A method for lowering HbA1c using a combination of a BET bromodomain inhibitor and a sodium-dependent glucose transporter 2 inhibitor.

Abstract

Provided herein are methods for reducing glycated hemoglobin (HbA1c) levels to treat and / or prevent a diabetes-related disease or disorder by administering to a subject in need thereof a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein the variables of Formula I are as defined herein. TIFF2023549703000008.tif6880

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 107,843, filed on 30 October 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to a method for treating and / or preventing diabetes-related diseases or disorders in subjects who require a reduction in glycated hemoglobin or hemoglobin A1c (HbA1c) levels (i.e., blood HbA1c levels) by administering a sodium-glucose transporter protein 2 (SGLT2) inhibitor and a compound of formula I, or a combination thereof, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates. [Background technology]

[0003] HbA1c is a form of glycated or glucose-coated hemoglobin. Hemoglobin functions by transporting oxygen through the circulatory system and can be coated with glycation or glucose from the bloodstream. HbA1c testing is used to assess glucose management and represents the mean blood glucose level (mean lifespan of red blood cells) over the past 90 days, expressed as a percentage (Sherwani et al. 2016). HbA1c testing is recognized as a standard of care for monitoring diabetes, particularly type 2 diabetes mellitus (T2DM) (WHO 2011). The American Diabetes Association recommends HbA1c testing for diagnosing diabetes as an alternative to fasting plasma glucose >7.0 mmol / L, which was widely used before the standardization of HbA1c diagnostic testing (Khan et al. 2007). Non-diabetic individuals typically have an HbA1c level between 4.0% and 5.6%, while pre-diabetic individuals typically have an HbA1c level between 5.7% and 6.4%, whereas patients with an HbA1c level of 6.5% or higher are clinically diagnosed with diabetes (American Diabetes Association 2011). Diabetes, and in particular type II diabetes, is characterized by chronically elevated blood glucose levels (hyperglycemia) resulting from an imbalance in hepatic glucose production and insulin secretion (Kharroubi and Darwish 2015).

[0004] Normalization of plasma glucose, as measured by HbA1c, in T2DM patients is known to be a target for improving insulin action and preventing the development of diabetic complications (Kharroubi and Darwish 2015).

[0005] Diabetes mellitus is known to be associated with several complications, including neuropathy, nephropathy, retinopathy, and amputation, as well as comorbidities including insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, progressive cognitive decline, elevated blood fatty acid or glycerol levels, hyperlipidemia including hypertriglyceridemia, obesity, poor muscle quality, muscle atrophy, and sarcopenia (Fowler 2008, Vithian and Hurel 2010, Beckman and Creager 2016, Klein et al. 1984, Rangel et al. 2016, Zheng et al. 2019, Naqvi et al. 2017, Sheth et al. 2015, Bae et al. 2016, Yoon et al. 2016, Kalyani et al. 2015, Park et al. 2006, Hirata et al. 2019, Sugimoto et al. al.2019, Ozturk et al.2018).

[0006] Elevated HbA1c levels are correlated with a decline in cognitive functions defined as multiple intelligences, including learning, thinking, reasoning, memory, problem-solving, decision-making, and attention. In the AgeCoDe cohort of 1,342 older individuals, which analyzed the association between HbA1c levels and the incidence of all-cause dementia and Alzheimer's disease dementia, it was observed that HbA1c levels of 6.5% or higher were associated with a 2.8-fold increased risk of developing all-cause dementia and Alzheimer's disease dementia. HbA1c levels of 7% or higher were associated with an even greater risk of developing all-cause dementia and Alzheimer's disease dementia, with a risk increase of up to 5 times (Ramirez et al. 2014). An analysis of participants in a health and retirement study of 8,888 people aged 50 and older reported that diabetes was associated with a rate of memory decline faster than 10%, and each 1% of HbA1c corresponds to a 0.05 SD decrease in memory score per decade (Marden et al. 2017). A large observational study of 353,214 individuals with T2DM from the Swedish National Diabetes Registry concluded that HbA1c levels of ≥10% increased the dementia rate by 23%–77%, depending on time-fixed or time-updated statistical analysis, and that lowering HbA1c and good management of general diabetes risk factors may help prevent dementia in T2DM patients (Rawshani et al. 2015). Similarly, another analysis of 378,299 individuals with T2DM identified in the Swedish National Diabetes Register, along with 1,886,022 age- and sex-matched controls, found a linear association between HbA1c and the risk of Alzheimer's disease, vascular dementia, and non-vascular dementia, identifying poor glycemic control as a risk factor for the development of dementia (Celis-Morales et al. 2020).

[0007] Individuals with T2DM are known to have a higher risk of cardiovascular mortality and morbidity than individuals without T2DM. Observational studies have reported an association between elevated HbA1c levels and cardiovascular risk in patients with T2DM. UKPDS-35 evaluated 3,642 patients newly diagnosed with T2DM and showed that each 1% reduction in HbA1c was associated with a 14%, 12%, and 16% reduction in the relative risk of myocardial infarction, stroke, and heart failure, respectively (Stratton et al. 2000). In the EPIC-Norfolk study, the cardiovascular risk and all-cause mortality of the participants (4,662 men and 5,570 women) had a continuous association with HbA1c levels. As a result, a 1% increase in HbA1c was associated with a relative risk of death from any cause of 1.24 in men and 1.28 in women, independent of age, body mass index, waist / hip ratio, systolic blood pressure, serum cholesterol concentration, smoking, and any history of cardiovascular disease (Khaw et al. 2004). A meta-analysis of observational studies of the association between HbA1c and cardiovascular events in patients with T2DM showed a relative risk estimate of 1.18 for coronary heart disease or stroke for each 1% increase in HbA1c (Selvin et al. 2004).

[0008] Observational evidence of the association between HbA1c levels and diabetes-related complications and comorbidities, including the above, is the basis for guidelines recommending glycemic control measured by HbA1c in patients with T2DM. Regulatory authorities (including the FDA and EMA) have approved pharmaceuticals for the treatment of T2DM based on the use of HbA1c as a primary treatment evaluation item (Shimazawa and Ikeda 2019).

