is CF 3 .

[0176] In certain embodiments, R 3 To R 6is hydrogen. 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 It is CF 3 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 It is Cl.

[0177] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(C 1 -C 4 )-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(C 1 -C 4 )-alkyl.

[0178] In certain embodiments, A 1 YesNR 7 , O, S or CH 2 In certain embodiments, A 1 YesNR 7 , O or S. In certain embodiments, A 1 YesNR 7 , S or CH 2 In certain embodiments, A 1 YesNR 7 Or O. In certain embodiments, A 1 YesNR 7 In certain embodiments, A 1 YesNR 7 In certain embodiments, A 1is O. In certain embodiments, A 1 It’s S.

[0179] In certain embodiments, A 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 It is CH.

[0180] In certain embodiments, A 3 NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S. In certain embodiments, A 3 YesNR 7 .

[0181] In certain embodiments, X 1 and X 2 It's hydrogen.

[0182] In certain embodiments, X 1 and X 2 In certain embodiments, X 1 and X 2 It is Cl.

[0183] 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 It's hydrogen.

[0184] In certain embodiments, Z is

[0185] In certain embodiments, Z is

[0186] In certain embodiments, R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 It is C 1 -C 4 In certain embodiments, R 7 It is C 1 -C 3In certain embodiments, R 7 It is C 1 -C 2 In certain embodiments, R 7 It is C 1 -C 4 In certain embodiments, R 7 It is C 1 -C 3 In certain embodiments, R 7 is (C(O)O-(C 1 -C 4 In certain embodiments, R 7 It is C(O)O-(C 1 -C 3 In certain embodiments, R 7 It is C(O)O-(C 1 -C 2 In certain embodiments, R 7 It is C(O)O-(C 1 -C 4 In certain embodiments, R 7 It is C(O)O-(C 1 -C 3 )-n-alkyl.

[0187] In certain embodiments, R 1 It is CO 2 R 2 ;

[0188] R 2 is H or (C 1 -C 6 )-alkyl;

[0189] X 1 It is H;

[0190] X 2 It is H;

[0191] Y is C=O;

[0192] Z is

[0193] A 1 NR 7 , O or S;

[0194] A 2 is N;

[0195] A 3 is O or S;

[0196] R3 To R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl; and

[0197] R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 )-alkyl.

[0198] In certain embodiments, R 1 It is CO 2 R 2 ;

[0199] R 2 is H or tert-butyl;

[0200] X 1 It is H;

[0201] X 2 It is H;

[0202] Y is C=O;

[0203] Z is A 1 NR 7 , O or S;

[0204] A 2 is N;

[0205] A 3 is O or S;

[0206] R 6 To R 6 are independently hydrogen, halogen, or haloalkyl; and R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 In certain embodiments, R 1 It is CO 2 R 2 ;

[0207] R 2 is H or tert-butyl;

[0208] X 1 It is H;

[0209] X 2 It is H;

[0210] Y is C=O;

[0211] Z is A 1 NR 7 , O or S;

[0212] A 2 is N;

[0213] A 3 is O or S;

[0214] R 3 , R 5 and R 6 It is hydrogen;

[0215] R 4 is hydrogen, halogen or haloalkyl; and R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 In certain embodiments, R 1 It is CO 2 R 2 ;

[0216] R 2 is H or (C 1 -C 6 )-alkyl;

[0217] X 1 It is a halogen;

[0218] X 2 It is a halogen;

[0219] Y is C=O;

[0220] Z is

[0221] A 1 NR 7 , O or S;

[0222] A 2 is N;

[0223] A 3 is O or S;

[0224] R3 To R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl; and

[0225] R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 )-alkyl.

