Aldose reductase inhibitor for treating phosphomannomutase 2 deficiency

Abstract

To provide an aldose reductase inhibitor for treating phosphomannomutase 2 deficiency.SOLUTION: Provided is a method for treating PMM2-CDG by using an aldose reductase inhibitor. In another embodiment, also provided is a method for treating PMM2-CDG in a subject who needs treatment of PMM2-CDG, which includes administering a therapeutically effective amount of an AR inhibitor which is a pharmaceutical composition containing any one compound of formulas (I) to (VI) for example, and a pharmaceutically acceptable carrier. Also provided is a method for increasing PMM2 enzymatic activity in a subject having PMM2-CDG, which includes administering, to the subject, a therapeutically effective amount of an aldose reductase inhibitor which is any one compound of the formulas (I) to (VI) for example.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 912,441, filed Oct. 8, 2019, which is incorporated herein by reference.

Background Art

[0002] Background Phosphomannomutase 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 dolichol-P-oligosaccharide, an important component for protein glycosylation.

[0003] PMM2 forms an absolute homodimer in the cytoplasm and converts mannose-6-phosphate to mannose-1-phosphate. Each PMM2 monomer forms a dimer with itself as an essential condition for catalytic activity, but only one functional active site per dimer is required. (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 coactivators of PMM2 function, binding to and stabilizing the PMM2 dimer (ibid.).

[0004] PMM2 deficiency underlies the most common congenital disorders of glycosylation (CDG) (Van, S. E. et al., FEBS Lett. 1995, 377, 318 - 320, Ferreira, C. R. et al., J. Inherit. Metab. Dis. 2018, 41, 541 - 553). PMM2 - CDG is a multi - system, multi - organ disease. This is because a minimum level of glycosylation is constantly required in all cells of the body, and different cell types and organs are more or less susceptible to the complex consequences of under - glycosylation. As the residual level of PMM2 enzyme activity increases, the number and severity of affected organ systems decrease. Mutations in the gene encoding PMM2 underlie PMM2 - CDG (Jaeken, J. et al., J Inherit Metab Dis. 2008, 31, 669 - 72), and more than 115 mutations causing PMM2 - CDG have been found in the PMM2 gene. All mutations causing the disease seem to reduce the enzyme activity of PMM2, resulting in an insufficient amount of activated mannose to form oligosaccharides for normal protein glycosylation. PMM2 - CDG is also known as CDG - 1A or Jaeken syndrome. PMM2 - CDG shows various clinical courses and presentations, and affected individuals typically develop signs and symptoms in infancy. Organs affected by PMM2 - CDG include the brain, liver, gastrointestinal tract, heart, and kidneys. Approximately 20% of affected infants die before 1 year of age due to multiple organ failure. The most severe cases of PMM2 - CDG are characterized by fetal hydrops, and in most cases, newborns with fetal hydrops are stillborn or die shortly after birth. Most PMM2 - CDG patients who survive infancy have intellectual disability and developmental delay (Schiff, M. et al., J Med Genet., 2017, 54, 843 - 851). Currently, there is no effective treatment approach for PMM2 - CDG, and the disease is managed with efforts to reduce the appearance of the disease (e.g., occupational therapy, physical therapy, and speech therapy) It is managed by. Therefore, there is a recognized but unmet need for a method for treating PMM2-CDG.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0006] Summary The present disclosure relates to a method for treating PMM2-CDG by administering a therapeutically effective amount of an aldose reductase (AR) inhibitor to a subject in need of treatment for PMM2-CDG. Without being bound by any particular theory, inhibition of AR is thought to be able to enhance PMM2 enzyme activity.

[0007] In one example, a method for the treatment of PMM2-CDG includes administering a therapeutically effective amount of zopolrestat to a subject in need thereof. In one example, a method for the treatment of PMM2-CDG includes administering a therapeutically effective amount of any one compound of formulas (I)-(VI) to a subject in need thereof. In some embodiments, the AR inhibitor to be administered is not ponalrestat, epalrestat, sorbinil or sorbitol, imirestat, AND-138, CT-112, zopolrestat, zerenrestat, BAL-AR18, AD-5467, M-79175, torlrestat, alconyl, statil, berberine or SPR-210. In one example, a method for the treatment or prevention of PMM2-CDG excludes the administration of epalrestat. In other examples, a method for the treatment or prevention of PMM2-CDG excludes the administration of epalrestat and α-cyano-4-hydroxycinnamic acid.

[0008] Subjects to be treated according to the methods disclosed herein may have classical pediatric clinical presentations such as developmental delay, severe encephalopathy with axial hypotonia, abnormal eye movements, psychomotor retardation and / or cerebellar hypoplasia. Subjects to be treated according to the methods disclosed herein may have hypogonadism, coagulation abnormalities and thrombotic events, retinitis pigmentosa and / or peripheral neuropathy.

[0009] In other embodiments, the disclosure relates to a method of treating PMM2-CDG in a subject in need of treatment for PMM2-CDG, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an AR inhibitor, such as any one compound of formulas (I)-(VI), and a pharmaceutically acceptable carrier. The disclosure relates to a method of increasing PMM2 enzyme activity in a subject having PMM2-CDG, the method comprising administering a therapeutically effective amount of an aldose reductase inhibitor, such as any one compound of formulas (I)-(VI), to the subject.

[0010] In other embodiments, the present disclosure is a method of treating PMM2-CDG in a subject in need of treatment for PMM2-CDG, the method comprising administering a therapeutically effective amount of (a) a compound of formula (I)-(VI) and a pharmaceutically acceptable carrier; and (b) one or more of alponalrestat, epalrestat, sorbinil or sorbitol, imirestat, AND-138, CT-112, zopolrestat, zerenestat, BAL-AR18, AD-5467, M-79175, torlrestat, alconyl, statil, berberine or SPR-210 The method includes administering.

[0011] In other embodiments, the present disclosure relates to the use of an AR inhibitor for increasing PMM2 enzyme activity for the treatment of PMM2-CDG.

[0012] In other embodiments, the present disclosure relates to the use of an AR inhibitor for the manufacture of a medicament for treating PMM2-CDG.

[0013] The present disclosure also relates to the use of an AR inhibitor (e.g., zopolrestat, epalrestat, a compound of any one of formulas (I)-(VI)) for the treatment of PMM2-CDG.

[0014] The present disclosure also relates to an AR inhibitor (e.g., zopolrestat, epalrestat, a compound of any one of formulas (I)-(VI)) for the manufacture of a medicament for the treatment of PMM2-CDG.

[0015] The present disclosure also relates to a pharmaceutical preparation for the treatment of PMM2-CDG, the pharmaceutical preparation containing an AR inhibitor (e.g., zopolrestat, epalrestat, a compound of any one of formulas (I)-(VI)) as an active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

[0016]

Figure 1

[0017]

Figure 2

[0018] Detailed Description The following describes various aspects in more detail. However, such aspects can be embodied in many different forms and should not be construed as limited to the embodiments shown herein; rather, these embodiments are provided so that this disclosure will be thorough and complete.

[0019] The present disclosure relates to the use of AR inhibitors for the treatment of PMM2-CDG.

[0020] When a range of values is provided in the present disclosure, each intervening value between the upper and lower limits of that range and any other stated value or intervening value within the stated range is intended to be encompassed within the present disclosure. For example, if a range of 1 μM to 8 μM is described, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, and 7 μM, as well as ranges of values greater than or equal to 1 μM and less than or equal to 8 μM are also intended to be explicitly disclosed.