[0009] SGLT2 inhibitors, which induce glucose secretion in the urine by inhibiting sodium glucose transport protein 2, have been shown to reduce HbA1c levels in patients with pre-existing cardiovascular disease, diabetes, and chronic kidney disease (Zinman et al. 2015, Neal et al. 2017, Perkovic et al. 2019, Wiviott et al. 2019). The ability of SGLT2 inhibitors to mitigate elevated HbA1c levels in patients with type 2 diabetes has been studied in several clinical trials, including EMPA-REG OUTCOME for empaglifozin (NCT01131676), the CANVAS program for canaglifozin (NCT01032629 and NCT01989754), and DECLARE-TIMI 58 (NCT01730534) for dapaglifozin. In summary, the EMPA-REG OUTCOME trial showed that empaglifodine reduced HbA1c by 0.54% (95% CI, -0.58 to -0.49) in the 10 mg group and by -0.60 percentage points (95% CI, -0.64 to -0.55) in the 25 mg group compared to placebo after 12 weeks (adjusted mean difference). By week 94, the adjusted mean difference in HbA1c levels between patients treated with empagliflozin and those treated with placebo was -0.42% (95% CI, -0.48 to -0.36) and -0.47% (95% CI, -0.54 to -0.41), respectively. At week 206, the difference was -0.24% (95% CI, -0.40 to -0.08) and -0.36% (95% CI, -0.51 to 0.20), respectively (Zinman et al. 2015). The CANVAS program also demonstrated that canagliflozin has the ability to mitigate the rise in HbA1c levels, with a mean difference of -0.58% (95% CI, -0.61 to -0.56) (p<0.001) between the canagliflozin group and the placebo group over the trial period (Neal et al. 2017).Similarly, in the CREDENCE trial of canagliflozin in patients with T2DM and proteinuric CKD, the least-squares mean HbA1c level at week 13 was 0.31% lower in the canagliflozin group than in the placebo group (95% CI, 0.26–0.37), the difference between groups then narrowed, and the overall mean difference in reduction throughout the trial was 0.25% (95% CI, 0.20–0.31) (Perkovic et al. 2019). For dapagliflozin, in the DECLARE-TIMI 58 study, patients in the dapagliflozin group had a slightly lower HbA1c level throughout the trial than patients in the placebo group, and the mean least-squares mean absolute difference between groups was 0.42% (95% CI, 0.40–0.45) (Wiviott et al. 2019).

[0010] There have been no studies on the effectiveness of SGLT2 inhibitor therapy in patients with low HDL cholesterol (less than 40 mg / dL in men and less than 45 mg / dL in women) and a recent acute coronary syndrome (ACS) event (in the past 7–90 days). Thus, because many patients have not yet achieved their glycemic targets (i.e., HbA1c levels of less than 7.0%) with SGLT2 therapy, there remains an important unmet need for reducing HbA1c elevation in patients with existing cardiovascular disease and T2DM (Owen et al 2017).

[0011] Apabetalone (RVX-208 or RVX000222) is a first-in-class bromodomain and extra-terminal (BET) inhibitor (BETi) that selectively binds to the second bromodomain of BET proteins. BET proteins (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that recognize and bind to acetylated lysine on histones 3 and 4, as well as on several transcription factors. Histone-bound BET mobilizes transcription factors and mechanisms to gene enhancer and promoter sites, promoting the transcription of proximal genes. Chronic diseases significantly alter the acetylation landscape (Chen et al. 2005, Villagra et al. 2010, Bayarsaihan 2011), rearranging BET proteins to super-enhancers and promoters of genes involved in inflammation, lipid metabolism, and vascular function (Huang et al. 2009, Brown et al. 2014, Das et al. 2017). Apabetalon prevents BET protein translocation and inhibits the transcription of genes that drive chronic diseases. Apabetalon treatment targeting the BET protein is characterized by multifaceted effects that are enhanced under conditions with more pronounced maladaptive BET regulation. [Overview of the project]

[0012] The recently completed Phase 3 clinical trial (BETonMACE; NCT02586155) evaluated the efficacy of RVX-208 against major adverse cardiac events (MACE) in T2DM patients, which differed from the patient population in the aforementioned SGLT2 trial in that BETonMACE patients had low HDL cholesterol (<40 mg / dL for men and <45 mg / dL for women) and a recent acute coronary syndrome (ACS) event (past 7-90 days). Furthermore, all patients in BETonMACE received high-intensity or maximally tolerated statin therapy. BETonMACE was the first clinical trial to administer a combination of a BET inhibitor and an SGLT2 inhibitor over a long period to high-risk cardiovascular disease patients with T2DM.

[0013] The same BETonMACE clinical trial also evaluated the efficacy of RVX-208 monotherapy, SGLT2 inhibitor monotherapy, and RVX-208 and SGLT2 inhibitor combination therapy on HbA1c levels in T2DM patients with recent ACS. Significantly, RVX-208 monotherapy did not demonstrate the ability to statistically reduce HbA1c levels in T2DM patients with recent ACS in the recently completed Phase 3 BETonMACE trial (Ray et al. 2020). As shown by the data and results presented in this application, SGLT2 inhibitor monotherapy also did not demonstrate a statistically significant ability to reduce HbA1c levels in T2DM patients with recent ACS.

[0014] Surprisingly, as detailed in Example 2, patients treated with the combination of RVX-208 and an SGLT2 inhibitor showed a significant reduction in HbA1c compared to treatment with either therapy alone. The summary of results discussed below, and a detailed explanation of the results in Example 2, demonstrate that RVX-208 or the SGLT2 inhibitor did not reduce HbA1c on their own in patients with recent ACS and T2DM. However, the combination of apavetalone with the SGLT2 inhibitor resulted in an unexpected and statistically significant reduction in HbA1c.

[0015] Notably, RVX-208 in combination with an SGLT2 inhibitor reduced HbA1c from a median of 8.2% at baseline to a median of 7.8% at the last treatment visit (LVT). This reduction in HbA1c levels was unexpected, as, as mentioned above, patients with BETonMACE receive maximally tolerable statin therapy, and statins have been shown to significantly increase HbA1c levels and worsen glycemic control in both diabetic and non-diabetic patients (Ooba et al. 2016, Cui et al. 2018). Therefore, the HbA1c reduction reported in the above SGLT2 clinical trials was unexpected to be observed in the BETonMACE patient population when combined with treatment using the compound of formula I. Indeed, and compared, SGLT2 inhibitor monotherapy among BETonMACE patients resulted in a median HbA1c of 8.0% at baseline and a median HbA1c of 8.2% at LVT (i.e., no reduction in median HbA1c). The RVX-208 monotherapy group resulted in a median HbA1c of 7.3% at baseline and a median HbA1c of 7.3% at LVT (i.e., similarly, no reduction in median HbA1c). Therefore, the reduction in HbA1c observed when the compound of formula I was administered with an SGLT2 inhibitor exceeded the individual additive effect of apabetalone and the SGLT2 inhibitor.

