Search

KR-102962157-B1 - Compounds and methods for the treatment of oxalate-related diseases

KR102962157B1KR 102962157 B1KR102962157 B1KR 102962157B1KR-102962157-B1

Abstract

The present specification discloses compounds and compositions for modulating glycolate oxidase that are useful for the treatment of oxalate-related diseases, e.g., hyperoxaluria, and modulation of glycolate oxidase is expected to be a therapeutic agent for patients requiring it. A method for modulating glycolate oxidase activity in human or animal subjects is also provided.

Inventors

  • 카바키비 아이만
  • 카라만 메멧
  • 클레어 마이클
  • 리돔 토마스

Assignees

  • 옥살럭스 인코포레이티드

Dates

Publication Date
20260508
Application Date
20200822
Priority Date
20190822

Claims (20)

  1. A compound having the structure of the following chemical formula III, or a salt or tautomer thereof: [During the meal, R1 is selected from hydrogen, C1 - C6 alkyl, and C1 - C6 cycloalkyl; L is selected from O, S, CH₂ , NH, NR₄ , S(O), SO₂ , and CR₄ = CR₅ ; Each R2 is independently selected from 5-10-membered heteroaryl, C1 - C6 alkoxy, C1 - C6 alkyl, C1 - C6 alkylsulfonyl, C1- C6 alkylthio, C1 - C6 haloalkoxy, C1 - C6 haloalkyl, C6 -C10 aryl , cyano, and halogen; n is 0, 1, or 2, and; R3 is selected from 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C1 - C6 alkyl, C1 - C6 sulfonyl, C3 - C6 cycloalkyl, C3 - C6 cycloalkylalkyl, C6 - C10 aryl, and C6 - C10 arylalkyl; R4 and R5 are each independently selected from hydrogen and C1 - C6 alkyl, or R4 and R5 form a cycloalkenyl together with the atoms to which they are attached; Each R6 is independently selected from 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl, amino, C1 - C6 alkoxy, C1 - C6 alkyl, C1 - C6 alkylsulfonyl, C1-C6 haloalkyl, C3 - C6 cycloalkyl, C3 -C6 cycloalkylalkyl , carboxyl, cyano, halogen, hydroxyl, methyl-4-6-membered heterocycloalkyl, and phenyl; m is 0, 1, 2, or 3].
  2. In claim 1, R3 is a compound or a salt thereof, wherein R3 is selected from methyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranil, cyclohexyl, tetrahydropyranil, piperidinyl, dihydropyranil, indazolyl, benzodioxolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, benzoxazolyl, oxodihydropyridinyl, thiazolyl, tetrazolyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, dioxaspirodecanil, oxocyclohexyl, and bicyclo[1.1.1]pentyl, any one of which is optionally substituted with one, two, or three R6 groups. Tautomer.
  3. A compound, or a salt or tautomer thereof, wherein R3 is selected from C1 - C6 alkyl, C3 - C6 cycloalkyl, and C3 - C6 cycloalkylalkyl, any one of which is optionally substituted with one, two, or three R6 groups.
  4. In claim 1, R3 is a compound selected from propyl and cyclopropylmethyl, or a salt or tautomer thereof.
  5. In claim 1, R6 is a compound selected from methyl, hydroxyl, amino, dimethylamino, propyl, cyclopropylmethyl, indazolyl, benzodioxolyl, cyclopropyl, tetrahydrofuranyl, cyclohexyl, tetrahydropyranyl, piperidinyl, methylpiperidinyl, phenyl, fluoro, chloro, methylsulfonyl, cyano, trifluoromethyl, methoxy, carboxyl, and fluoromethyl, or a salt or tautomer thereof.
  6. In paragraph 5, R6 is a compound selected from chloro, methyl, cyano, fluoro, methylsulfonyl, methoxy, carboxyl, and trifluoromethyl, or a salt or tautomer thereof.
  7. In paragraph 1, m is a compound of 0, or a salt or tautomer thereof.
  8. In claim 1, a compound having the structure of the following chemical formula V, or a salt or tautomer thereof: [During the meal, R1 is selected from hydrogen, C1 - C6 alkyl, and C1 - C6 cycloalkyl; L is selected from O and S; Each R2 is independently selected from 5-10-membered heteroaryl, C1 - C6 alkoxy, C1 - C6 alkyl, C1 - C6 alkylsulfonyl, C1- C6 alkylthio, C1 - C6 haloalkoxy, C1 - C6 haloalkyl, C6 -C10 aryl , cyano, and halogen; n is 0, 1, or 2, and; R3 is selected from C2 - C6 alkyl, C3 - C6 cycloalkyl, and C3 - C6 cycloalkylalkyl; Each R6 is a C1 - C6 alkoxy, C1 - C6 alkyl, C1 - C6 haloalkyl, C3 - C6 cycloalkyl, cyano, halogen, and hydroxyl; m is 0, 1, 2, or 3].
  9. In paragraph 8, R1 is a compound in which hydrogen is present, or a salt or tautomer thereof.
  10. In paragraph 8, a compound in which n is 0, or a salt or tautomer thereof.
  11. In paragraph 8 , n is 0 or 1; a compound, or a salt or tautomer thereof, which is a halogen if present.
  12. In claim 8, R3 is a compound selected from C2 - C6 alkyl, C3 - C6 cycloalkyl, and C3 - C6 cycloalkylmethyl, or a salt or tautomer thereof.
  13. In claim 8, R3 is a compound selected from ethyl, propyl, isopropyl, isobutyl, sec -butyl, tert -butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and bicyclo[1.1.1]pentylmethyl, or a salt or tautomer thereof.
  14. In paragraph 8, R3 is a compound selected from ethyl, propyl, isopropyl, isobutyl, sec -butyl, tert -butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, or a salt or tautomer thereof.
  15. In paragraph 8, R3 is a compound selected from isobutyl and cyclopropylmethyl, or a salt or tautomer thereof.
  16. In claim 1, a compound having the structure of the following chemical formula VI, or a salt or tautomer thereof: [During the meal, R1 is selected from hydrogen, C1 - C6 alkyl, and C1 - C6 cycloalkyl; L is selected from O, S, CH2 , and NH; R3 is selected from C2 - C6 alkyl, C3 - C6 cycloalkyl, and C3 - C6 cycloalkylalkyl.
  17. In claim 1, R1 is a compound selected from methyl, ethyl, isopropyl, t-butyl, and hydrogen, or a salt or tautomer thereof.
  18. In paragraph 17, R1 is a compound in which hydrogen is present, or a salt or tautomer thereof.
  19. In paragraph 16, L is a compound that is O or S, or a salt or tautomer thereof.
  20. In paragraph 16, R3 is a compound selected from isobutyl and cyclopropylmethyl, or a salt or tautomer thereof.