[0021] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. Thus, for example, references to "a compound of Formula I" include a single compound and two or more of the same or different compounds; references to "an excipient" include a single excipient and two or more of the same or different excipients, and so on.

[0022] Unless otherwise indicated in the context of this disclosure or unless inconsistent with such an interpretation, the term "about" means within plus or minus 10% of that value; for example, "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, and so on. For example, in a list of numerical values such as "about 49, about 50, about 55", "about 50" means a range that extends up to less than half the interval between the value before and the value after, for example, greater than 49.5 and less than 52.5. Further, phrases such as "less than about a value" or "greater than about a value" should be understood in view of the definition of the term "about" provided herein.

[0023] To provide a complete, concise, and clear description of the various embodiments, this disclosure includes descriptions of various elements, groups of elements, ranges, and other elements of a broader disclosure. It is intended that such elements can be combined in various ways to provide further embodiments of this disclosure. It is also intended that any disclosed feature (e.g., substituent, analog, compound, structure, element) including any individual member of any disclosed group that includes any subrange or combination of subranges within the group can be excluded from this disclosure or an embodiment of this disclosure for any reason.

[0024] The various embodiments of this disclosure are described in further detail in the paragraphs numbered below. I. Method

[0025] Generally, the present disclosure relates to a method for the treatment of PMM2-CDG, the method 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 5 kDa or less), a biological agent (e.g., inhibitory RNA against 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 are disclosed herein. Small molecule AR inhibitors include ponalrestat, sorbinil, sorbitol, imirestat, AND-138, CT-112, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alconil, statil, berberine, SPR-210, zopolrestat, epalrestat, the compounds disclosed in U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, U.S. Patent No. 10,150,779, and the 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, the compounds disclosed in U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, U.S. Patent No. 10,150,779, and the compounds disclosed herein. The AR inhibitor can be administered in any suitable molecular form, including pharmaceutically acceptable salts, solvates, prodrugs, and compounds containing one or more stable isotopic forms of atoms in place of hydrogen, such as deuterium.

[0026] In one example, a method for the treatment of PMM2-CDG comprises administering to a subject in need thereof a therapeutically effective amount of zopolrestat.

[0027] In one example, a method for the treatment of PMM2-CDG comprises administering to a subject in need thereof a therapeutically effective amount of epalrestat.

[0028] In one example, a method for the treatment of PMM2-CDG comprises administering a therapeutically effective amount of aldose reductase to a subject in need thereof, wherein the aldose reductase inhibitor is not ponalrestat, epalrestat, sorbinil or sorbitol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alconil, statil, berberine or SPR-210. In certain embodiments, the method for the treatment of PMM2-CDG disclosed herein does not comprise administering epalrestat. In certain embodiments, the method for the treatment of PMM2-CDG disclosed herein does not comprise administering epalrestat or α-cyano-4-hydroxycinnamic acid.

[0029] In one example, a method for the treatment of PMM2-CDG comprises administering to a subject in need thereof a therapeutically effective amount of any one compound 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. [Chemical formula]

[0030] As used herein, the term "treating" refers to a curative or palliative (e.g., controlling or alleviating a disease or disease symptom) treatment. This can include methods of improving or stabilizing a subject's symptoms, and restoring, reducing, arresting or delaying the symptoms, clinical signs and underlying conditions of PMM2-CDG. Thus, the methods can be used for the treatment of PMM2-CDG, the treatment of complications of PMM2-CDG (e.g., symptoms and clinical signs), and / or the treatment and prevention of complications of PMM2-CDG (e.g., symptoms and clinical signs).

[0031] As used herein, "therapeutically effective amount" means an amount of a compound sufficient to achieve the desired therapeutic effect under the administration conditions, e.g., an amount that reduces or ameliorates the severity of PMM2-CDG, prevents the progression of symptoms or syndromes associated with PMM2-CDG, or enhances or otherwise improves the therapeutic effect of another treatment for the treatment or management of PMM2-CDG. A therapeutically effective amount can be an amount that increases PMM2 enzyme activity in the subject being treated. The actual amount administered can be determined by a clinician of ordinary skill, based on, for example, the age, weight, sex, general health and drug tolerance of the subject, the severity of the disease, the dosage form selected, the route of administration and other factors. Typically, the amount of AR inhibitor administered is about 0.5 to about 60 mg / kg body weight / day, e.g., about 1.0 to 10 mg / kg.

[0032] In some examples of the practice of the methods disclosed herein, a 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, e.g., about 100% (compared to pre-treatment levels). A therapeutically effective amount can be an amount that increases PMM2 enzyme activity by at least about 20%, about 3 0%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, e.g., about 100% (compared to pre-treatment levels). A therapeutically effective amount can be sufficient to restore the PMM2 enzyme level in a subject having PMM2-CDG.

[0033] The "subject" can be any animal having PMM2-CDG, particularly a mammal, including but not limited to human subjects, domestic animals such as cats or dogs, livestock such as, but not limited to, bovine, equine, caprine, ovine, avian, and porcine subjects, wild animals (whether wild or in a zoo), research animals or experimental animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., and birds such as chickens, turkeys, songbirds, etc. Typically, a human subject to be treated using the methods disclosed herein is diagnosed with PMM2-CDG at birth by enzymatic or genetic screening and has a deficiency in PMM2 activity.

[0034] The present disclosure also relates to the prevention or treatment of at least one clinical feature or complication of PMM2-CDG in a subject. Representative clinical features or complications that can be present in children, adolescents, or adults include, for example, alternating internal strabism and other abnormal eye movements, axial hypotonia, intellectual disability, ataxia, and hyporeflexia. After infancy, symptoms include retinitis pigmentosa, often seizure-like episodes, and sometimes epilepsy. Other features are various dysmorphisms (large, hypoplastic / dysmorphic ears), abnormal distribution of subcutaneous fat tissue (fat pads, depressed nipples), mild to moderate hepatomegaly, skeletal abnormalities (such as atlantoaxial subluxation), and hypogonadism. Some infants develop endocardial effusion and / or cardiomyopathy. At the other end of the clinical spectrum are patients with a very mild phenotype (without dysmorphisms, very mild intellectual disability, ataxia) (Jaeken, J. et al, "Glycosylation and its Disorders: General Overview," Elsevier, Reference Module in Biomedical Sciences, 2016).

[0035] In certain aspects, the present disclosure relates to a method for treating a clinical feature or complication of PMM2-CDG, comprising administering to a subject in need thereof a therapeutically effective amount of zopolrestat.

[0036] In one example, the present disclosure relates to a method for treating clinical features or complications of PMM2-CDG, comprising administering a therapeutically effective amount of eparrestat to a subject in need thereof.

[0037] In one example, the present disclosure relates to a method for treating clinical features or complications of PMM2-CDG, comprising administering a therapeutically effective amount of any one of the compounds of formulas (I) to (VI) to a subject in need thereof.