[0016] Accordingly, the technical solutions provided by this disclosure include methods for administering sodium-glucose transport protein 2 (SGLT2) inhibitors and compounds of formula I or Ia, or combinations thereof of stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, to subjects who require a reduction in HbA1c levels to treat and / or prevent diabetes-related diseases or disorders as defined herein.

[0017] Compounds of formula I are already described in U.S. Patent No. 8,053,440, which is incorporated herein by reference. Compounds of formula I are [ka] This includes stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof. During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen. R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen. R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen. R6 is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy. W is selected from C and N. If W is N, then p is either 0 or 1. If W is C, then p is 1, W-(R4) p For this case, W is C, p is 1, and R4 is H, or W is N, and p is 0.

[0018] Apabetalon (RVX-208 or RVX000222) is a representative example of formula I.

[0019] In some embodiments, the diabetes-related disease or disorder treated and / or prevented by the methods of the present disclosure is a diabetic comorbidity associated with elevated HbA1c levels (e.g., 6.5% or higher + 10%). Non-limiting examples of such comorbidities include insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, progressive cognitive decline, elevated blood fatty acid or glycerol levels, hyperlipidemia including hypertriglyceridemia, obesity, poor muscle quality, muscular atrophy, sarcopenia, and combinations thereof.

[0020] In some embodiments, the diabetes-related disease or disorder treated and / or prevented by the methods of the present disclosure is a diabetic complication associated with elevated HbA1c levels. Non-limiting examples of such diabetic complications include neuropathy, nephropathy, retinopathy, amputation, and combinations thereof.

[0021] In some embodiments, the diabetes-related disease or disorder treated and / or prevented by the methods of the present disclosure is another diabetic comorbidity associated with elevated HbA1c levels, namely, dementia associated with elevated HbA1c levels. Non-limiting examples of dementia associated with elevated HbA1c levels include mild cognitive impairment, vascular dementia, Alzheimer's disease dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (vascular dementia and Alzheimer's disease), and combinations thereof.

[0022] In some embodiments, the compound of formula I or Ia, or its stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate, is administered simultaneously with the SGLT2 inhibitor. In some embodiments, the compound of formula I or Ia, or its stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate, is administered sequentially with the SGLT2 inhibitor. In some embodiments, the compound of formula I or Ia, or its stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate, is administered in a single pharmaceutical composition with the SGLT2 inhibitor. In some embodiments, the compound of formula I or Ia, or its stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate, and the SGLT2 inhibitor are administered as separate compositions.

[0023] In some embodiments, the compound of formula Ia is [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, and hydrogen. R2 is selected from alkoxy, alkyl, and hydrogen. R5 and R7 are each independently selected from alkyl, alkoxy, and hydrogen. R6 is selected from alkyl, hydroxyl, and alkoxy. W is selected from C and N. If W is N, then p is either 0 or 1. If W is C, then p is 1, W-(R4) p For this case, W is C, p is 1, and R4 is H, or W is N, and p is 0.

[0024] In some embodiments, the compound of formula I or Ia is 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (RVX-208;RVX000222), or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the dose of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one is 100 to 300 mg per day.

[0026] In some embodiments, the compound of formula I is administered once daily. In some embodiments, it is administered twice daily.

[0027] In some embodiments, the SGLT2 inhibitor is empagliflozin, canagliflozin, dapagliflozin, remogliflozin, ipragliflozin, bexagliflozin, erzgliflozin, sotagliflozin, luseogliflozin, tofogliflozin, or HM41322.

[0028] In some embodiments, the SGLT2 inhibitor is empagliflozin, canagliflozin, or dapagliflozin.

[0029] In some embodiments, the SGLT2 inhibitor is dapagliflozin.

[0030] In some embodiments, the dose of dapagliflozin is 5 to 10 mg.

[0031] In some embodiments, the dose of dapagliflozin is 5 mg or 10 mg.

[0032] In some embodiments, the present disclosure provides methods for treating and / or preventing diabetes-related disorders or conditions, which are diabetes comorbidities associated with elevated HbA1c levels, selected from insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, and combinations thereof, by lowering HbA1c levels.

[0033] In some embodiments, the present disclosure provides methods for reducing HbA1c levels to treat and / or prevent diabetes-related disorders or conditions, which are diabetes complications associated with elevated HbA1c levels, including insulin resistance (impaired glucose homeostasis).

[0034] In some embodiments, the present disclosure provides methods for treating and / or preventing diabetes-related disorders or conditions, which are diabetes comorbidities associated with elevated HbA1c levels, selected from hyperglycemia, hyperinsulinemia, and combinations thereof, by lowering HbA1c levels.

[0035] In some embodiments, the Disclosure provides methods for treating and / or preventing diabetes-related disorders or disabilities, which are complications of diabetes associated with elevated HbA1c levels, selected from neuropathy, nephropathy, retinopathy, and combinations thereof, by lowering HbA1c levels. In some embodiments, the Disclosure provides methods for treating and / or preventing diabetes-related disorders or disabilities, which are complications of diabetes associated with elevated HbA1c levels, selected from mild cognitive impairment, vascular dementia, Alzheimer's disease dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (vascular dementia and Alzheimer's disease), and combinations thereof, by treating to lower HbA1c levels. [Brief explanation of the drawing]

[0036] [Figure 1] This shows a comparison of the median change in HbA1c from baseline to LVT in patients treated with RVX-208 in combination with an SGLT2 inhibitor, compared to patients treated with placebo in combination with an SGLT2 inhibitor. [Figure 2] This shows a comparison of the median change in HbA1c from baseline to LVT in patients treated with RVX-208 in combination with an SGLT2 inhibitor, compared to patients treated with RVX-208 without an SGLT2 inhibitor. [Figure 3] This shows a drug interaction matrix comparing the median change in HbA1c from baseline to LVT in patients treated with RVX-208 with or without an SGLT2 inhibitor. [Figure 4] This shows a drug interaction matrix comparing the mean change in HbA1c from baseline to LVT in patients treated with RVX-208 with or without an SGLT2 inhibitor. [Modes for carrying out the invention]

[0037] Definition: "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "optionally substituted aryl" includes both "aryl" and "substituted aryl" as defined below. Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable.