[0226] In certain embodiments, R 1 It is CO 2 R 2 ;

[0227] R 2 is H or tert-butyl;

[0228] X 1 It is a halogen;

[0229] X 2 It is a halogen;

[0230] Y is C=O;

[0231] Z is

[0232] A 1 NR 7 , O or S;

[0233] A 2 is N;

[0234] A 3 is O or S;

[0235] R 3 To R 6 are independently hydrogen, halogen, or haloalkyl; and

[0236] R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 )-alkyl.

[0237] In certain embodiments, R 1 It is CO 2 R 2 ;

[0238] R 2 is H or tert-butyl;

[0239] X 1 It is Cl;

[0240] X 2 It is Cl;

[0241] Y is C=O;

[0242] Z is A 1 YesNR 7 , O or S;

[0243] A 2 is N;

[0244] A 3 is O or S;

[0245] R 3 To R 6 are independently hydrogen, halogen, or haloalkyl; and R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 In certain embodiments, R 1 It is CO 2 R 2 ;

[0246] R 2 is H or tert-butyl;

[0247] X 1 It is Cl;

[0248] X 2 It is Cl;

[0249] Y is C=O;

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

[0251] A 2 is N;

[0252] A 3 is O or S;

[0253] R 3 , R 5 and R6 It is hydrogen;

[0254] R 4 is hydrogen, halogen or haloalkyl; and R 7 is hydrogen, C1-C4 alkyl or (C(O)O-(C1-C4)-alkyl.

[0255] In certain embodiments, the compound of formula (III) is selected from:

[0256]

[0257] In certain embodiments, the compound of formula (III) is selected from: or a pharmaceutically acceptable salt thereof.

[0258] In certain embodiments, the compound of formula (III) is selected from: or a pharmaceutically acceptable salt thereof.

[0259] Compounds of formula (IV), (V) and (VI)

[0260] The AR inhibitor may be a compound of formula (IV) or a pharmaceutically acceptable salt and solvate thereof,

[0261]

[0262] in,

[0263] X 1 is H or halogen;

[0264] X 2 is H or halogen;

[0265] Y is a bond, C=O, C=S, C=NH or C=N(C 1 -C 4 )-alkyl;

[0266] 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

[0267]

[0268] in,

[0269] X is substituted or unsubstituted C 2 -C 5 Alkylene;

[0270] Z is

[0271] A1 YesNR 7 , O, S or CH 2 ;

[0272] A 2 is N or CH;

[0273] A 3 NR 7 , O or S;

[0274] R 3 To R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl; and

[0275] R 7 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 )-alkyl.

[0276] C 2 -C 5 Suitable substituents on the alkylene group include one or more alkyl, alkoxy, aryl, aryloxy, halogen, haloalkyl, haloalkoxy, haloalkylthio. Preferred substituted C 2 -C 5 The alkylene group is a substituted ethylene group. More preferably, the substituted C 2 -C 5 Alkylene is -C(CH 3 ) 2 C(CH 3 ) 2 -.

[0277] Those skilled in the art will recognize that

[0278] Z is or Z is It means that when Z is Compounds of formula (IV) are understood to encompass and

[0279] When Z is The compound of formula (IV) is understood to be

[0280]

[0281] in,

[0282] 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

[0283]

[0284] in,

[0285] X is substituted or unsubstituted C 2 -C 5 Alkylene.

[0286] In certain embodiments, R of formula (IV) 3 To R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl.

[0287] 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.

[0288] In certain embodiments, R of formula (IV) 3 and R 6 is hydrogen. In certain embodiments, R 3 , R 5 and R 6 It's hydrogen.

[0289] In certain embodiments, R of formula (IV) 4 is hydrogen, halogen or haloalkyl. 4 is hydrogen. In certain embodiments, R4 In certain embodiments, R 4 In certain embodiments, R 4 It is CF 3 .

[0290] In certain embodiments, R of formula (IV) 3 To R 6 is hydrogen. 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 is a haloalkyl group. 3 , R 5 , R 6 is hydrogen and R 4 It is CF 3 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 It is Cl.