[0038] In some embodiments, the aforementioned method is performed by administering a formulation comprising one or more AR inhibitors. The formulation may be adapted for administration once, twice, three times or four times a day over a desired treatment period. Typically, the formulation is adapted for chronic administration over weeks, months, years or decades. Typically, the method is performed by administering a formulation adapted for administration over a period of several months. In yet other embodiments, the method is performed by administering a formulation adapted for administration over years or decades. II. AR Inhibitors

[0039] Suitable small molecule AR inhibitors are known in the art and are disclosed herein. Sma Examples of the molecular AR inhibitors include ponalrestat, solvinil, sorbinol, imirestat, AND-138, CT-112, zenerestat, BAL-AR18, AD-5467, M-79175, torlrestat, alconil, statil, berberine, SPR-210, zopolrestat, epalrestat, the compounds disclosed in U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, International Publication No. 2012 / 009553, and the compounds disclosed herein. Preferred AR inhibitors for use in the present invention include zopolrestat, epalrestat, the compounds disclosed in U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, International Publication No. 2017 / 038505, U.S. Patent No. 10,150,779, and the compounds disclosed herein. The disclosures of U.S. Patent No. 8,916,563, U.S. Patent No. 9,650,383, U.S. Patent No. 10,150,779, International Publication No. 2012 / 009553, and International Publication No. 2017 / 038505 are hereby incorporated by reference in their entirety and disclose compounds suitable for use in the methods described herein. Compounds of Formulas I and II

[0040] In one example, the AR inhibitor is a compound of formula (I)

Chemical formula

[0041] wherein,

[0042] R 1 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, or (C1-C6)-aminoalkyl;

[0043] X 1 is N or CR 3 ;

[0044] X 2 is N or CR4 and;

[0045] X 3 is N or CR 5 and;

[0046] X 4 is N or CR 6 and; provided that X 1 X 2 X 3 or X 4 two or three of which are N;

[0047] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

[0048] Z is

Chemical formula

[0049] A 1 is NR 11 O, S or CH2;

[0050] A 2 is N or CH;

[0051] A 3 is NR 11 O or S;

[0052] R 3 ~R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl; or two of R 3 ~R 6 or two of R 7 ~R 10 are together (C1-C4)-alkylenedioxy; and

[0053] R 11 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0054] When Z is

Chem.

Chem.

[0055] when Z is

Chem.

[0056] the compound of formula (I) includes

Chem.

[0057] when Z is

Chem.

[0058] the compound of formula (I) includes

Chem.

[0059] In certain embodiments, R 1 is hydrogen or (C1-C6)-alkyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is (C1-C6)-alkyl. In certain embodiments, R 1 is tert-butyl.

[0060] In certain embodiments, R 3 ~R 10 are independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 3 ~R 10 are independently hydrogen, halogen, or trihaloalkyl.

[0061] In certain embodiments, R 3 ~R 6 is hydrogen.

[0062] In certain embodiments, R 7 ~R 10 are independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 7 ~R 10 are independently hydrogen, halogen, or trihaloalkyl.

[0063] In certain embodiments, R 7 and R 10 are hydrogen.

[0064] In certain embodiments, R 8 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is halogen. In certain embodiments, R 8 is haloalkyl.

[0065] In certain embodiments, R 9 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is halogen. In certain embodiments, R 9 is haloalkyl.

[0066] 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.

[0067] In certain embodiments, A 1 is NR 11 , S or CH2. In certain embodiments, A 1 is NR 11 or O. In certain embodiments, A 1 is NR 11 or S. In certain embodiments, A 1 is NR 11 . In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0068] In certain embodiments, A 2 is N or CH. In certain embodiments, A 1 is N. In certain embodiments, A 1 is CH.

[0069] In certain embodiments, A 3 is O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S.

[0070] In certain embodiments, X 1 and X 4 are nitrogen.

[0071] In certain embodiments, X 1 and X 2 are nitrogen.

[0072] In certain embodiments, X 1 and X 3 are nitrogen.

[0073] In certain embodiments, X 2 and X 3 are nitrogen.

[0074] In certain embodiments, X 2 and X 4 are nitrogen.

[0075] In certain embodiments, X 3 and X 4 are nitrogen.

[0076] In certain embodiments, Z is

Chemical formula

[0077] In certain embodiments, Z is

Chemical formula

[0078] In certain embodiments, R 1 is hydrogen or (C1-C6)-alkyl;

[0079] X 1 and X 4 are N;

[0080] X 2 is CR 4 ;

[0081] X 3 is CR 5 ;

[0082] Y is C=O;

[0083] Z is

Chemical formula

[0084] A 1is NR 11 is O or S;

[0085] A 2 is N;

[0086] A 3 is O or S;

[0087] R 4 and R 5 are hydrogen;

[0088] R 7 ~R 10 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl; and

[0089] R 11 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0090] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0091] X 1 and X 4 are N;

[0092] X 2 is CR 4 ;

[0093] X 3 is CR 5 ;

[0094] Y is C=O;

[0095] Z is

Chemical formula

[0096] A 1 is NR 11 , O or S;

[0097] A 2 is N;

[0098] A 3 is O or S;

[0099] R 4 and R 5 are hydrogen;

[0100] R 7 ~R 10 are independently hydrogen, halogen or haloalkyl; and

[0101] R 11 is hydrogen, (C1-C4)-alkyl or C(O)O-tert-butyl.

[0102] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0103] X 1 and X 4 are N;

[0104] X 2 is CH;

[0105] X 3 is CH;

[0106] Y is C=O;

[0107] Z is

Chemical formula

[0108] A 1 is NR 11 , O or S;

[0109] A 2 is N;

[0110] A 3 is O or S;

[0111] R 7 , R 8 and R 10 are independently hydrogen, halogen or haloalkyl;

[0112] R 9 is halogen or haloalkyl; and

[0113] R 11 is hydrogen or methyl.

[0114] In certain embodiments, R 1 is hydrogen or tert-butyl;

[0115] X 1 and X 4 are N;

[0116] X 2 is CH;

[0117] X 3 is CH;

[0118] Y is C=O;

[0119] Z is

Chemical formula

[0120] A 1 is NR 11 , O or S;

[0121] A 2 is N;

[0122] A 3 is O or S;

[0123] R 7 、R 8 and R 10 are independently hydrogen, halogen or haloalkyl;

[0124] R 9 is chlorine or trifluoromethyl; and

[0125] R 11 is hydrogen or methyl.

[0126] In certain embodiments, the AR inhibitor is a compound of formula (II):

Chemical formula

[0127] wherein R 1 、R 7 -R 9 and Y are as described in formula (I), preferably, R 1 is hydrogen or (C1-C6)-alkyl and Y is C=O. Exemplary compounds of formula (II) include the following and their salts:

Chemical formula

[0128] The AR inhibitor can be a compound of formula (III)

[0129]

Chemical formula

[0130] wherein,

[0131] R 1 is CO2R 2 or CO2 - X+ and;

[0132] R 2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl or (C1-C6)-aminoalkyl;

[0133] X 1 is H or halogen;

[0134] X 2 is H or halogen;

[0135] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

[0136] Z is

Chemical formula

[0137] A 1 is NR 7 , O, S or CH2;

[0138] A 2 is N or CH;

[0139] A 3 is NR 7 , O or S;

[0140] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl;

[0141] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl; and

[0142] X + is a counter ion.

[0143] By those skilled in the art

[0144]

[0145] Z is

Chemical formula

Chemical formula

[0146]

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0147] In certain embodiments, R 1 is CO2R 2 or CO2 - X + . In certain embodiments, R 1 is CO2R 2 . In certain embodiments, R 1 is CO2 - X + .