[0038] As used herein, the term “hydrate” refers to a crystalline form having either stoichiometric or nonstoichiometric amounts of water incorporated into its crystalline structure.

[0039] As used herein, the term “alkenyl” refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond, such as a linear or branched group of 2 to 8 carbon atoms, referred herein as a (C2-C8) alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl 2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

[0040] As used herein, the term “alkoxy” refers to an alkyl group (O-alkyl) bonded to oxygen. The “alkoxy” group also includes an alkenyl group ("alkenyloxy") or an alkynyl group ("alkynyloxy"). Exemplary alkoxy groups include, but are not limited to, alkyl, alkenyl, or alkynyl groups with 1 to 8 carbon atoms, referred herein as (C1-C8)alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy.

[0041] As used herein, the term “alkyl” refers to a saturated linear or branched hydrocarbon, for example, a linear or branched group of 1 to 8 carbon atoms, referred herein as (C1-C8)alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0042] As used herein, the term "amide" refers to NR a C(O)(R b ) or C(O)NR b R c wherein R a , R b , and R c are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amide can be attached to another group via carbon, nitrogen, R b , or R c . The amide can also be cyclic; for example, R b and R c can be joined to form a 3- to 8-membered ring, such as a 5- or 6-membered ring. The term "amide" encompasses groups such as sulfonamides, ureas, ureides, carbamates, carbamic acids, and their cyclic versions. The term "amide" also encompasses amide groups attached to carboxy groups, such as salts like amide-COOH or amide-COONa, and amino groups attached to carboxy groups (such as salts like amino-COOH or amino-COONa).

[0043] As used herein, the term "amine" or "amino" refers to NR d R e or N(Rd)R e wherein R d and R e are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen. The amino can be attached to a parent molecular group via nitrogen. The amino can also be cyclic; for example, any two of R<9000019>and R e can be joined together or attached to N to form a 3- to 12-membered ring (such as morpholino or piperidinyl). The term amino also includes the quaternary ammonium salts of any corresponding amino group. Exemplary amino groups include, but are not limited to, alkylamino groups, Rd and R e At least one of them is an alkyl group. In some embodiments, R d and R e Each of these may be optionally substituted with a hydroxyl, halogen, alkoxy, ester, or amino.

[0044] As used herein, the term “aryl” refers to monocyclic, bicyclic, or other polycyclic carbocyclic, aromatic ring systems. The aryl group may optionally be fused to one or more rings selected from aryl, cycloalkyl, and heterocyclyl groups. The aryl groups of this disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azlenyl, and naphthyl, as well as benzo-condensed carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups include, but are not limited to, monocyclic aromatic ring systems, the rings containing six carbon atoms, which are referred to herein as "(C6)aryl".

[0045] As used herein, the term “arylalkyl” refers to an alkyl group having at least one aryl substituent (e.g., aryl-alkyl). Exemplary arylalkyl groups include, but are not limited to, arylalkyl groups having a monocyclic aromatic ring system, the ring containing six carbon atoms, which are referred to herein as “(C6)arylalkyl.”

[0046] As used herein, the term "carbamate" means R g OC(O)N(Rh), RgOC(O)N(R h )Ri , or OC(O)NR h R i It refers to the form, R g , R h and R i Each of these is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates or heteroarylcarbamates (e.g., R g , R h , and R i At least one of these is independently selected from aryl and heteroaryl compounds, such as pyridine, pyridazine, pyrimidine, and pyrazine.

[0047] As used herein, the term "carbocyclic ring" refers to an aryl group or a cycloalkyl group.

[0048] As used herein, the term “carboxy” refers to a COOH group or its corresponding carboxylate salt (e.g., COONa). The term “carboxy” also includes “carboxycarbonyl,” for example, a carboxyl group bonded to a carbonyl group, e.g., C(O)-COOH or its salt, e.g., C(O)-COONa.

[0049] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group bonded to oxygen.

[0050] As used herein, the term “cycloalkyl” refers to a saturated or unsaturated cyclic, bicyclic, or crosslinked 3- to 12 carbon or 3- to 8 carbon bicyclic hydrocarbon group, and is referred herein to as “(C3-C8) cycloalkyl” derived from cycloalkanes. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups may be fused with other cycloalkyl saturated or unsaturated groups, aryl groups, or heterocyclyl groups.

[0051] As used herein, the term “dicarboxylic acid” refers to a group comprising at least two carboxylic acid groups, such as saturated and unsaturated hydrocarbon dicarboxylic acids and their salts. Exemplary dicarboxylic acids include, but are not limited to, alkyldicarboxylic acids. Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Examples of dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+) / (-)-malic acid, (+) / (-)-tartaric acid, isophthalic acid, and terephthalic acid. Dicarboxylic acids further include carboxylic acid derivatives such as anhydrides, imides, and hydrazides (e.g., succinic anhydride and succinimide).

[0052] The term "ester" refers to structures C(O)O-, C(O)OR j , R k C(O)OR j , or R k It refers to C(O)O-, where O is not bonded to hydrogen, and R j and R k R can be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl. k R can be hydrogen, but j It cannot be hydrogen. Esters may be cyclic, for example, carbon atoms and R j , oxygen atom and R k , or R j and R k They may bond to form a 3-12 membered ring. Examples of esters include, but are not limited to, R j and R k Examples of alkyl esters include alkyls in which at least one of the elements is an alkyl such as OC(O)alkyl, C(O)-O-alkyl, and alkylC(O)-O-alkyl. Exemplary esters also include aryl or heteroaryl esters, for example, R j and R k At least one of these is a heteroaryl group such as pyridine, pyridazine, pyrimidine, and pyrazine, e.g., nicotinic ester. Exemplary esters also include reverse esters having the structure RkC(O)O-, where oxygen is bonded to the parent molecule. Exemplary reverse esters include succinates, D-arginates, L-arginates, L-lysinates, and D-lysinates. Esters also include carboxylic acid anhydrides and acid halides.

[0053] As used herein, the terms "halo" or "halogen" refer to F, Cl, Br, or I.

[0054] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms. “Haloalkyl” also includes an alkenyl or alkynyl group substituted with one or more halogen atoms.

[0055] As used herein, the term “heteroaryl” refers to a monocyclic, dicyclic, or polycyclic aromatic ring system containing one or more heteroatoms, such as 1 to 3 heteroatoms, including nitrogen, oxygen, and sulfur. Heteroaryls may be substituted with one or more substituents included in alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heteroaryls may also be fused to non-aromatic rings. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)triazolyl, pyrazinyl, pyrimidylyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings, the rings containing 2 to 5 carbon atoms and 1 to 3 heteroatoms, and are referred to herein as "(C2-C5) heteroaryl."