[0291] In certain embodiments, Y of formula (IV) is C=O, C=S, C=NH, or C=N(C 1 -C 4 )-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(C 1 -C 4 )-alkyl.

[0292] In certain embodiments, A of formula (IV) 1 YesNR 7 , O, S or CH 2 In certain embodiments, A 1 YesNR 7 , O or S. In certain embodiments, A 1 YesNR 7 , S or CH2 In certain embodiments, A 1 YesNR 7 Or O. In certain embodiments, A 1 YesNR 7 In certain embodiments, A 1 YesNR 7 In certain embodiments, A 1 is O. In certain embodiments, A 1 It’s S.

[0293] In certain embodiments, A of formula (IV) 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 It is CH.

[0294] In certain embodiments, A of formula (IV) 3 YesNR 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 YesNR 7 .

[0295] In certain embodiments, X of formula (IV) 1 and X 2 It's hydrogen.

[0296] In certain embodiments, X of formula (IV) 1 and X 2 In certain embodiments, X 1 and X 2 It is Cl.

[0297] 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 It's hydrogen.

[0298] In certain embodiments, Z of formula (IV) is

[0299] In certain embodiments, Z of formula (IV) is

[0300] In certain embodiments, R of formula (IV) 7It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 It is C 1 -C 4 In certain embodiments, R 7 It is C 1 -C 3 In certain embodiments, R 7 It is C 1 -C 2 In certain embodiments, R 7 It is C 1 -C 4 In certain embodiments, R 7 It is C 1 -C 3 In certain embodiments, R 7 is (C(O)O-(C 1 -C 4 In certain embodiments, R 7 It is C(O)O-(C 1 -C 3 In certain embodiments, R 7 It is C(O)O-(C 1 -C 2 In certain embodiments, R 7 It is C(O)O-(C 1 -C 4 In certain embodiments, R 7 It is C(O)O-(C 1 -C 3 )-n-alkyl.

[0301] In certain embodiments, the compound of formula (IV) is

[0302]

[0303] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0304] in,

[0305] 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

[0306]

[0307] in,

[0308] X is substituted or unsubstituted C 2 -C 5 Alkylene.

[0309] In certain embodiments, the compound of formula (IV) is

[0310]

[0311] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0312] in,

[0313] 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

[0314]

[0315] in,

[0316] X is substituted or unsubstituted C 2 -C 5 Alkylene.

[0317] In certain embodiments, the compound of formula (IV) is

[0318]

[0319] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0320] in,

[0321] 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

[0322]

[0323] in,

[0324] X is substituted or unsubstituted C 2 -C 5 Alkylene.

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

[0326]

[0327]

[0328] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0329] in,

[0330] 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

[0331]

[0332] in,

[0333] X is substituted or unsubstituted C 2 -C 5 Alkylene.

[0334] In another aspect, the aldose reductase inhibitor is a compound of formula (V)

[0335]

[0336] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0337] in,

[0338] X 3 Is N or CR 8 ;

[0339] X 4 Is N or CR 9 ;

[0340] X 5 Is N or CR 10 ;

[0341] X 6 Is N or CR 11 ; The condition is X 3 , X 4 , X 5 or X 6 Two or three of them are N;

[0342] 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

[0343]

[0344] in,

[0345] X is substituted or unsubstituted C 2 -C 5 Alkylene;

[0346] Z 3 yes

[0347] A 4 YesNR 16 , O, S or CH 2 ;

[0348] A 5 is N or CH;

[0349] A 6 YesNR 16 , O or S;

[0350] R 8 To R 15 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl or (C 1 -C 4 )-alkylsulfonyl; or R 8 To R 11 Two or R 12 To R 15 The two together are (C 1 -C 4 )-alkylenedioxy; and

[0351] R 16 It is hydrogen, C 1 -C 4 Alkyl or (C(O)O-(C 1 -C 4 )-alkyl.