[0148] In certain embodiments, R 2is hydrogen or (C1-C6)-alkyl. In certain embodiments, R 2 is hydrogen or (C1-C4)-alkyl. In certain embodiments, R 2 is hydrogen or (C1-C3)-alkyl. In certain embodiments, R 2 is hydrogen, methyl or ethyl. In certain embodiments, R 2 is hydrogen or methyl. In certain embodiments, R 2 is methyl or ethyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is (C1-C6)-alkyl. In certain embodiments, R 2 is (C1-C6)-n-alkyl. In certain embodiments, R 2 is (C1-C2)-alkyl. In certain embodiments, R 2 is (C1-C3)-alkyl. In certain embodiments, R 2 is (C1-C4)-alkyl. In certain embodiments, R 2 is tert-butyl.

[0149] In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl.

[0150] In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen or haloalkyl. In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen or trihaloalkyl.

[0151] In certain embodiments, R 3 and R6 is hydrogen. In certain embodiments, R 3 , R 5 and R 6 are hydrogen.

[0152] In certain embodiments, R 4 is hydrogen, halogen or haloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is haloalkyl. In certain embodiments, R 4 is CF3.

[0153] In certain embodiments, R 3 ~R 6 are hydrogen. In certain embodiments, R 3 , R 5 , R 6 are hydrogen and R 4 is halogen or haloalkyl. In certain embodiments, R 3 , R 5 , R 6 are hydrogen and R 4 is haloalkyl. In certain embodiments, R 3 , R 5 , R 6 are hydrogen and R 4 is CF3. In certain embodiments, R 3 , R 5 , R 6 are hydrogen and R 4 is halogen. In certain embodiments, R 3 , R 5 , R 6 are hydrogen and R 4 is F. In certain embodiments, R 3 , R 5 , R 6 are hydrogen and R 4 is Cl.

[0154] 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.

[0155] In certain embodiments, A 1 is NR 7 , O, S or CH2. In certain embodiments, A 1 is NR 7 , O or S. In certain embodiments, A 1 is NR 7 , S or CH2. In certain embodiments, A 1 is NR 7 or O. In certain embodiments, A 1 is NR 7 or S. In certain embodiments, A 1 is NR 7 . In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0156] In certain embodiments, A 2 is N or CH. In certain embodiments, A 2 is N . In certain embodiments, A 2 is CH.

[0157] In certain embodiments, A 3 is NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S. In certain embodiments, A 3 is NR 7 .

[0158] In certain embodiments, X 1 and X 2 are hydrogen.

[0159] In certain embodiments, X 1 and X 2 are halogen. In certain embodiments, X 1 and X 2 are Cl.

[0160] In certain embodiments, X 1 and X 2 are independently hydrogen or halogen. In certain embodiments, X 1 is hydrogen and X 2 is Cl. In certain embodiments, X 1 is Cl and X 2 is hydrogen.

[0161] In certain embodiments, Z is

Chemical formula

[0162] In certain embodiments, Z is

Chemical formula

[0163] In certain embodiments, R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C4 alkyl. In certain embodiments, R 7 is C1-C3 alkyl. In certain embodiments, R 7 is C1-C2 alkyl. In certain embodiments, R 7 is C1-C4n-alkyl. In certain embodiments, R 7 is C1-C3n-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C4)-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C3)-alkyl. In certain embodiments, R 7is C(O)O-(C1-C2)-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C4)-n-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C3)-n-alkyl.

[0164] In certain embodiments, R 1 is CO2R 2 ;

[0165] R 2 is H or (C1-C6)-alkyl;

[0166] X 1 is H;

[0167] X 2 is H;

[0168] Y is C=O;

[0169] Z is

Chemical formula

[0170] A 1 is NR 7 , O or S;

[0171] A 2 is N;

[0172] A 3 is O or S;

[0173] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl; and

[0174] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0175] In certain embodiments, R 1 is CO2R 2 ;

[0176] R 2 is H or tert-butyl;

[0177] X 1 is H;

[0178] X 2 is H;

[0179] Y is C=O;

[0180] Z is

Chemical formula

[0181] A 1 is NR 7 , O or S;

[0182] A 2 is N;

[0183] A 3 is O or S;

[0184] R 6 ~R 6 are independently hydrogen, halogen, haloalkyl; and

[0185] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0186] In certain embodiments, R 1 is CO2R 2 ;

[0187] R 2 is H or tert-butyl;

[0188] X 1 is H;

[0189] X 2 is H;

[0190] Y is C=O;

[0191] Z is

Chemical formula

[0192] A 1 is NR 7 , O or S;

[0193] A 2 is N;

[0194] A 3 is O or S;

[0195] R 3 , R 5 and R 6 are hydrogen;

[0196] R 4 is hydrogen, halogen or haloalkyl; and

[0197] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0198] In certain embodiments, R 1 is CO2R 2 ;

[0199] R 2 is H or (C1-C6)-alkyl;

[0200] X 1is a halogen;

[0201] X 2 is a halogen;

[0202] Y is C=O;

[0203] Z is

Chemical formula

[0204] A 1 is NR 7 , O or S;

[0205] A 2 is N;

[0206] A 3 is O or S;

[0207] R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl; and

[0208] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0209] In certain embodiments, R 1 is CO2R 2 ;

[0210] R 2 is H or tert-butyl;

[0211] X 1 is a halogen;

[0212] X2 is a halogen;

[0213] Y is C=O;

[0214] Z is

Chem.

[0215] A 1 is NR 7 , O or S;

[0216] A 2 is N;

[0217] A 3 is O or S;

[0218] R 3 ~R 6 are independently hydrogen, halogen, haloalkyl; and

[0219] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl .

[0220] In certain embodiments, R 1 is CO2R 2 ;

[0221] R 2 is H or tert-butyl;

[0222] X 1 is Cl;

[0223] X 2 is Cl;

[0224] Y is C=O;

[0225] Z is

Chem.

[0226] A 1 is NR 7 , O or S;

[0227] A 2 is N;

[0228] A 3 is O or S;

[0229] R 3 ~R 6 are independently hydrogen, halogen, haloalkyl; and

[0230] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0231] In certain embodiments, R 1 is CO2R 2 ;

[0232] R 2 is H or tert-butyl;

[0233] X 1 is Cl;

[0234] X 2 is Cl;

[0235] Y is C=O;

[0236] Z is

Chemical formula

[0237] A 1 is NR 7 , O or S;

[0238] A 2 is N;

[0239] A 3 is O or S;

[0240] R 3 、R 5 and R 6 are hydrogen;

[0241] R 4 is hydrogen, halogen or haloalkyl; and

[0242] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0243] In certain embodiments, the compound of formula (III) is

Chemical formula

[0244] In certain embodiments, the compound of formula (III) is

Chemical formula

[0245] In certain embodiments, the compound of formula (III) is

Chemical formula

[0246] AR inhibitor is the compound of formula (IV)

[0247]

Chemical formula

[0248] wherein,

[0249] X 1 is H or halogen;

[0250] X 2 is H or halogen;

[0251] Y is a bond, C=O, C=S, C=NH or C=N(C1-C4)-alkyl;

[0252] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached,

[0253]

Chemical formula

[0254] where

[0255] X is substituted or unsubstituted C2-C5 alkylene;

[0256] Z is

Chemical formula

[0257] A 1 is NR 7 , O, S or CH2;

[0258] A 2 is N or CH;

[0259] A 3 is NR 7 , O or S;

[0260] R 3 ~R 6is 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

[0261] R 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0262] Suitable substituents on C2-C5 alkylene include one or more alkyl, alkoxy, aryl, aryloxy, halo, haloalkyl, haloalkoxy, haloalkylthio. Preferred substituted C2-C5 alkylene is substituted ethylene. More preferred substituted C2-C5 alkylene is -C(CH3)2C(CH3)2-.

