Granted Patent
B2
US 12,653,825 · App. 18/344,262 · Granted Jun 16, 2026
Aldose reductase inhibitors and uses thereof
Inventors:
Andrew Wasmuth (Brooklyn, NY); Donald W. Landry (New York, NY); Shixian Deng (White Plains, NY); Banavara L. Mylari (East Lyme, CT); Ravichandran Ramasamy (Ardsley, NY); Ann Marie Schmidt (Franklin Lakes, NJ)
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Abstract
The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, and the treatment of various other disorders, such as complications arising from diabetes with the compounds and compositions of the invention. Other disorders can include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, infections of the skin, peripheral vascular disease, stroke, and the like.
Claims (37)
1 . A method for inhibiting aldose reductase activity in a subject, comprising orally administering to a subject a dose of about 10 mg/kg to about 75 mg/kg body weight of a compound of formula (I):
wherein,
R 1 is H or (C 1 -C 6 )-alkyl;
X 1 is N;
X 2 is CH;
X 3 is CH;
X 4 is N;
Y is a C═O, C═S, C═NH, or C═N(C 1 -C 4 )-alkyl;
Z is
A 1 is S;
A 2 is N; and
R 7 through 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 two of R 7 through R 10 taken together are (C 1 -C 4 )-alkylenedioxy; or a pharmaceutically acceptable salt or solvate thereof.
2 . The method of claim 1 , wherein Y is C═O; and R 7 through 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.
3 . The method of claim 2 , wherein R 7 through R 10 are independently hydrogen, halogen, or haloalkyl.
4 . The method of claim 2 , wherein R 7 , R 8 , and R 10 are hydrogen; and R 9 is hydrogen, halogen, or haloalkyl.
5 . The method of claim 1 , wherein R 1 is H.
6 . The method of claim 1 , wherein the compound of formula (I) is
or a pharmaceutically acceptable salt thereof, wherein R 1 is H or (C 1 -C 6 )-alkyl.
7 . The method of claim 6 , wherein R 1 is H.
8 . The method of claim 1 , wherein the compound of formula (I) is
or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is H or (C 1 -C 6 )-alkyl.
9 . The method of claim 8 , wherein R 1 is H.
10 . The method of claim 1 , comprising orally administering to the subject the compound of formula (I), twice daily.
11 . The method of claim 1 , comprising orally administering to the subject the compound of formula (I) at a dose of about 20 mg/kg to about 75 mg/kg body weight per day.
12 . The method of claim 1 , comprising orally administering to the subject the compound of formula (I) at a dose of about 25 mg/kg body weight, twice daily.
13 . The method of claim 6 , comprising orally administering to the subject the compound of formula (I), twice daily.
14 . The method of claim 6 , comprising orally administering to the subject the compound of formula (I) at a dose of about 20 mg/kg to about 75 mg/kg body weight per day.
15 . The method of claim 6 , comprising orally administering to the subject the compound of formula (I) at a dose of about 25 mg/kg body weight, twice daily.
16 . The method of claim 1 , wherein the subject has diabetes.
17 . The method of claim 1 , wherein the subject has a complication arising from diabetes.
18 . The method of claim 1 , wherein the subject has a cardiovascular disorder.
19 . The method of claim 6 , wherein the subject has diabetes.
20 . The method of claim 6 , wherein the subject has a complication arising from diabetes.
21 . The method of claim 6 , wherein the subject has a cardiovascular disorder.
22 . The method of claim 15 , wherein the subject has diabetes.
23 . The method of claim 15 , wherein the subject has a complication arising from diabetes.
24 . The method of claim 15 , wherein the subject has a cardiovascular disorder.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 20, 2023
From: WASMUTH, ANDREW; LANDRY, DONALD W, MD; DENG, SHIXIAN; RAMASAMY, RAVICHANDRAN; SCHMIDT, ANN MARIE; MYLARI, BANAVARA L
To: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
Reel/Frame 064965/0590 →
Continuity (8)
Continuation In Part
PCTUS2011044038
· Jul 14, 2011
Provisional Application
61365098
· Jul 16, 2010
References Cited (136)
US 4868301A
· Mylari et al.
· 1989
[cited by applicant]
US 4939140A
· Larson et al.
· 1990
[cited by applicant]
US 4954629A
· Mylari et al.
· 1990
[cited by applicant]
US 4996204A
· Mylari et al.
· 1991
[cited by applicant]
US 5155259A
· Suzuki et al.