[0056] As used herein, the terms “heterocycle,” “heterocyclyl,” or “heterocyclic formula” refer to a saturated or unsaturated 3, 4, 5, 6, or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heterocycles may be aromatic (heteroaryl) or non-aromatic. Heterocycles may be substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. The heterocycle also includes bicyclic, tricyclic, and tetracyclic groups, in which any of the above heterocycles is fused to one or two rings independently selected from aryl, cycloalkyl, and heterocycles. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, sinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, Examples include, but are not limited to, piperazinyl, piperidinyl, pyranil, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridadinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidine-2-onyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranil, and triazolyl.

[0057] As used herein, the terms "hydroxy" and "hydroxyl" refer to -OH.

[0058] As used herein, the term "hydroxyalkyl" refers to a hydroxyl group bonded to an alkyl group.

[0059] As used herein, the term "hydroxyaryl" refers to a hydroxyl group bonded to an aryl group.

[0060] As used herein, the term "ketone" refers to C(O)-R n (For example, C(O)CH3 as acetyl) or R n -C(O)-R o This refers to the structure of ketones. n or R o It can be bonded to another group via R. n and R o may be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R n and R o These can combine to form a ring with 3 to 12 members.

[0061] As used herein, the term “phenyl” refers to a six-membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. Phenyl can be substituted with one or more substituents, including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.

[0062] As used herein, the term "thioalkyl" refers to an alkyl group bonded to sulfur (S-alkyl).

[0063] The "alkyl," "alkenyl," "alkynyl," "alkoxy," "amino," and "amide" groups may be optionally substituted with, or blocked by, or branched by, at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N. The substituents may branch to form substituted or unsubstituted heterocycles or cycloalkyls.

[0064] As used herein, suitable substitutions on optionally substituted substituents refer to groups that do not impair the synthetic or pharmaceutically useful properties of the compounds of this disclosure or intermediates useful for their preparation. Examples of suitable substitutions include, but are not limited to, C1-C8 alkyl, C2-C8 alkenyl or alkynyl; C6 aryl, 5 or 6-membered heteroaryl; C3-C7 cycloalkyl; C1-C8 alkoxy; C6 aryloxy; CN; OH; oxo; halo, carboxy; amino, e.g., NH(C1-C8 alkyl), N(C1-C8 alkyl)2, NH((C6)aryl), or N((C6)aryl)2; formyl; ketone, e.g., CO(C1-C8 alkyl), -CO((C6 aryl) ester, e.g., CO2(C1-C8 alkyl), and CO2(C6 aryl). Those skilled in the art can easily select suitable substitutions based on the stability, pharmacological activity, and synthetic activity of the compounds of this disclosure.

[0065] As used herein, the term “pharmaceutically acceptable composition” means a composition comprising at least one compound disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0066] As used herein, the term “pharmaceutically acceptable carrier” refers to any and all solvents, dispersions, coatings, isotonic agents, and absorption retarders, etc., that are compatible with pharmaceutically active substances. The use of such media and formulations for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic function. As used herein, the term “pharmaceutically acceptable composition” refers to a composition comprising at least one compound disclosed herein formulated with one or more pharmaceutically acceptable carriers.

[0067] As used herein, the term “pharmaceutically acceptable prodrug” means a prodrug of the compounds disclosed herein that, within the bounds of sound pharmaceutically judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, has a reasonable benefit / risk ratio, is effective for its intended use, and, if possible, is a zwitterionic form of the compound of Formula I. Discussions are provided in Higuchi et al., “Prodrugs as Novel Delivery Systems”, Symposium Series, Vol. 14, and Roche, EB, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0068] The term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in the compounds used in this composition. Compounds in this composition, which are essentially basic, can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions (sulfates, citrates, matates, acetates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinic acid, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, acid tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, gluconates, glucarons, saccharates, formates, benzoates, gluten Examples of amino acids include, but are not limited to, methylates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts). Compounds in this composition containing an amino moiety may form pharmaceutically acceptable salts having various amino acids in addition to the acids mentioned above. Compounds in this composition that are inherently acidic may form base salts having various pharmaceutically acceptable cations. Examples of such salts include, but are not limited to, alkali metal salts or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0069] Furthermore, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acidic salt. Conversely, when the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts.

[0070] Compounds of formula I or Ia may contain one or more chiral centers and / or double bonds, and thus exist as stereoisomers such as geometric isomers, enantiomers, or diastereomers. As used herein, the term “stereoisomer” comprises all geometric isomers, enantiomers, or diastereomers. These compounds may be designated with the symbol “R” or “S” depending on the configuration of substituents around the stereocentral carbon atom. This disclosure encompasses a variety of stereoisomers of these compounds and mixtures thereof. Stereoiomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in the terminology, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center.

[0071] Individual stereoisomers of compounds for use in the methods of this disclosure may be prepared synthetically from commercially available starting materials containing chiral or stereocenters, or by the preparation of racemic mixtures followed by separation methods well known to those skilled in the art. These separation methods are exemplified by (1) the attachment of an enantiomer mixture to a chiral auxiliary, separation of a diastereomer mixture obtained by recrystallization or chromatography, and release of an optically pure product from the auxiliary, (2) the formation of a salt using an optically active decomposition agent, or (3) the direct separation of a mixture of optical enantiomers on a chiral chromatography column. Stereoisomer mixtures may also be separated into their constituent stereoisomers by well known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers may also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well known asymmetric synthesis methods.

[0072] Geometric isomers may also exist in compounds of formula I or Ia. This disclosure encompasses a variety of geometric isomers and mixtures thereof arising from the arrangement of substituents around a carbon-carbon double bond or around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated by the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures exhibiting a double bond encompass both E and Z isomers.

[0073] Substituents around a carbon-carbon double bond may be alternatively referred to as "cis" or "trans," where "cis" refers to a substituent on the same side of the double bond and "trans" refers to a substituent on the opposite side of the double bond. The arrangement of substituents around a carbon ring is indicated as "cis" or "trans." The term "cis" refers to a substituent on the same side of the ring's plane, and the term "trans" refers to a substituent on the opposite side of the ring's plane. A mixture of compounds in which substituents are located on both the same and opposite planes of the ring's plane is indicated as "cis / trans."