[0263] by those skilled in the art

[0264] when Z is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0265] when Z is

Chemical formula

Chemical formula

[0266] Here,

[0267] Z 1 and Z 2 is independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached,

[0268] [Chemical formula] forms,

[0269] Here,

[0270] X is substituted or unsubstituted C2-C5 alkylene.

[0271] In certain embodiments, R in formula (IV) 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl.

[0272] In certain embodiments, R in formula (IV) 3 ~R 6 are independently hydrogen, halogen or haloalkyl. In certain embodiments, R 3 ~R 6 are independently hydrogen, halogen or trihaloalkyl.

[0273] In certain embodiments, R in formula (IV) 3 and R 6 are hydrogen. In certain embodiments, R 3 , R5 and R 6 is hydrogen.

[0274] In certain embodiments, R of formula (IV) 4 is hydrogen, halogen or haloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is haloalkyl. In certain embodiments, R 4 is CF3.

[0275] In certain embodiments, R of formula (IV) 3 ~R 6 is hydrogen. In certain embodiments, R 3 , R 5 , R 6 are hydrogen, and R 4 is halogen or haloalkyl. In certain embodiments, R 3 , R 5 , R 6 are hydrogen, and R 4 is haloalkyl. In certain embodiments, R 3 , R 5 , R 6 are hydrogen, and R 4 is CF3. In certain embodiments, R 3 , R 5 , R 6 are hydrogen, and R 4 is halogen. In certain embodiments, R 3 , R 5 , R 6 are hydrogen, and R 4 is F. In certain embodiments, R 3 , R 5 , R 6 are hydrogen, and R 4 is Cl.

[0276] In certain embodiments, Y in formula (IV) is C=O, C=S, C=NH or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0277] In certain embodiments, A in formula (IV) 1 is NR 7 , O, S or CH2. In certain embodiments, A 1 is NR 7 , O or S. In certain embodiments, A 1 is NR 7 , S or CH2. In certain embodiments, A 1 is NR 7 or O. In certain embodiments, A 1 is NR 7 or S. In certain embodiments, A 1 is NR 7 . In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0278] In certain embodiments, A in formula (IV) 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 is CH.

[0279] In certain embodiments, A in formula (IV) 3 is NR 7 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A in formula (IV) 3 is S. In certain embodiments, A 3 is NR 7 .

[0280] In certain embodiments, X in formula (IV) 1 and X 2 are hydrogen.

[0281] In certain embodiments, X of formula (IV) 1 and X 2 are halogen. In certain embodiments, X 1 and X 2 are Cl.

[0282] In certain embodiments, X of formula (IV) 1 and X 2 are independently hydrogen or halogen. In certain embodiments, X 1 is hydrogen and X 2 is Cl. In certain embodiments, X 1 is Cl and X 2 is hydrogen.

[0283] In certain embodiments, Z of formula (IV) is

Chemical formula

[0284] In certain embodiments, Z of formula (IV) is

Chemical formula

[0285] In certain embodiments, R of formula (IV) 7 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C4 alkyl. In certain embodiments, R 7 is C1-C3 alkyl. In certain embodiments, R 7 is C1-C2 alkyl. In certain embodiments, R 7 is C1-C4 n-alkyl. In certain embodiments, R 7 is C1-C3 n-alkyl. In certain embodiments, R 7is C(O)O-(C1-C4)-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C3)-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C2)-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C4)-n-alkyl. In certain embodiments, R 7 is C(O)O-(C1-C3)-n-alkyl.

[0286] In certain embodiments, the compound of formula (IV) is

[0287]

Chemical formula

[0288] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0289] wherein

[0290] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached,

[0291]

Chemical formula

[0292] where

[0293] X is substituted or unsubstituted C2-C5 alkylene.

[0294] In certain embodiments, the compound of formula (IV) is

[0295]

Chemical formula

[0296] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0297] wherein,

[0298] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached,

[0299]

Chemical formula

[0300] here,

[0301] X is substituted or unsubstituted C2-C5 alkylene.

[0302] In certain embodiments, the compound of formula (IV) is

[0303]

Chemical formula

[0304] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0305] wherein,

[0306] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached,

[0307]

Chemical formula

[0308] Here,

[0309] X is substituted or unsubstituted C2-C5 alkylene.

[0310] In certain embodiments, the compound of formula (IV) is

[0311]

Chemical formula

[0312]

Chemical formula

[0313]

Chemical formula

[0314] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0315] wherein

[0316] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached

[0317]

Chemical formula

[0318] Here,

[0319] X is substituted or unsubstituted C2-C5 alkylene.

[0320] In another aspect, the aldose reductase inhibitor is a compound of formula (V)

[0321] [Chemical formula]

[0322] or a pharmaceutically acceptable salt, prodrug or solvate thereof;

[0323] wherein,

[0324] X 3 is N or CR 8 ;

[0325] X 4 is N or CR 9 ;

[0326] X 5 is N or CR 10 ;

[0327] X 6 is N or CR 11 ; provided that X 3 X 4 X 5 or X 6 two or three of which are N;

[0328] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached,

[0329] [Chemical formula] form

[0330] wherein,

[0331] X is a substituted or unsubstituted C2-C5 alkylene;

[0332] Z 3 is

Chemical formula

[0333] A 4 is NR 16 , O, S or CH2;

[0334] A 5 is N or CH;

[0335] A 6 is NR 16 , O or S;

[0336] R 8 ~R 15 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl or (C1-C4)-alkylsulfonyl; or two of R 8 ~R 11 or two of R 12 ~R 15 are together (C1-C4)-alkylenedioxy; and

[0337] R 16 is hydrogen, C1-C4 alkyl or C(O)O-(C1-C4)-alkyl.

[0338] Suitable substituents on C2-C5 alkylene include one or more alkyl, alkoxy, aryl, aryloxy, halo, haloalkyl, haloalkoxy, haloalkylthio. Preferred substituted C2-C5 alkylene is substituted ethylene. More preferred substituted C2-C5 alkylene is -C(CH3)2C(CH3)2-.

[0339] by those skilled in the art

[0340] Z is [Chemical formula] or Z is [Chemical formula] the designation that Z is [Chemical formula] in the case where Z is, the compound of formula (V) is understood to include [Chemical formula] and; in the case where Z is [Chemical formula] in the case where Z is, the compound of formula (V) is understood to include [Chemical formula] It will be recognized that this indicates that

[0341] In some compounds of formula (V), R 8 ~R 15 are independently hydrogen, halogen or haloalkyl, for example, R 8 ~R 15 are independently hydrogen, halogen or trihaloalkyl (for example, -CF3).

[0342] In other compounds of formula (V), R 8 ~R 11 is hydrogen.

[0343] In a specific embodiment of the compound of formula (V), R 12 ~R 15 are independently hydrogen, halogen or haloalkyl, for example, R 12 ~R 15is independently hydrogen, halogen or trihaloalkyl (e.g., -CF3).

[0344] In certain embodiments, R of formula (V) 12 and R 15 are hydrogen.

[0345] In certain embodiments, R of formula (V) 13 is hydrogen, halogen or haloalkyl. In certain embodiments, R 13 is hydrogen. In certain embodiments, R 13 is halogen. In certain embodiments, R 13 is haloalkyl.