· 1992
[cited by applicant]
US 5304557A
· Mylari
· 1994
[cited by applicant]
US 5677342A
· Malamas et al.
· 1997
[cited by applicant]
US 5728704A
· Mylari et al.
· 1998
[cited by applicant]
US 6159976A
· Lambert et al.
· 2000
[cited by applicant]
US 6570013B2
· Mylari
· 2003
[cited by applicant]
US 6579879B2
· Mylari
· 2003
[cited by applicant]
US 6849629B2
· Mylari
· 2005
[cited by applicant]
US 7572910B2
· Mylari
· 2009
[cited by applicant]
US 8916563B2
· Wasmuth et al.
· 2014
[cited by applicant]
US 9650383B2
· Wasmuth et al.
· 2017
[cited by applicant]
US 20060293265A1
· Srivastava et al.
· 2006
[cited by applicant]
US 20060293371A1
· Kamiyama
· 2006
[cited by applicant]
US 20090305963A1
· Sukhatme et al.
· 2009
[cited by applicant]
US 20170216291A1
· Wasmuth et al.
· 2017
[cited by applicant]
US 20170216292A1
· Wasmuth et al.
· 2017
[cited by applicant]
AU 2021203801B2
· 2023
[cited by applicant]
CN 1047499
· 1990
[cited by applicant]
CN 101143868A
· 2008
[cited by applicant]
CN 102512407A
· 2012
[cited by applicant]
EP 0189272A2
· 1986
[cited by applicant]
EP 0222576A2
· 1987
[cited by applicant]
EP 0397350A1
· 1990
[cited by applicant]
EP 0401981A1
· 1990
[cited by applicant]
EP 3757107
· 2020
[cited by applicant]
EP 3597650B1
· 2022
[cited by applicant]
EP 4124620
· 2023
[cited by applicant]
FR 2647676A1
· 1990
[cited by applicant]
JP S62114988A
· 1987
[cited by applicant]
JP H01216975A
· 1989
[cited by applicant]
JP H03005479
· 1991
[cited by applicant]
JP H03005481
· 1991
[cited by applicant]
JP H03258766A
· 1991
[cited by applicant]
JP 2003155274A
· 2003
[cited by applicant]
JP 5934206B2
· 2016
[cited by applicant]
WO WO8906651A1
· 1989
[cited by applicant]
WO WO9109019A1
· 1991
[cited by applicant]
WO WO9915529A1
· 1999
[cited by applicant]
WO WO02079198A1
· 2002
[cited by applicant]
WO WO03061660A1
· 2003
[cited by applicant]
WO WO2006078717A2
· 2006
[cited by applicant]
WO WO2008002678A2
· 2008
[cited by applicant]
WO WO2012009553A1
· 2012
[cited by applicant]
WO WO2014113380
· 2014
[cited by applicant]
WO WO2017223179
· 2017
[cited by applicant]
Alexander et al., “(Acyloxy)alkyl carbamates as novel bioreversible prodrugs for amines: increased permeation through biological membranes,” J. Med. Chem., 31, pp. 318-322 (1988).
[cited by applicant]
Antonetti D.A. et al., “Vascular Permeability in Experimental Diabetes Is Associated With Reduced Endothelial Occludin Content: Vascular Endothelial Growth Factor Decreases Occludin in Retinal Endothelial Cells,” Diabet…
[cited by applicant]
Ayres et al., “Synthesis of derivatives of cyclobuteno[c]thiophen and attempts to synthesise thiophen analogues of biphenylene,” Tetrahedron, 31, pp. 1755-1760 (1975).
[cited by applicant]
Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66(1), pp. 1-19 (1977).
[cited by applicant]
Beyer-Mears et al., “Glomerular Polyol Accumulation in Diabetes and its Prevention by Oral Sorbinil,” Diabetes, 33:6, pp. 604-607 (Jun. 1984).
[cited by applicant]
Caliceti et al., “New Insights from Pharmacological Aspects to Clinical Evidences in the Management of Metabolic Disorders,” Curr. Med. Chem. Abstract Only, 23:14, pp. 1460-1476 (2016).
[cited by applicant]
Cannon, “Chapter Nineteen: Analog Design,” Burger's Medicinal Chemistry and Drug Discovery: Fifth Edition, 1: Principles and Practice, Wiley-Interscience, pp. 783-802 (1995).