[0352] C 2 -C 5 Suitable substituents on the alkylene group include one or more of alkyl, alkoxy, aryl, aryloxy, halogen, haloalkyl, haloalkoxy, and haloalkylthio. Preferred substituted C 2 -C 5The alkylene group is a substituted ethylene group. More preferably, the substituted C 2 -C 5 Alkylene is -C(CH 3 ) 2 C(CH 3 ) 2 -.

[0353] Those skilled in the art will recognize that

[0354] 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

[0355] In some compounds of formula (V), R 8 To R 15 are independently hydrogen, halogen or haloalkyl, for example, R 8 To R 15 are independently hydrogen, halogen, or trihaloalkyl (e.g., -CF 3 ).

[0356] In other compounds of formula (V), R 8 To R 11 It's hydrogen.

[0357] 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 are independently hydrogen, halogen, or trihaloalkyl (e.g., -CF 3 ).

[0358] In certain embodiments, R of formula (V) 12 and R 15 It's hydrogen.

[0359] In certain embodiments, R of formula (V) 13 is hydrogen, halogen or haloalkyl. 13 is hydrogen. In certain embodiments, R 13 In certain embodiments, R 13 It is a haloalkyl group.

[0360] In certain embodiments, R of formula (V) 14 is hydrogen, halogen or haloalkyl. 14 is hydrogen. In certain embodiments, R14 In certain embodiments, R 14 It is a haloalkyl group.

[0361] In certain embodiments, Y of formula (V) is C=O, C=S, C=NH, or C=N(C 1 -C 4 )-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(C 1 -C 4 )-alkyl.

[0362] In certain embodiments, A of formula (V) 4 YesNR 16 , S or CH 2 In certain embodiments, A 4 YesNR 16 Or O. In certain embodiments, A 4 YesNR 16 In certain embodiments, A 4 YesNR 16 In certain embodiments, A 4 is O. In certain embodiments, A 4 It’s S.

[0363] In certain embodiments, A of formula (V) 5 is N or CH. In certain embodiments, A 4 is N. In certain embodiments, A 4 It is CH.

[0364] In certain embodiments, A of formula (V) 6 is O or S. In certain embodiments, A 6 is O. In certain embodiments, A 6 It’s S.

[0365] In certain embodiments, X of formula (V) 3 and X 6 It's nitrogen.

[0366] In certain embodiments, X of formula (V) 3 and X 4 It's nitrogen.

[0367] In certain embodiments, X of formula (V) 3 and X 5 It's nitrogen.

[0368] In certain embodiments, X of formula (V) 4 and X5 It's nitrogen.

[0369] In certain embodiments, X of formula (V) 4 and X 6 It's nitrogen.

[0370] In certain embodiments, X of formula (V) 5 and X 6 It's nitrogen.

[0371] In certain embodiments, Z of formula (V) 3 yes

[0372] In certain embodiments, Z of formula (V) 3 yes

[0373] In some embodiments, the compound of formula (V) is

[0374]

[0375] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0376] in,

[0377] R 14 is hydrogen, halogen, or trihaloalkyl (e.g., -CF 3 );and

[0378] 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

[0379]

[0380] in,

[0381] X is substituted or unsubstituted C 2 -C 5 Alkylene.

[0382] In an embodiment, the compound of formula (V) is

[0383]

[0384] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0385] In one aspect, the aldose reductase inhibitor is a compound of formula (VI)

[0386]

[0387] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0388] in,

[0389] 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

[0390]

[0391] in,

[0392] X is substituted or unsubstituted C 2 -C 5 Alkylene.

[0393] In one embodiment, the aldose reductase inhibitor of formula (VI) is

[0394]

[0395] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0396] In one embodiment, the AH inhibitor of formula (VI) is

[0397]

[0398] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0399] As used herein, unless otherwise indicated, the term "alkyl" refers to a monovalent aliphatic hydrocarbon group having a linear, branched, monocyclic or polycyclic portion, or combinations thereof, wherein the group is optionally substituted at one or more carbons of the linear, branched, monocyclic or polycyclic portion, or combinations thereof, with one or more substituents at each carbon, wherein the one or more substituents are independently C 1 -C 10 Alkyl. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like.