[0346] In certain embodiments, R of formula (V) 14 is hydrogen, halogen or haloalkyl. In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is halogen. In certain embodiments, R 14 is haloalkyl.

[0347] 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.

[0348] In certain embodiments, A of formula (V) 4 is NR 16 , S or CH2. In certain embodiments, A 4 is NR 16 or O. In certain embodiments, A 4 is NR 16 or S. In certain embodiments, A 4 is NR 16 . In certain embodiments, A 4 is O. In certain embodiments, A 4is S.

[0349] In certain embodiments, A of formula (V) 5 is N or CH. In certain embodiments, A 4 is N. In certain embodiments, A 4 is CH.

[0350] In certain embodiments, A of formula (V) 6 is O or S. In certain embodiments, A 6 is O. In certain embodiments, A 6 is S.

[0351] In certain embodiments, X of formula (V) 3 and X 6 are nitrogen.

[0352] In certain embodiments, X of formula (V) 3 and X 4 are nitrogen.

[0353] In certain embodiments, X of formula (V) 3 and X 5 are nitrogen.

[0354] In certain embodiments, X of formula (V) 4 and X 5 are nitrogen.

[0355] In certain embodiments, X of formula (V) 4 and X 6 are nitrogen.

[0356] In certain embodiments, X of formula (V) 5 and X 6 are nitrogen.

[0357] In certain embodiments, Z of formula (V) 3 is

Chemical formula

[0358] In certain embodiments, Z of formula (V) 3 is

Chemical formula

[0359] In some embodiments, the compound of formula (V) is

[0360]

Chemical formula

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

[0362] wherein

[0363] R 14 is hydrogen, halogen or trihaloalkyl (e.g., -CF3); and

[0364] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached

[0365]

Chemical formula

[0366] where

[0367] X is substituted or unsubstituted C2-C5 alkylene.

[0368] In an embodiment, the compound of formula (V) is

[0369]

Chemical formula

[0370] [Chemical formula]

[0371] [Chemical formula]

[0372] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0373] In one aspect, the aldose reductase inhibitor is a compound of formula (VI)

[0374] [Chemical formula]

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

[0376] wherein,

[0377] Z 1 and Z 2 are independently selected from the group consisting of hydroxy, alkoxy, aryloxy, or Z 1 and Z 2 together with the boron atom to which they are attached,

[0378]

[0379] [Chemical formula] form

[0380] wherein,

[0381] X is substituted or unsubstituted C2-C5 alkylene.

[0382] In one embodiment, the aldose reductase inhibitor of formula (VI) is

[0383]

Chemical formula

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

[0385] In one embodiment, the AH inhibitor of formula (VI) is

[0386]

Chemical formula

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

[0388] As used herein, the term "alkyl" refers to a monovalent aliphatic hydrocarbon radical having a straight-chain, branched-chain, monocyclic or polycyclic moiety or a combination thereof, which is optionally substituted at one or more carbons of the straight-chain, branched-chain, monocyclic or polycyclic moiety or a combination thereof with one or more substituents at each carbon, and 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, etc.

[0389] As used herein, the term "halogen" or "halo-" means chlorine (Cl), fluorine (F), iodine (I) or bromine (Br).

[0390] As used herein, the term "acyl" is used in a broad sense to designate a radical of the type RCO- (wherein R represents an organic radical which may be a substituted or unsubstituted, saturated or unsaturated alkyl, aralkyl, aryl, alicyclic or heterocyclic radical); or according to a different definition, the term "acyl" is used to broadly designate a monovalent radical remaining when the OH group of the carboxyl radical is removed from the molecule of a carboxylic acid.

[0391] The term "alkoxy" is used to designate a group of the formula -O-R (wherein R is an alkyl group which may optionally contain substituents such as halogen). Preferably, the term "alkoxy" is used to designate an alkoxy having an alkyl group of 1 to 6 carbon atoms. Most preferably, the term "alkoxy" is used to designate an alkoxy having an alkyl group of 1 to 3 carbon atoms, such as methoxy or ethoxy.

[0392] As used herein, the term "cycloalkyl group" is used to specifically identify a cycloalkyl group having 3 to 6 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0393] As used herein, the term "solvate" 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 acceptable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is termed a "hydrate".

[0394] "Prodrug" refers to a drug that is converted in vivo to the parent drug. Prodrugs are often useful because in some cases they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent drug is less or not at all bioavailable. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a compound may carry a protecting group that is cleaved by hydrolysis in a body fluid, such as blood stream, to release the active compound, or is oxidized or reduced in the body fluid to release the compound. The term "prodrug" can be applied to such functional groups, for example the acidic functional groups of the compounds of formula (I). A prodrug can consist of a structure in which the acidic group is protected, for example as an ester or an amide. Further 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 containing a biodegradable moiety, such as biodegradable amides, biodegradable esters, biodegradable carbamates, biodegradable carbonates, and analogs of biodegradable phosphates. Prodrugs are also described, for example, in The Practice of Medicinal Chemistry (Camille Wermuth, ed., 1999, Academic Press (which is incorporated herein by reference in its entirety)). In certain embodiments, the prodrug of a compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is conveniently formed by esterifying any of the carboxylic acid moieties present in the molecule. Prodrugs are typically prepared by well-known methods, such as those described in Burger’s Medicinal Chemistry and Drug Discovery 6 thIt can be prepared using those described by ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh (each of which is hereby incorporated by reference in its entirety)). The biodegradable moiety of the compound of formula I may (a) not interfere with the biological activity of the compound but confer upon the compound advantageous properties in vivo, such as uptake, duration of action or onset of action; or (b) be biologically inactive but be converted in vivo to a biologically active compound. Examples of biodegradable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl esters and choline esters. Examples of biodegradable amides include, but are not limited to, lower alkylamides, α-amino acid amides, alkoxyacylamides and alkylaminoalkylcarbonylamides . Examples of biodegradable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocycles and heterocyclic aromatic amines and polyetheramines.

[0395] The term "salt" includes salts derived from any suitable organic and inorganic counterions well-known in the art, by way of example, the hydrochloride or hydrobromide or alkali or acid salts of the aforementioned amino acids. This term is intended to include salts derived from inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid and other acids; and salts derived from inorganic or organic bases such as, for example, sodium, potassium, calcium, ammonium or tetrafluoroborate salts. Exemplary pharmaceutically acceptable salts can be found, for example, in Berge et al. (J. Pharm. Sci. 1977, 66(1), 1; as well as U.S. Patent No. 6,570,013 and U.S. Patent No. 4,939,140, which are hereby incorporated by reference in their entireties). Pharmaceutically acceptable salts are also intended to include half salts in which the compound:acid ratio is 2:1 respectively. Exemplary half salts are salts derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary half salts are salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred half salts include, but are not limited to, hemimaleate, hemifumarate and hemisuccinate.