[0074] The compounds of formula I disclosed herein may exist as tautomers, and although only one tautomer structure is illustrated, both tautomer forms are intended to be encompassed within the scope of this disclosure.

[0075] As used herein, the term “SGLT2 inhibitor” refers to substances such as small organic chemical compounds (≤1 kDa), or large biomolecules such as peptides (e.g., soluble peptides), proteins (e.g., antibodies), nucleic acids (e.g., siRNA), or conjugates combining any two or more of the above, which have the activity to inhibit sodium-glucose transport protein 2 (SGLT2). Non-limiting examples of SGLT2 inhibitors include empagliflozin, canagliflozin, dapagliflozin, remogliflozin, ipragliflozin, HM41322, bexagliflozin, erzgliflozin, sotagliflozin, luseogliflozin, tofogliflozin, or any pharmaceutically acceptable salt of any of the above. Further examples of SGLT2 inhibitors include WO01 / 027128, WO04 / 013118, WO04 / 080990, EP1852439A1, WO01 / 27128, WO03 / 099836, WO2005 / 092877, WO2006 / 034489, WO2006 / 064033, WO2006 / 117359, and WO2006 / 117 Disclosed in 360, WO2007 / 025943, WO2007 / 028814, WO2007 / 031548, WO2007 / 093610, WO2007 / 128749, WO2008 / 049923, WO2008 / 055870, and WO2008 / 055940, each of which is incorporated herein by reference in its entirety.

[0076] As used herein, “treatment” or “treating” means improvement of a disease or disorder, or at least one identifiable symptom thereof. In another embodiment, “treatment” or “treating” means improvement of at least one measurable physical parameter, which is not necessarily identifiable by the patient. In yet another embodiment, “treatment” or “treating” means mitigating the progression of a disease or disorder, either physically, such as stabilizing an identifiable symptom, or physiologically, such as stabilizing a physical parameter, or both. In yet another embodiment, “treatment” or “treating” means delaying the onset or progression of a disease or disorder. For example, treating a cholesterol disorder may include reducing blood cholesterol levels.

[0077] As used herein, “prevention” or “prevention” means reducing the risk of acquiring a given disease or disability, or the symptoms of a given disease or disability.

[0078] As used herein, “dementia associated with elevated HbA1c levels” refers to dementias such as mild cognitive impairment, vascular dementia, Alzheimer’s disease dementia, Lewy body dementia, frontotemporal dementia, and mixed dementia (vascular dementia and Alzheimer’s disease), and combinations thereof, in which subjects suffering from these conditions have a blood HbA1c level of 6.5% or greater + 10% (i.e., 6.5% to 7.15%) when measured or at the time of measurement.

[0079] As used herein, “progression of cognitive decline” refers to a self-reported experience of worsening or more frequent confusion or memory loss in a subject having a blood HbA1c level of 6.5% or greater + 10% when measured or at the time measured. This is a form of cognitive impairment and one of the earliest prominent symptoms of Alzheimer’s disease and disease-related dementia.

[0080] As used herein, “mild cognitive impairment (MCI)” refers to a stage between the expected cognitive decline of normal aging and the more severe decline of dementia, in which a person has a blood HbA1c level of 6.5% or greater + 10% when measured or at the time measured. MCI is a potential early indicator of more severe disease-related dementia, as it may increase the risk of later-onset dementia caused by Alzheimer's disease or other neurological conditions.

[0081] As used herein, “diabetes-related disease or disorder” means a disease, disorder, and condition that is a complication of diabetes and / or a diabetes-related condition associated with elevated HbA1c levels, in which a person having such a condition has a blood HbA1c level of 6.5% or greater + 10% when measured or at the time measured. Non-limiting examples of diabetes-related diseases or disorders that are complications of diabetes or diabetes-related conditions associated with elevated HbA1c levels include neuropathy, nephropathy, retinopathy, amputation, and combinations thereof. Non-limiting examples of diabetes-related diseases or disorders that are complications of diabetes or diabetes-related conditions associated with elevated HbA1c levels include insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, progressive cognitive decline, elevated blood fatty acid or glycerol levels, hyperlipidemia including hypertriglyceridemia, obesity, poor muscle quality, muscular atrophy, sarcopenia, and combinations thereof. Another non-exclusive example of a diabetes-related disorder or condition associated with elevated HbA1c levels, or a comorbidity of diabetes, is dementia associated with elevated HbA1c levels.

[0082] Exemplary Embodiments In one embodiment, the present disclosure provides a method for treating and / or preventing diabetes-related diseases or disorders by lowering glycated hemoglobin (HbA1c) levels, the method comprising, to a subject requiring the treatment, a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of formula I: [ka] Or administering a combination of its stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen. R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen. R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen. R6 is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy. W is selected from C and N. If W is N, then p is either 0 or 1. If W is C, then p is 1, W-(R4) p For this case, W is C, p is 1, and R4 is H, or W is N, and p is 0.

[0083] In one embodiment, the compound of formula I is the compound of formula Ia: [ka] or its stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, During the ceremony, R1 and R3 are each independently selected from alkoxy, alkyl, and hydrogen. R2 is selected from alkoxy, alkyl, and hydrogen. R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen. R6 is selected from alkyl, hydroxyl, and alkoxy. W is selected from C and N. If W is N, then p is either 0 or 1. If W is C, then p is 1, W-(R4) p For this case, W is C, p is 1, and R4 is H, or W is N, and p is 0.

[0084] In one embodiment, the compound of formula I or Ia is 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (RVX-208 or RVX000222), or a pharmaceutically acceptable salt thereof.

[0085] In one embodiment, the method of the present disclosure involves administering 100 to 300 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof to a subject.

[0086] In one embodiment, the method of the present disclosure involves administering a daily dose of 200 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof to a subject.

[0087] In one embodiment, the SGLT2 inhibitor is selected from empagliflozin, canagliflozin, dapagliflozin, bexagliflozin, erzgliflozin, sotagliflozin, luseogliflozin, tofogliflozin, and HM41322.

[0088] In one embodiment, the SGLT2 inhibitor is selected from empagliflozin, canagliflozin, and dapagliflozin.

[0089] In one embodiment, the compound of formula I or Ia is administered simultaneously with the SGLT2 inhibitor as a separate composition.

[0090] In one embodiment, the compound of formula I or Ia is administered as a single pharmaceutical composition with an SGLT2 inhibitor.