[0400] As used herein, the term "halogen" or "halo-" refers to chlorine (Cl), fluorine (F), iodine (I), or bromine (Br).

[0401] As used herein, the term "acyl" is used in a broad sense to refer to a group of the RCO-type, where R represents an organic group, which can be a substituted or unsubstituted, saturated or unsaturated alkyl, aralkyl, aryl, alicyclic or heterocyclic group; or, defined differently, the term "acyl" is used broadly to refer to the monovalent group remaining when the OH group of the carboxyl group is removed from a carboxylic acid molecule.

[0402] 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.

[0403] The term "cycloalkyl" is used herein to denote a cycloalkyl group having 3 to 6 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0404] The term "solvate" as used herein means a compound or a pharmaceutically acceptable salt thereof, in which molecules of a suitable solvent are incorporated into the crystal lattice. 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 referred to as a "hydrate."

[0405] "Prodrug" refers to an agent that is converted into a parent drug in vivo. Prodrugs are generally useful, and 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 not bioavailable. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a compound carries a protecting group that is split by hydrolysis in a body fluid, such as in the bloodstream, thereby releasing the active compound or being oxidized or reduced in a body fluid to release the compound. The term "prodrug" can be applied to such functions, for example; an acid functional group of a compound of formula (I). A prodrug can be composed of a structure in which the acidic group is masked, for example, as an ester or amide. Other examples of prodrugs are discussed herein. See also Alexander et al. (J. Med. Chem. 1988, 31, 318), which is incorporated by reference. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable phosphate analogs. Prodrugs are also described in, for example, The Practice of Medicinal Chemistry (Camille Wermuth, ed., 1999, Academic Press; incorporated herein by reference). In certain embodiments, prodrugs of compounds having a carboxyl functional group are lower alkyl esters of carboxylic acids. Carboxylic acid esters are conveniently formed by esterifying any carboxylic acid moieties present on the molecule. Prodrugs can generally be prepared using well-known methods, such as Burger's Medicinal Chemistry and Drug Discovery 6 thEd. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh; each of which is incorporated herein by reference). The biohydrolyzable portion of the compound of formula I (a) does not interfere with the biological activity of the compound, but may impart favorable in vivo properties to the compound, such as uptake, duration of action, or onset of action; or (b) may be biologically inactive but converted into a biologically active compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylamidoalkyl esters, and choline esters. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkyl carbonyls. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyetheramines.

[0406] The term "salt" includes salts derived from any suitable organic and inorganic counterions well known in the art, such as 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 other acids; and salts derived from inorganic or organic bases, including, for example, sodium, potassium, calcium, ammonium or tetrafluoroborate. Exemplary pharmaceutically acceptable salts can be 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 incorporated herein by reference). 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 dibasic acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemi-succinate.

[0407] The term "acid" encompasses all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are linear or branched, saturated or unsaturated C1 -C 20 an aliphatic carboxylic acid, which is optionally substituted with a halogen or a hydroxyl group, or C 6 -C 12 Aromatic carboxylic acid substitution. 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 4-24 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, glucoheptonic acid and lactobionic acid.

[0408] III. Composition

[0409] The compound can be administered in the form of a suitable composition, such as a pharmaceutical composition. Pharmaceutical compositions are physiologically acceptable and typically include an active compound and a carrier. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids, such as water and oils, including oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. The pharmaceutical carrier can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, adjuvants, 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, 21 st Ed. (Lippincot, Williams & Wilkins (2005); Modern Pharmaceutics, vol. 121 (Gilbert Banker and Christopher Rhodes, CRC Press (2002); each of which is herein incorporated by reference in its entirety).