[0396] The term "acid" contemplates all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are straight-chain or branched saturated or unsaturated C1-C 20 aliphatic carboxylic acids, or C6-C 12It is an aromatic carboxylic acid. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid and lactobionic acid. III. Composition

[0397] The compound can be administered in the form of a suitable composition such as a pharmaceutical composition. The pharmaceutical composition is pharmaceutically acceptable and typically contains an active compound and a carrier. The term "carrier" refers to a diluent, adjuvant, excipient or vehicle administered with the compound. Non-limiting examples of such pharmaceutical carriers include liquids of petroleum, animal, plant or synthetic origin such as water and oils such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carrier can also be physiological saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants and coloring agents can be used. Other examples of suitable pharmaceutical carriers are Remington’s Pharmaceutical Sciences(Alfonso Gen naro ed.,Krieger Publishing Company(1997);Remington’s:The Science and Practice of Pharmacy,21 stEd. (Lippincot, Williams & Wilkins (2005); Modern Pharmaceutics, vol. 121 (Gilbert Banker and Christopher Rhodes, CRC Press (2002) (each of which is incorporated herein by reference in its entirety)).

[0398] The composition can be in a desired form that is physiologically and / or pharmaceutically acceptable, such as a tablet, capsule, solution, emulsion, suspension, gel, sol or colloid. Optionally, the carrier can include, for example, buffer solutions such as alkaline buffer solutions such as ammonium buffer solutions, acidic buffer solutions such as ethanate, citrate, lactate, acetate, etc., or zwitterionic buffer solutions such as glycine, alanine, valine, leucine, isoleucine and phenylalanine, Krebs-Ringer buffer solution, TRIS, MES, ADA, ACES, PIPES, MOPSO, cholamine chloride, MOPS, BES, TES, HEPES, DIPSO, MOBS, TAPSO, acetamidoglycine, TEA, POPSO, HEPPSO, EPS, HEPPS, tricine, TRIZMA, glycine amide, glycyl-glycine, HE PBS, bicine, TAPS, AMPB, CHES, AMP, AMPSO, CAPSO, CAPS and CABS.

[0399] 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 (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids (such as triglycerides, vegetable oils, liposomes) and combinations thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin; by maintaining the required particle size by dispersion in a carrier such as a liquid polyol or lipid; by the use of surfactants such as hydroxypropylcellulose; or by a combination of such methods. Optionally, tonicity modifiers such as sugars, sodium chloride or combinations thereof can be included. In some embodiments, the composition is isotonic.

[0400] The composition may also contain additional components, such as acceptable surfactants, co-solvents, emollients, agents for adjusting pH and osmotic pressure, and / or antioxidants that retard the oxidation of one or more components.

[0401] The composition can be prepared for administration by any suitable route, such as ocular (including periocular and intravitreal administration), oral, parenteral, intranasal, rectal, vaginal, topical, subcutaneous, intravenous, intraarterial, subarachnoid, and intraperitoneal administration. Thus, subarachnoid administration is optional and can be selected by the clinician (for example, when an aldose reductase inhibitor is not a central nervous system penetrant), but it is generally preferred not to administer an aldose reductase inhibitor subarachnoidally. Oral compositions can be directly incorporated into foodstuffs for consumption. Preferred carriers for oral administration include inert diluents, edible carriers, or combinations thereof. Examples of pharmaceutically acceptable carriers can include, for example, water or physiological saline, polymers such as polyethylene glycol, carbohydrates and their derivatives, oils, fatty acids or alcohols. For example, surfactants such as detergents are also suitable for use in the formulation. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives such as methacrylate, anionic surfactants such as alkaline stearates, especially sodium stearate, stearic acid Potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; 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 radicals are the same or different hydrocarbon radicals which may be hydroxylated as required, and Y’’ is an anion of a strong acid, such as a halide, sulfate and sulfonate anion); cetyltrimethylammonium bromide, which is one of the cationic surfactants that can be used, amine salts of NR’R’R” (wherein the R radicals are the same or different hydrocarbon radicals which may be hydroxylated as required); octadecylamine hydrochloride, which is one of the cationic surfactants that can be used, nonionic surfactants, such as polyoxyethylenated esters of sorbitan, especially polysorbate 80 or polyoxyethyleneated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethyleneated fatty alcohols, polyoxyethyleneated fatty acids or copolymers of ethylene oxide and propylene oxide, zwitterionic surfactants, such as substituted lauryl compounds of betaine, may be mentioned.

[0402] Optionally, the oral composition may include one or more binders, excipients, disintegrants, lubricants, flavoring agents, and combinations thereof. In certain embodiments, the composition comprises the following: binders such as tragacanth, acacia, corn starch, gelatin, or combinations thereof; excipients such as dicalcium phosphate, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, or combinations thereof; disintegrants such as corn starch, potato starch, alginic acid, or combinations thereof; lubricants such as magnesium stearate; sweetening agents such as sucrose, lactose, saccharin, or combinations thereof; flavoring agents such as peppermint, wintergreen oil, cherry flavor, orange flavor, or one or more combinations thereof containing two or more of the above may be included.

[0403] Additional formulations suitable for other modes of administration include suppositories. Also, sterile injection solutions can be prepared using suitable solvents. Generally, dispersions are prepared by incorporating various sterile amino acid components into a sterile vehicle containing a basic dispersion medium and / or other components. Suitable formulation methods for any desired mode of administration are well known in the art (generally, see Remington’s Pharmaceutical Sciences, 18 th Ed. Mack Printing Company, 1990).

[0404] Typical pharmaceutically acceptable compositions may contain the AR inhibitor and / or a pharmaceutically acceptable salt thereof at a concentration in the 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 can be formulated as a solution, suspension, ointment, or capsule, etc. The pharmaceutical composition can be prepared as an aqueous solution and may contain additional components such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity modifiers, etc. Other equivalent modes of administration can be found in U.S. Patent No. 4,939,140.

[0405] When administered to a subject, the AR inhibitor and the pharmaceutically acceptable carrier can be sterile. Suitable pharmaceutical carriers can also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene, glycol, propylene glycol 300, water, ethanol, polysorbate 20, etc. The composition can optionally contain a small amount of wetting agent or emulsifier or a pH buffering agent.

[0406] The pharmaceutical formulations of the present disclosure are prepared by methods well known in pharmacy. If necessary, one or more auxiliary components (e.g., buffer, flavoring agent, surfactant, 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.

[0407] In some embodiments, the composition is a unit dosage form, such as a tablet, capsule, or single-dose vial. The appropriate unit dose, i.e., the therapeutically effective amount, can be determined during clinical trials appropriately designed for each condition in which administration of the selected compound is indicated and will, of course, vary depending on the desired clinical endpoint.

[0408] Any of the compounds and / or compositions of the present disclosure can be provided in a kit containing the compound and / or composition. Thus, in one embodiment, the compounds and / or compositions of the present disclosure are provided in a kit containing, in the same package or separate packages, the carrier and, optionally, instructions for using the kit for therapeutic or prophylactic use. IV. COMBINATION THERAPY

[0409] The methods described herein include the administration of an AR inhibitor and one or more additional therapeutic agents. The additional therapeutic agents can be administered before, simultaneously with, or after the AR inhibitor, but can be administered in a manner that provides an overlap in the pharmacological activity of the AR inhibitor and the additional therapeutic agents. The additional therapeutic agents can be, for example, a second aldose reductase inhibitor, an antioxidant, or both.

[0410] For example, the second aldose reductase can be a compound described in, for example, U.S. Patent No. 5,677,342; U.S. Patent No. 5,155,259; U.S. Patent No. 4,939,140; U.S. Patent Application Publication No. 2006 / 0293265; and Roy et al. (Diabetes Research and Clinical Practice, 10, Issue 1, 91-97, 1990; and references cited therein, which are each incorporated herein by reference in their entirety). Aldose reductase inhibitors include, for example, zopolrestat, epalrestat, ranirestat, berberine, and sorbinil as described in U.S. Patent No. 4,939,140; U.S. Patent No. 6,159,976; and U.S. Patent No. 6,570,013. Preferably, the second aldose reductase inhibitor is selected from ponalrestat, epalrestat, sorbinil or sorbinol, imirestat, AND-138, CT-112, zopolrestat, zenarestat, BAL-AR18, AD-5467, M-79175, tolrestat, alconil, statil, berberine, or SPR-210.