[cited by applicant]
Carbone, V. et al., “Structure of aldehyde reductase in ternary complex with a 5-arylidene-2,4-thiazolidinedione aldose reductase inhibitor”, European Journal of Medicinal Chemistry, 45(3):1140-1145, Mar. 31, 2010 avail…
[cited by applicant]
Chatzopoulou et al., “Novel aldose reductase inhibitors: a patent survey (2006—present),” Expert Opin. Ther. Pat., 22, pp. 1303-1323 (2012).
[cited by applicant]
Cheng and González, “The effect of high glucose and oxidative stress on lens metabolism, aldose reductase, and senile cataractogenesis,” Metabolism, 35(4), Suppl. 1, pp. 10-14 (Apr. 1986) Abstract Only, 1 page.
[cited by applicant]
Cheng et al., “The effect of high glucose and oxidative stress on lens metabolism, aldose reductase, and senile cataractogenesis,” Metabolism, Abstract Only, 35:4(Suppl. 1), pp. 10-14 (Apr. 1986).
[cited by applicant]
Cheung et al., “Aldose Reductase Deficiency Prevents Diabetes-Induced Blood-Retinal Barrier Breakdown, Apoptosis, and Glial Reactivation in the Retina of db/db Mice,” Diabetes, 54(11), pp. 3119-3125 (Nov. 2005).
[cited by applicant]
ClinicalTrials.gov, “Ezetimibe Versus Nutraceuticals in Statin-intolerant Patients (ECLIPSE),” ClinicalTrials.Gov Identifier No. NCT01490229, first received Dec. 8, 2011 (4 pages).
[cited by applicant]
ClinicalTrials.gov, “Low-dose Statins and Nutraceuticals in High-intensity Statin-intolerant Patients (ADHERENCE),” ClinicalTrials.Gov Identifier No. NCT02001883, first received Nov. 24, 2013 (4 pages).
[cited by applicant]
Digiacomao, “Synthesis and functional evaluation of novel aldose reductase inhibitors,” The Open Medicinal Chemistry Journal, 11, 2 pages (Apr. 14, 2017).
[cited by applicant]
English translation of Notice of Reasons for Rejection issued Nov. 7, 2016 for corresponding Japanese patent application No. 2016-005570 (9 pages).
[cited by applicant]
European Extended Search Report issued in European Patent Application No. EP22183971.5, dated Dec. 23, 2022 (15 pages).
[cited by applicant]
Extended European Search Report issued in EP19194956.9, dated Nov. 26, 2019 (13 pages).
[cited by applicant]
Zhou et al., “Neuroprotective effects of berberine on stroke models in vitro and in vivo,” Neurosci. Lett., Abstract Only, 447:1, pp. 31-36 (Dec. 5, 2008).
[cited by applicant]
Extended European Search Report issued in European Patent Application No. EP20188323.8, dated Sep. 28, 2020 (7 pages).
[cited by applicant]
Extended European Search Report issued Oct. 2, 2013 for European Patent Application No. 11807523.3 (6 pages).
[cited by applicant]
Gu et al., “Effects of lignans extracted from Eucommia ulmoides and aldose reductase inhibitor epalrestat on hypertensive vascular remodeling,” J. Ethnopharmacol., Abstract Only, 133(1), pp. 6-13 (Jan. 7, 2011).
[cited by applicant]
Hartsock, M.J. et al., “A Mouse Model of Retinal Ischemia-Reperfusion Injury Through Elevation of Intraocular Pressure,” Journal of Visualized Experiments, 113, e54065, 6 pages (Jul. 2016).
[cited by applicant]
Zhu, “Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications,” Diabetes Mellitus—Insights and Perspectives, Chapter 2, pp. 17-46 (Jan. 23, 2013).
[cited by applicant]
Hohman, T.C. et al., “Probing the inhibitor-binding site of aldose reductase with site-directed mutagenesis,” Eur. J. Biochem, 256, pp. 310-316 (1998).
[cited by applicant]
Hotta et al., “Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy,” Diabetes Care, 29(7), pp. 1538-1544 (Jul. 2006).
[cited by applicant]
Hotta et al., “Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestat,” Diabet. Med., 25(7), pp. 818-825 …
[cited by applicant]
Hotta, et al., “Short Report: Treatment—Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on progression of diabetic neuropathy and other microvascular complications: multivariate epidemiological …
[cited by applicant]
Hu et al., “Efficacy and safety of aldose reductase inhibitor for the treatment of diabetic cardiovascular autonomic neuropathy: systematic review and meta-analysis,” PLoS One, 9(2), e87096, pp. 1-11 (2014).