[0410] The composition can be in a physiologically and / or pharmaceutically acceptable desired form, such as tablets, capsules, solutions, emulsions, suspensions, gels, sols or colloids. If desired, the carrier can include a buffer, such as an alkaline buffer, such as an ammonium buffer, an acidic buffer, such as glycolate, 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, glycylamide, glycylglycine, HEPBS, Bicine, TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS and CABS.

[0411] 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. The desired particle size can be maintained, for example, by using a coating such as lecithin; by dispersing in a carrier such as a liquid polyol or lipid; by using a surfactant such as hydroxypropylcellulose; or a combination of these methods to maintain appropriate fluidity. If necessary, a tonicity modifier such as a sugar, sodium chloride, or a combination thereof can be included. In some embodiments, the composition is isotonic.

[0412] The composition may also include additional ingredients such as acceptable surfactants, cosolvents, emollients, agents to adjust pH and osmotic pressure, and / or antioxidants to retard oxidation of one or more components.

[0413] 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. Therefore, although intrathecal administration is a choice and can be selected by a clinician (for example, when the aldose reductase inhibitor is not a central nervous system permeant), it is generally preferred not to administer the aldose reductase inhibitor intrathecally. Oral compositions can be directly incorporated into the food of the diet. Preferred carriers for oral administration include inert diluents, edible carriers or combinations thereof. Examples of pharmaceutically acceptable carriers can include, for example, water or saline solutions, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids or alcohols. Surfactants such as detergents are also suitable for use in preparations. Specific examples of surfactants include polyvinyl alcohol, polyvinyl pyrrolidone, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives, such as methacrylates and the like, anionic surfactants, such as alkaline stearates, especially sodium stearate, potassium stearate or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, especially those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of the formula NR'R"R'"R""Y", wherein the R groups are identical or different The same optionally hydroxylated hydrocarbon group, and Y "is an anion of a strong acid, such as a halogen anion, a sulfate anion and a sulfonate anion; hexadecyltrimethylammonium bromide is one of the cationic surfactants that can be used, an amine salt of the formula NR'R'R", wherein the R groups are the same 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, especially 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.

[0414] 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.

[0415] Additional formulations suitable for other modes of administration include suppositories. In addition, sterile injectable solutions may be prepared using suitable solvents. Dispersions are typically prepared by incorporating the various sterilized amino acid components into a sterile carrier containing a basic dispersion medium and / or other ingredients. Suitable formulation methods for any desired mode of administration are well known in the art (see generally Remington's Pharmaceutical Sciences, 18 th Ed. Mack Printing Company, 1990).

[0416] 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% by weight, such as 0.01 to about 1% by weight or about 0.05 to about 0.5% by weight. The composition may be formulated as a solution, 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.

[0417] 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 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.

[0418] The pharmaceutical preparations disclosed herein are prepared by methods well known in pharmacy. Optionally, one or more auxiliary ingredients (e.g., buffers, flavoring agents, surfactants, etc.) are also added. The choice of carrier depends on the solubility and chemical properties of the compound, the selected route of administration and standard pharmaceutical practice.

[0419] 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 requiring administration of the selected compound, and will of course vary depending on the desired clinical endpoint.

[0420] 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 the form of a kit comprising a carrier and optionally instructions for using the kit for treatment or prevention of an end-use in the same or separate packaging.

[0421] IV. Combination Therapy

[0422] The methods described herein include administering an AR inhibitor and one or more additional therapeutic agents. The additional therapeutic agent can be administered before, simultaneously with, or after the AR inhibitor, but in a manner that provides an overlap of the pharmacological activities of the AR inhibitor and the additional therapeutic agent. The additional therapeutic agent can be, for example, a second aldose reductase inhibitor, an antioxidant, or both.