[0411] Other therapeutic agents that can be administered include, for example, corticosteroids such as prednisone, methylprednisolone, dexamethasone or triamcinolone acetonide, or non-corticosteroid anti-inflammatory compounds such as ibuprofen or flurbiprofen. Similarly, vitamins and minerals such as zinc and micronutrients can be co-administered. In addition, inhibitors of the protein tyrosine kinase pathway, including natural protein tyrosine kinase inhibitors such as quercetin, lavendustin A, herbimycin A and herbimycin 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 dimeth Xylylidenemalononitrile, analogs of lavendustin A (e.g., AG814 and AG957), quinazolines (e.g., AG1478), 4,5-dianilinophthalimide, and thiazolidinedione 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 described in U.S. Patent No. 5,637,703 to Mazurek et al. Selenoindoles (2-thioindoles) and related disulfide selenides, such as those described in U.S. Patent No. 5,464,961 to Dobrusin et al., are useful protein tyrosine kinase inhibitors. Neutralizing proteins against growth factors, such as monoclonal antibodies specific for a given growth factor, e.g., VEGF (see, e.g., Aiello et al., PNAS USA 92:10457-10461 (1995)) or phosphotyrosine (Dhar et al., Mol. Pharmacol. 37:519-525 (1990)), can be co-administered.Other various compounds that can be co-administered include inhibitors of protein kinase C (see, e.g., U.S. Patent Nos. 5,719,175 and 5,710,145), cytokine modulators, growth endothelial cell-specific inhibitors such as thrombospondin, endothelial cell-specific inhibitory growth factors such as TNFα, antiproliferative peptides such as SPARC and profelin-like peptides, glutamate receptor antagonists, aminoguanidine, angiotensin-converting enzyme inhibitors such as angiotensin II, calcium channel blockers, y-tectorigenin, ST638, somatostatin analogs such as SMS 201-995, monosialoganglioside GM1, ticlopidine, neurotrophic growth factors, methyl-2,5-dihydroxycinnamate, angiogenesis inhibitors such as recombinant EPO, sulfonylurea oral hypoglycemic agents such as glibladine (non-insulin-dependent diabetes), ST638 (Asahi et al., FEBS Letter 309:10-14 (1992)), thalidomide, nifedipine hydrochloride, aspirin, piceatannol, staurosporine, adriamycin, epidermatatin, (+)-aeroplysinin-1, phenazocine, halomethyl ketone, antilipemic agents such as etofibrate, chlorpromazine, sphingosine and retinoic acid and their analogs (Burke et al., Drugs of the Future 17(2):119-131 (1992); and Tomlinson et al., Pharmac. Ther. 54:151-194 (1992)).

[0412] The present disclosure further provides for the use of a compound of formula (I)-(VI) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof in a method of treating a disease state and / or symptom caused by or associated with PMM2-CDG. In another embodiment, the present disclosure is a method of treating a disease state and / or symptom caused by or associated with PMM2-CDG, comprising: (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, suppress and / or prevent a disease state or symptom in a subject in need of such treatment. 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 as described above.

[0413] In another embodiment, the present disclosure is a method of treating a disease state and / or symptom caused by or associated with PMM2-CDG, comprising: (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, suppress and / or prevent a disease state or symptom in a subject in need of such treatment. 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 as described above.

[0414] In the foregoing embodiments, the compound or composition is preferably used orally.

Examples

[0415] V. Example - In Vitro Activation of PMM2 by Compound B The in vitro activation of PMM2 by compound B was studied in fibroblasts derived from PMM2-CDG patients. Compound B is a potent and selective inhibitor of aldose reductase. The AR inhibitory activity of compound B was determined 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 presented as the percentage of inhibition of maximal activity are summarized in Figure 1. Compared with epalrestat, which has a reported mean AR inhibitory concentration [IC 50 , compound B (IC 50 = 0.10 nM) was noted to be a significantly more potent inhibitor of aldose reductase enzyme activity.

[0416] Since compound B, a CNS-penetrant aldose reductase inhibitor, has a detrimental effect on the central nervous system of PMM2-CDG patients, it was tested in a cell line of fibroblasts derived from four unique individuals with PMM2-CDG to determine whether PMM2 enzyme activation could be detected.

[0417] 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 antipain) was added, and the plates were subjected to two cycles of freezing-thawing at -80 °C to lyse the cells. Subsequently, reaction buffer containing 200 μM mannose-1-phosphate as a substrate (50 mM HEPES, 5 mM MgCl2, 0.5 mM NADP+, 10 μg / ml yeast glucose-6-phosphate dehydrogenase, 10 μM glucose-1,6-diphosphate, 10 μg / ml phosphoglucoisomerase, 5.25 μg / ml phosphomannoseisomerase) was added to the wells of each plate. The plates were incubated at 37 °C for 270 minutes, and the absorbance was read at 340 nm at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, and 270 minutes by removing the plates from the incubation at each time point. All incubations were performed with or without the substrate (mannose-1-phosphate), and the difference between these two values was calculated as the enzyme activity. The enzyme activity was normalized to the total soluble protein level. The enzyme activity of fibroblasts in the absence of an AR inhibitor was determined. To evaluate the effect of compound B on the enzyme activity, compound B was incubated with the cell line at a concentration of 50 nM for 24 hours. Thereafter, the enzyme activity was evaluated as described above. At least two biological replicate experiments were performed, and the enzyme activity in the presence of compound B was compared with the enzyme activity of the DMSO-treated mutant cell line used as a control. To facilitate the analysis, the enzyme activity (represented by the NADPH concentration) of each treatment condition was compared with the activity at the last time point of the baseline untreated mutant cell line.

[0418] The results of these studies are shown in Figure 2. The heterozygous amino acid substitutions of each individual patient are shown below each bar in the graph of Figure 2. Compound B increased PMM2 enzyme activity in each of the cell lines from the four patients tested. Compound B was shown to be a potent activator of PMM2 activation in fibroblasts from PMM2-CDG patients.

[0419] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0420] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described in the foregoing paragraphs. In addition, the materials and methods are illustrative only and not intended to be limiting. All U.S. patents and published or unpublished U.S. patent applications cited herein are hereby incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference into this specification. All published references, documents, manuscripts, and scientific literature cited herein are hereby incorporated by reference into this specification. All identifiers and accession numbers for scientific databases (e.g., PUBMED, NCBI, GENBANK, EBI) referenced herein are hereby incorporated by reference into this specification. In one embodiment, for example, the following items are provided. (Item 1) A method of treating PMM2-CDG, comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor. (Item 2) A method of increasing PMM2 enzyme activity in a subject having PMM2-CDG, comprising administering to the subject a therapeutically effective amount of an aldose reductase inhibitor. (Item 3) The method according to any one of Items 1 to 2, wherein the aldose reductase inhibitor is a compound of formula (III) or a salt thereof. (Item 4) The aldose reductase inhibitor is as follows

Chemical formula

Chemical formula

Claims

【Claim 1】 The invention described in the specification.

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