Description

Compounds and methods for the treatment of oxalate-related diseases This application claims the benefit of priority of U.S. Provisional Application No. 62/890,378 filed on August 22, 2019, the disclosure of which is incorporated by reference in its entirety for all purposes. The present disclosure relates to novel compounds and compositions and their use as pharmaceutical agents for treating diseases. A method for treating oxalate-related diseases, including hyperoxaluria and related pathological conditions in human or animal subjects, is also provided. Oxalate-related diseases are characterized by abnormal regulation of glyoxylate metabolism or oxalate accumulation in subjects. Hyperoxaluria is an oxalate-related disease characterized by elevated urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical manifestations of hyperoxaluria. Primary hyperoxaluria is a genetic metabolic error resulting from mutations in at least one of several different liver enzymes involved in the metabolism of glyoxylate and hydroxyproline (HYP). Oxalate is generated endogenously via a pathway in which human glycolate oxidase (GO or hGOX) oxidizes glycolate to glyoxylate. Glyoxylate is then subsequently converted to oxalate by lactate dehydrogenase (LDH). Mutations in the liver enzymes involved in these related metabolic pathways lead to excessive oxalate formation and excretion through the kidneys. In contrast, secondary hyperoxaluria is caused by increased dietary intake or absorption of oxalates or their precursors, or by changes in the gut microbiome. Dietary oxalates originate from spinach, bran, rhubarb, beets, potatoes, nuts, peanut butter, and other foods. Since urinary oxalate levels are elevated in hyperoxaluria, insoluble crystals of calcium oxalate begin to form in the urinary tract and deposit in the tubules, leading to a decline in kidney function. The disease spectrum of hyperoxaluria extends from recurrent kidney stones (nephrolithiasis), nephrocalcinosis, and urinary tract infections to chronic kidney disease and, ultimately, end-stage renal disease. When the calcium oxalate burden exceeds renal excretory capacity, calcium oxalate is also deposited in various organ systems through systemic oxalicosis. Elevated urinary oxalate levels help establish an initial diagnosis of hyperoxaluria, whereas elevated plasma oxalate levels appear to be a better indicator of when a patient has developed chronic kidney disease. The definitive diagnosis of primary hyperoxaluria is best achieved through genetic analysis; if genetic studies prove inconclusive, a liver biopsy is performed to confirm the diagnosis. Diagnostic clues indicating secondary hyperoxaluria include a supplementary dietary history and tests detecting increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes active hydration and the administration of crystallization inhibitors to reduce calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% of patients with type 1 primary hyperoxaluria. The onset of the disease can occur at any time from infancy to adulthood and is typically fatal upon early onset in the absence of an organ transplant. Hepatorenal and isolated kidney transplants are treatment options for type 1 and type 2 primary hyperoxaluria, respectively. Data on the role of transplantation in type 3 primary hyperoxaluria are scarce. Currently, there are no widely effective treatment options for primary hyperoxaluria. More better options are needed, for example, compounds that inhibit glycolate oxidase to reduce the concentration of glyoxylates available for conversion to oxalate. Initial treatment to inhibit GO (often called "substrate depletion therapy") reduces urinary oxalate concentrations before organ function is impaired. Accordingly, the present specification discloses a new composition and method for targeting glycolate oxidase inhibition and treating hyperoxaluria. Figure 1 shows urinary oxalates as a percentage of the vehicle-treatment control over time as a number of days for compound 1 administered at 10 and 30 mg/kg in a primary hyperoxaluria 1 (PH-1) alanine-glyoxylate aminotransferase knockout ( Agxt-/- ) mouse model. Figure 2 shows urine glycolate (µg/mL) over time as a number of days for Compound 1 administered to Agxt-/- mice at 10 and 30 mg/kg twice daily. Figure 3 shows the mean plasma 24-hour AUC (multiples) for compounds 1, 302, 343, and 356 at a dose of 10 mg/kg in CD-1 mice. Figure 4 shows plasma glycolate concentrations (µg/mL) for the vehicle and compound 302 on study days -1, 2, and 4. Male C57B1/6 mice were orally administered 30 mg/kg of compound 302 twice daily from day 1 to day 4. Figure 5 shows urinary oxalate (μM) over time as a number of days for Compound 302 orally administered to Agxt-/- mice at 3, 10, and 30 mg/kg twice daily on study days 0 to 4. Figure 6 shows urine glycolate (µg/mL) over time as a