[0423] For example, the second aldose reductase can be a compound described in, for example, U.S. Pat. Nos. 5,677,342; 5,155,259; 4,939,140; US 2006 / 0293265; and Roy et al., (Diabetes Research and Clinical Practice, 10, Issue 1, 91-97, 1990; and references cited therein; each of which is incorporated herein by reference). Aldose reductase inhibitors include, for example, zopolrestat, epalrestat, ranirestat, berberine, and sobinir, as described in, for example, U.S. Pat. Nos. 4,939,140; 6,159,976; and 6,570,013. Preferably, the second aldose reductase inhibitor is selected from pranosastat, epalrestat, sobinil or sorbinol, mirestat, AND-138, CT-112, zopolrestat, zenastat, BAL-AR18, AD-5467, M-79175, torestat, alconil, statil, berberine or SPR-210.

[0424] Other therapeutic agents that may be administered include, for example, corticosteroids, such as prednisone, methylprednisolone, dexamethasone or triamcinolone acetate, or non-corticosteroid anti-inflammatory compounds, such as ibuprofen or flurbiprofen. 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, lavandin A, erbstatin, and herbimycin A, and synthetic protein tyrosine kinase inhibitors such as tyrosine phosphorylation inhibitors (e.g., AG490, AG17, AG213 (RG50864), AG18, AG82, AG494, AG825, AG879, AG1112, AG1296, AG1478, AG126, RG13022, RG14620, and AG555), dihydroxy and dimethoxybenzylidenemalononitrile, analogs of lavandin A (e.g., AG814 and AG957), quinazolines (e.g., AG1478), 4,5-diphenylaminephthalimide, and thiazolidinediones, can be co-administered with genistein or its analogs, prodrugs, or pharmaceutically acceptable salts (see Levitzki et al., Science 2013). 267:1782-1788 (1995); and Cunningham et al., Anti-Cancer Drug Design 7:365-384 (1992)). In this regard, derivatives of genistein that may be useful include those described 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)).

[0425] The present disclosure also 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 PMM2-CDG or associated with PMM2-CDG. 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 PMM2-CDG or associated with PMM2-CDG, 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 a therapeutically effective amount of the compound of formula (I)-(VI) to treat, inhibit and / or prevent a disease state or condition in a subject in need of such treatment.

[0426] 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 PMM2-CDG, 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 a therapeutically effective amount of the composition to treat, inhibit and / or prevent a disease state or condition in a subject in need of such treatment.

[0427] In the above embodiments, the compound or composition is preferably administered orally.

[0428] V. Example - In vitro activation of PMM2 by Compound B

[0429] The in vitro activation of PMM2 by compound B was studied in PMM2-CDG patient-derived fibroblasts. Compound B is a potent and selective inhibitor of aldose reductase. The AR inhibitory activity of compound B was demonstrated in a microplate assay using D-glyceraldehyde and NADPH as substrates for aldose reductase in the presence of compound B at concentrations ranging from 0.1 nM to 10 μM. The results, expressed as percentage inhibition of maximal activity, are summarized in Figure 1 Of note, compared with the reported average AR inhibitory concentration [IC 50 ] was 72 nM compared to epalrestat, compound B (IC 50 =0.10 nM) is a significantly more potent inhibitor of aldose reductase enzyme activity.

[0430] Due to the negative impact on the central nervous system in PMM2-CDG patients, Compound B was tested as a CNS-penetrant aldose reductase inhibitor in fibroblast cell lines derived from 4 unique PMM2-CDG patients to determine whether PMM2 enzyme activation could be detected.