[cited by applicant]
Hwang et al., “Central role for aldose reductase pathway in myocardial ischemic injury,” The FASEB Journal, 18(11), pp. 1192-1199 (Aug. 2004).
[cited by applicant]
International Search Report and Written Opinion issued Apr. 16, 2014 for International Application No. PCT/US14/11465 (9 pages).
[cited by applicant]
International Search Report and Written Opinion issued by the U.S. Patent and Trademark Office as International Searching Authority for PCT Application No. PCT/US17/38505 issued Oct. 13, 2017 (11 pages).
[cited by applicant]
International Search Report and Written Opinion issued Dec. 6, 2011 for International Patent Application No. PCT/US11/44038 (8 pages).
[cited by applicant]
Jacoby and Nesto, “Acute Myocardial Infarction in the Diabetic Patient: Pathophysiology, Clinical course and Prognosis,” J. Am. Coll. Cardiol., 20(3), pp. 736-744 (1992).
[cited by applicant]
Zhu, “Diabetes Mellitus—Insights and Perspectives,” chapter 2, book edited by Oluwafemi 0. Oguntibeju, Published: Jan. 23, 2013 under CC By 3.0 license.
[cited by applicant]
Johnson et al., “Cardiac Abnormalities in Diabetic Patients With Neuropathy”, Diabetes Care, 27(2), pp. 448-454 (Feb. 2004).
[cited by applicant]
Kajiwara et al., “Lower incidence of myocardial infarction in type 2 diabetic patients with polyneuropathy who were treated with an aldose reductase inhibitor (epalrestat): a retrospective study,” Presentation Abstract,…
[cited by applicant]
Kalofoutis et al., “Type II diabetes mellitus and cardiovascular risk factors: Current therapeutic approaches,” Exp. Clin. Cardiol., 12(1), pp. 17-28 (2007).
[cited by applicant]
Kasajima et al., “Enhanced in situ expression of aldose reductase in peripheral nerve and renal glomeruli in diabetic patients,” Virchows Arch., Abstract Only, 439:1, pp. 46-54 ( Jul. 2001).
[cited by applicant]
Kinoshita, “A thirty year journey in the polyol pathway,” Exp. Eye. Res., 50(6), pp. 567-573 (1990).
[cited by applicant]
Li et al., “Polyol pathway and modulation of ischemia-reperfusion injury in Type 2 diabetic BBZ rat hearts,” Cardiovascular Diabetology, 7(33), 11 pages (Oct. 28, 2008).
[cited by applicant]
Lightman, “Does Aldose Reductase have a role in the development of the ocular complications of diabetes?” Eye, 7, pp. 238-241 (1993).
[cited by applicant]
Liu et al., “Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice,” Diabetologia, 54(5), pp. 1242-1251 (Jan. 27, 2011).
[cited by applicant]
Lorenzi, M., “The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient,” Experimental Diabetes Research, vol. 2007, Article ID 61038, 10 pages (2007).
[cited by applicant]
Marin-Neto et al., “Cardiovascular effects of berberine in patients with severe congestive heart failure,” Clin. Cardiol., Abstract Only, 11:4, pp. 253-260 (Apr. 1988).
[cited by applicant]
Mylari et al., “Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (zopolrestat) and congeners,” J. Med. Chem., 34, pp. 108-122 (1991).
[cited by applicant]
Mylari et al., “Orally Active Aldose Reductase Inhibitors: Indazoleacetic, Oxopyridazineacetic, and Oxopyridazineacetic Acid Derivatives,” J. Med. Chem., 35, pp. 2155-2162 (1992).
[cited by applicant]
Mylari et al., “Potent, Orally Active Aldose Reductase Inhibitors Related to Zopolrestat: Surrogates for Benzothiazole Side Chain,” J. Med. Chem., 35, pp. 457-465 (1992).
[cited by applicant]
Mylari, B.L. et al., “A Novel Series of Non-Carboxylic Acid, Non-Hydantoin Inhibitors of Aldose Reductase with Potent Oral Activity in Diabetic Rat Models: 6-(5-Chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one a…
[cited by applicant]
NCBI Reference Sequence NP_005555.2, “Neutrophil gelatinase-associated lipocalin precursor [
[cited by applicant]
Nour et al., “Ischemia-Reperfusion Injury in Stroke,” Intervent. Neurol., 1, pp. 185-199 (2012).