[0091] In one embodiment, the subject is a human being.

[0092] In one embodiment, the subject is a person receiving statin therapy. In one embodiment, the subject is a person receiving high-intensity or maximally tolerable statin therapy. In one embodiment, high-intensity statin treatment or therapy refers to a daily dose of at least 20 mg, or at least 40 mg, or 20-80 mg, or 20-40 mg, or 40-80 mg. In one embodiment, maximally tolerable statin treatment or therapy refers to a daily dose of at least 40 mg, or 40-80 mg, or 80 mg. In one embodiment, the subject is receiving rosuvastatin therapy. In one embodiment, the subject is receiving atorvastatin therapy.

[0093] In one embodiment, the subjects are individuals with type 2 diabetes and low HDL cholesterol (less than 40 mg / dL for men and less than 45 mg / dL for women), as well as a recent acute coronary syndrome (ACS) (past 7-90 days).

[0094] In one embodiment, diabetes-related disorder or impairment is a diabetic comorbidity associated with elevated HbA1c levels. In one embodiment, diabetes-related disorder or impairment is a diabetic comorbidity associated with elevated HbA1c levels that is insulin resistance (impaired glucose homeostasis). In one embodiment, diabetes-related disorder or impairment is a diabetic comorbidity associated with elevated HbA1c levels selected from reduced muscle quality, muscle atrophy, sarcopenia, and combinations thereof. In one embodiment, diabetes-related disorder or impairment is a diabetic comorbidity associated with elevated HbA1c levels that is dementia associated with elevated HbA1c levels. In one embodiment, dementia associated with elevated HbA1c levels is selected from mild cognitive impairment, vascular dementia, Alzheimer's disease dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (vascular dementia and Alzheimer's disease), and combinations thereof.

[0095] In one embodiment, diabetes-related disease or disorder is a complication of diabetes associated with elevated HbA1c levels. In one embodiment, the complication of diabetes is selected from nephropathy, neuropathy, retinopathy, and combinations thereof.

[0096] In one embodiment, the present disclosure provides a method for lowering glycated hemoglobin (HbA1c) levels, the method comprising administering to a subject in need a combination of a sodium-glucose transporter protein 2 (SGLT2) inhibitor as defined above, and a compound of formula I or formula Ia, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates. In one embodiment, the method for lowering HbA1c levels treats and / or prevents diabetes-related diseases or disorders. Exemplary embodiments of methods for lowering HbA1c, for example, specific compounds of formula I or Ia, or their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates; specific daily doses of compounds of formula I or Ia, or their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates; specific SGLT2 inhibitors; methods of administering compounds of formula I or Ia, or their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, and SGLT2 inhibitors (i.e., simultaneously, sequentially, as separate compositions, or as a single composition); target criteria, target subgroups; and specific diabetes-related diseases and disorders are as described in one or more of the above exemplary embodiments.

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[0098] Example 1: Clinical Development Apabetalon (RVX-208) was evaluated in a recently completed Phase 3 clinical trial (BETonMACE; NCT02586155) for its efficacy against MACE in patients with type 2 diabetes who had low HDL cholesterol (<40 mg / dL in men and <45 mg / dL in women) and a recent acute coronary syndrome (ACS) (past 7-90 days). All patients received high-intensity statin therapy or maximally tolerated statin therapy, which was 20-40 mg or a maximum daily dose of 40 mg for rosuvastatin, or 40-80 mg or a maximum daily dose of 80 mg for atorvastatin.

[0099] Patients with type 2 diabetes and low HDL cholesterol (≤40 mg / dL for men and ≤45 mg / dL for women) who had experienced ACS in the past 7–90 days (n=2425) and were receiving intensive or maximally tolerated therapy with atorvastatin or rosuvastatin were assigned in a double-blind manner to receive oral apabetalone 100 mg twice daily or the corresponding placebo. Basic characteristics included sex (25%), myocardial infarction as an index ACS event (74%), coronary revascularization as an index ACS event (76%), treatment with dual antiplatelet therapy (87%) and treatment with renin-angiotensin system inhibitors (91%), median LDL cholesterol of 65 mg / dL, and median HbA1c of 7.3%. The primary measure of efficacy was time to the first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. This study enrolled 2425 patients, and the MACE outcome population consisted of 2418 patients.

[0100] Example 2: Post-hoc analysis In the BETonMACE clinical study, a total of 298 patients (150 in the RVX-208 treatment group and 148 in the placebo treatment group) received SGLT2 inhibitors (empagliflozin, dapagliflozin, or canagliflozin) in addition to specific statin therapies (atorvastatin and rosuvastatin) and other guideline-defined treatments. Specifically, a total of 150 patients received both RVX-208 and an SGLT2 inhibitor, a total of 148 patients received an SGLT2 inhibitor but not RVX-208, a total of 1062 patients received RVX-208 but not an SGLT2 inhibitor, and a total of 1058 patients received neither RVX-208 nor an SGLT2 inhibitor.

[0101] Patients who were randomized and actively administered the investigational drug (RVX-208 or placebo) while receiving at least one dose of SGLT2 therapy were counted as patients who received a combination of SGLT2 therapy with either RVX-208 or placebo. Patients receiving two or more therapies within the SGLT2 inhibitor class were counted only once, based on which therapy was continued at the end of treatment with the investigational drug (RVX-208 or placebo). For patients who were receiving two or more therapies within the SGLT2 inhibitor class at the end of treatment with the investigational drug, the longer-received SGLT2 inhibitor therapy was counted.

[0102] The time of the last visit to treatment (LVT) represents the longest study exposure period for patients treated with RVX-208 or placebo with and without an SGLT2 inhibitor, and is the focus of this analysis. For patients treated with an SGLT2 inhibitor, the median time to LVT (and total investigational drug exposure) for patients with baseline HbA1c and LVT measurements (N=298) was 744 days (2.04 years). For patients treated with an SGLT2 inhibitor and RVX-208 (N=150), the median time to LVT was 740 days (2.03 years), and for patients treated with an SGLT2 inhibitor and placebo (N=148), the median time to LVT was 745 days (2.04 years). No statistical differences were observed during the investigational drug exposure period, indicating a balance between treatment groups.

[0103] In patients receiving RVX-208 in addition to SGLT2 inhibitors (N=150), the median age was 58 years, 16% were female, 92% were Caucasian, the mean duration of diabetes was 9.9 years, and the mean BMI was 30.3 kg / m². 2 The baseline HbA1c was 8.2%.