[0431] Cells were seeded in 96-well plates, homogenization buffer (20 mM HEPES, 25 mM KCl, 1 mM DTT, 10 μg / ml leupeptin, 10 μg / ml antiprotease) was added, and the plates were frozen and thawed twice at -80°C to lyse the cells. Then, reaction buffer (50 mM HEPES, 5 mM MgCl) containing 200 μM mannose-1-phosphate as substrate was added. 2, 0.5mM NADP+, 10μg / ml yeast glucose-6-phosphate dehydrogenase, 10μM glucose-1,6-bisphosphate, 10μg / ml phosphoglucose isomerase, 5.25μg / ml phosphomannose isomerase) were added to the wells of each plate. The plate was incubated at 37°C for 270 minutes, and the plate was removed from the culture at the corresponding time point to read the absorbance at 340nm at 30, 60, 90, 120, 150, 180, 210, 240 and 270 minutes. All incubations were carried out with or without substrate (mannose-1-phosphate), and the difference between the two values ​​was calculated as enzyme activity. Enzyme activity was standardized to total lysate protein level. The enzyme activity of fibroblasts in the absence of AR inhibitors was determined. In order to evaluate the effect of compound B on enzyme activity, compound B was incubated with cell lines at a concentration of 50nM for 24 hours. Thereafter, enzyme activity was evaluated as described above. At least two biological replicates were performed and the enzyme activity in the presence of compound B was compared to that of the DMSO-treated mutant cell line used as a control. For ease of analysis, the enzyme activity (represented by NADPH concentration) of each treatment condition was compared to the activity of the baseline, untreated mutant cell line at the last time point.

[0432] The results of these studies are Figure 2 The heterozygous amino acid substitutions for each individual patient are shown in Figure 2 Compound B increased PMM2 enzyme activity in each of the four patient-derived cell lines tested. Compound B was shown to be a potent activator of PMM2 activity in PMM2-CDG patient-derived fibroblasts.

[0433] 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.

[0434] Although methods and materials similar or equivalent to those described herein can be used for practicing or testing the present disclosure, suitable methods and materials are described in the preceding paragraphs. In addition, materials and methods are only illustrative, rather than restrictive. All U.S. patents cited herein and published or unpublished U.S. patent applications are incorporated herein by reference. All disclosed foreign patents and patent applications cited herein are incorporated herein by reference. All disclosed references, documents, 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 PMM2-CDG, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor.

2. A method of increasing PMM2 enzyme activity in a subject suffering from PMM2-CDG, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor.

3. The method according to any one of claims 1 to 2, wherein the aldose reductase inhibitor is a compound of formula (III) or a salt thereof.

4. The method of claim 3, wherein the aldose reductase inhibitor is selected from the following or a salt thereof:

5. The method according to any one of claims 1 to 4, wherein the aldose reductase inhibitor is compound B or a salt thereof.

6. The method of any one of claims 1-2, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof.

7. The method of claim 6, wherein the aldose reductase inhibitor is selected from the following or a salt thereof:

8. The method according to claim 7, wherein the aldose reductase inhibitor is Compound A or a salt thereof.

9. The method according to any one of claims 1 to 2, wherein the aldose reductase inhibitor is a compound of any one of formulae (I) to (VI) or a salt thereof.

10. The method of any one of claims 1-9, wherein the subject is a human.

11. An aldose reductase inhibitor for use in treating PMM2-CDG.

12. The use of claim 11, wherein the treatment increases the activity of the PMM2 enzyme in a subject suffering from PMM2-CDG.

13. The use according to any one of claims 11 to 12, wherein the aldose reductase inhibitor is a compound of formula (III) or a salt thereof.

14. The use according to claim 13, wherein the aldose reductase inhibitor is selected from the following or a salt thereof:

15. The use according to any one of claims 11 to 14, wherein the aldose reductase inhibitor is compound B or a salt thereof.

16. The use according to any one of claims 11 to 12, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof.

17. The method of claim 16, wherein the aldose reductase inhibitor is selected from the following or a salt thereof:

18. The method according to claim 17, wherein the aldose reductase inhibitor is Compound A or a salt thereof.

19. The method of any one of claims 11-12, wherein the aldose reductase inhibitor is a compound of any one of formula (I)-(VI) or a salt thereof.

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