[cited by applicant]
Office Action issued May 25, 2015 for Japanese Patent Application No. 2013-520752 (7 pages).
[cited by applicant]
Office Action issued Nov. 25, 2014 for Chinese Patent Application No. 201180034944.5 (12 pages).
[cited by applicant]
Price et al., “Mitogen-Activated Protein Kinase p38 Mediates Reduced Nerve Conduction Velocity in Experimental Diabetic Neuropathy,” Diabetes, 53(7), pp. 1851-1856 (Jul. 2004).
[cited by applicant]
Pubchem, Substance Record for SID 227698804, Available Date: Feb. 12, 2015, Retrieved from the Internet: https://pubchem.ncbi.nlm.nih.gov/substance/227698804 (7 pages).
[cited by applicant]
Ramana, K.V. et al., “Inhibition of Aldose Reductase Prevents Growth Factor-Induced G
[cited by applicant]
Ramasamy and Goldberg, “Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model,” Circ. Res., 106(9), pp. 1449-1458 (May 2010).
[cited by applicant]
Ramasamy et al., “Aldose reductase inhibition protects diabetic and nondiabetic rat hearts from ischemic injury,” Diabetes, Abstract Only, 46:2, pp. 292-300 (Feb. 1997).
[cited by applicant]
Roy et al., “The effect of an aldose reductase inhibitor on cardiovascular performance in patients with diabetes mellitus,” Diabetes Research and Clinical Practice, 10, pp. 91-97 (1990).
[cited by applicant]
Satoh et al., “Effect of Ranirestat on Sensory and Motor Nerve Function in Japanese Patients with Diabetic Polyneuropathy: A Randomized Double-Blind Placebo-Controlled Study,” J. Diabetes Res., 2016, article ID 5383797,…
[cited by applicant]
Schulz et al., “Identification of novel downstream targets of platelet glycoprotein VI activation by differential proteome analysis: implications for thrombus formation,” Blood, 115(20), pp. 4102-4110 (May 20, 2010).
[cited by applicant]
Sheridan, “The Most Common Replacements in Drug-Like Compounds,” J. Chem. Inf. Comput. Sci., 42, pp. 103-108 (2002).
[cited by applicant]
Srivastava et al., “Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders,” Chem. Biol. Interact., 191, pp. 330-338 (2011).
[cited by applicant]
Tammali, R. et al., “Inhibition of Aldose Reductase Prevents Angiogenesis in vitro and in vivo,” Author Manuscript, published in final edited form as: Angiogenesis, 14(2), pp. 209-221 (May 2011) (19 pages).
[cited by applicant]
Tammali, R. et al., “Inhibition of aldose reductase prevents colon cancer metastasis,” Carcinogenesis, 32(8), pp. 1259-1267 (2011) (9 pages).
[cited by applicant]
Tang et al., “Aldose reductase, oxidative stress, and diabetic mellitus,” Frontiers in Pharmacology, 3:87, 8 pages (May 9, 2012).
[cited by applicant]
Tang et al., “Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane,” The Journal of Clinical Investigation, 121(11), pp. 4462-4476 (Nov. 2011).
[cited by applicant]
Tawata et al., “Anti-platelet action of isoliquiritigenin, an aldose reductase inhibitor in licorice,” Eur. J. Pharmacol., Abstract Only, 212:1, pp. 87-92 (Feb. 25, 1992).
[cited by applicant]
Vedantham et al., “Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic apoE-/- Mice,” Author Manuscript published in final edited form as: Arterioscler. Thromb. Vasc. Biol., 31(8), pp. 1805-1813, (…
[cited by applicant]
Veves, “Aldose Reductase Inhibitors for the Treatment of Diabetic Neuropathy,” Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition, Humana Press, chapter 18, pp. 309-320 (2007).
[cited by applicant]
Wilson et al., “Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat,” Proc. Natl. Acad. Sci. USA, 90:21, pp. 9847-9851 (Nov. 1993).
[cited by applicant]
Yagihashi et al., “Neuropathy in diabetic mice overexpressing human aldose reductase and effects of aldose reductase inhibitor,” Brain, Abstract Only, 124, Pt. 12, pp. 2448-2458 (Dec. 2001).
[cited by applicant]
Zeng et al., “Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy,” Am. J. Cardiol., Abstract Only, 92:2, pp. 173-176 (Jul. 15, 2003).
[cited by applicant]