[0104] In patients receiving SGLT2 inhibitors in addition to placebo (N=148), the median age was 59 years, 18% were female, 89% were Caucasian, the mean duration of diabetes was 10.6 years, and the mean BMI was 30.2 kg / m².2 The baseline HbA1c was 8.0%.

[0105] No statistical differences were observed in any of these parameters, indicating a balance between treatment groups.

[0106] Figures 1 and 2 compare the median change in HbA1c from baseline to LVT between two patient groups, the test group and the control group, as described below. i. Patients treated with SGLT2 inhibitors and RVX-208 (trial), and patients treated with SGLT2 inhibitors alone and given placebo (control) (Figure 1), ii. Patients treated with RVX-208 and an SGLT2 inhibitor (trial), and patients treated with RVX-208 alone (control) (Figure 2).

[0107] In Figure 1, when patients were treated with an SGLT2 inhibitor and administered either RVX-208 or placebo, the effect of co-administration of RVX-208 inhibitor and SGLT2 inhibitor (quantified using the reduction in HbA1c levels from baseline) showed a significant reduction in HbA1c compared to placebo and SGLT2 inhibitor in LVT, with a median treatment difference of -0.25% (p<0.0001, Mann-Whitney) and a mean treatment difference of -0.33% (ANOVA 95% CI, -0.09~0.8) (p=0.13, ANOVA; p=0.11, Rank-ANOVA).

[0108] In particular, RVX-208 in combination with an SGLT2 inhibitor reduced HbA1c from a median of 8.2% at baseline to a median of 7.8% at the last treatment visit (LVT). The mean change in HbA1c from baseline to LVT in this combination therapy group was -0.21% (Figure 4), and the median change from baseline to LVT was -0.05% (Figure 3). In comparison, the SGLT2 inhibitor monotherapy group had a median HbA1c of 8.0% at baseline and a median HbA1c of 8.2% at LVT. The mean change from baseline to LVT in this SGLT2 inhibitor monotherapy group was +0.12% (Figure 4), and the median change from baseline to LVT was +0.20% (Figure 3).

[0109] In Figure 2, when patients were treated with a combination of RVX-208 and an SGLT2 inhibitor, or with RVX-208 alone, the effect of co-administration of the RVX-208 inhibitor and the SGLT2 inhibitor (quantified using the reduction in HbA1c levels from baseline) showed a significant reduction in HbA1c in LVT compared to RVX-208 without an SGLT2 inhibitor, with a median treatment difference of -0.25% (p<0.0001, Mann-Whitney) and a mean treatment difference of -0.43% (ANOVA 95% CI, 0.09~0.8) (p=0.01, ANOVA; p=0.01, Rank-ANOVA).

[0110] In particular, the RVX-208 monotherapy group had a median HbA1c of 7.3% at baseline and a median HbA1c of 7.3% at LVT. The mean change in HbA1c from baseline to LVT in this RVX-208 monotherapy group was +0.22% (Figure 4), and the median change in HbA1c from baseline to LVT was +0.20% (Figure 3). The statistical parameters for RVX-208 and SGLT2 inhibitor combination therapy are as described above.

[0111] In conclusion, the results shown in Figures 1-4 indicate that neither RVX-208 monotherapy nor SGLT2 inhibitor monotherapy reduced the median or mean HbA1c levels in patients with T2DM and recent ACS. In some cases, baseline HbA1c actually increased when measured at LVT in both RVX-208 monotherapy and SGLT2 inhibitor monotherapy. Therefore, it was unexpected that the combination therapy of RVX-208 and an SGLT2 inhibitor resulted in any reduction of HbA1c, let alone a statistically significant reduction in both the median and mean HbA1c change from baseline to LVT, as well as in the median HbA1c level, within the same patient population. Thus, the combination of the compound of formula I with an SGLT2 inhibitor is synergistic in reducing the median or mean HbA1c levels in patients with T2DM and recent ACS.

Claims

1. A pharmaceutical product for treating and / or preventing diabetes-related diseases or disorders by lowering glycated hemoglobin (HbA1c) levels in subjects requiring treatment, wherein the pharmaceutical product comprises a sodium-glucose transport protein 2 (SGLT2) inhibitor and 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (RVX-208 or RVX000222), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates. SGLT2 inhibitors are selected from empagliflozin, canagliflozin, and dapagliflozin. The subjects are individuals with type 2 diabetes, low HDL cholesterol (less than 40 mg / dL for men and less than 45 mg / dL for women), and a recent acute coronary syndrome (ACS) (past 7-90 days). The pharmaceutical product.

2. The pharmacopoeia according to claim 1, comprising administering 100 to 300 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (RVX-208 or RVX000222) or an equivalent amount of a pharmaceutically acceptable salt thereof to a subject requiring the treatment, and optionally administering 200 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (RVX-208 or RVX000222) or an equivalent amount of a pharmaceutically acceptable salt thereof to the subject requiring the treatment.

3. The pharmaceutical product according to any one of Claim 1 or 2, wherein 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (RVX-208 or RVX000222) is administered simultaneously with the SGLT2 inhibitor as a separate composition.

4. The pharmaceutical product according to any one of Claim 1 or 2, wherein 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (RVX-208 or RVX000222) is administered together with the SGLT2 inhibitor as a single composition.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein the statin therapy is rosuvastatin therapy or atorvastatin therapy.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein the diabetes-related disease or disorder is a comorbidity of diabetes associated with an elevated HbA1c level, which is insulin resistance (impairment of glucose homeostasis).

7. The pharmaceutical product according to any one of claims 1 to 5, wherein the diabetes-related disease or disorder is a diabetic comorbidity associated with elevated HbA1c levels selected from decreased muscle quality, muscle atrophy, sarcopenia, and combinations thereof.

8. The pharmaceutical product according to any one of claims 1 to 5, wherein the diabetes-related disease or disorder is a complication of diabetes associated with an increase in HbA1c levels, and the complication of diabetes is appropriately selected from nephropathy, neuropathy, retinopathy, and combinations thereof.

9. The pharmaceutical product according to any one of claims 1 to 5, wherein the diabetes-related disease or disorder is dementia associated with an elevated HbA1c level, or a comorbidity of diabetes associated with an elevated HbA1c level, and the dementia associated with an elevated HbA1c level is appropriately selected from mild cognitive impairment, vascular dementia, Alzheimer's disease dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (vascular dementia and Alzheimer's disease), and combinations thereof.

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