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Antidiabetic tricyclic compounds

a tricyclic compound and antidiabetic technology, applied in the field of antidiabetic tricyclic compounds, can solve the problems of increased and premature morbidity and mortality, inadequate insulin-mediated repression of lipolysis in adipose tissue, oxidation and storage of glucose in muscle,

Inactive Publication Date: 2014-02-13
WUXI APPTEC BVI INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about new chemical compounds that can treat different diseases, including Type 2 diabetes, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Metabolic Syndrome, and atherosclerosis, by targeting a specific receptor in the body. These compounds are suitable for use as medications and can be used alone or in combination with other drugs. The invention also covers the methods for making these compounds and the use of them in treating the above-mentioned diseases.

Problems solved by technology

This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle, and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality.
Patients with Type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy.
Patients with Metabolic Syndrome, whether or not they have or develop overt diabetes mellitus, have an increased risk of developing the macrovascular and microvascular complications that occur with Type 2 diabetes, such as atherosclerosis and coronary heart disease.
Compliance with this treatment is generally very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of fat and carbohydrates.
However, phenformin and metformin can induce lactic acidosis and nausea / diarrhea.
Compounds that are agonists of both the PPAR alpha and PPAR gamma subtypes (PPAR alpha / gamma dual agonists) have been made and tested, but so far none have been approved by the regulatory authorities.
The currently marketed compounds do not greatly improve lipid metabolism and may actually have a negative effect on the lipid profile.
This can cause insulin secretion even if the glucose level is low, resulting in hypoglycemia, which can be fatal in severe cases.

Method used

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  • Antidiabetic tricyclic compounds
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Examples

Experimental program
Comparison scheme
Effect test

reference example 1-9

4-Hydroxy-1,1a,6,6a-tetrahydro-3-aza-cyclopropa[a]indene-1-carboxylic acid ethyl ester (1-9)

[0537]

Step A: (4-Bromo-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine (1-2)

[0538]

[0539]To a suspension of sodium hydride (60% in oil, 93 g, 2.32 mol) in DMF (1.8 L), was added compound 1-1 (100 g, 0.58 mol) in DMF (500 mL) slowly at 0° C. Then the resulting mixture was allowed to stir at r.t. for 0.5 h under N2 protection. PMBCl (227 g, 1.45 mol) was added to the above mixture and the temperature was kept between 0-10° C. After addition, the mixture was allowed to stir at room temperature for 2 h. The mixture was carefully cpoured into ice water, and the resulting solid precipitate was collected, filtered and washed with PE (150 mL×3). The filtrate was concentrated to afford compound 1-2. MS (ESI) m / e (M+H+): 414.1 / 416.1.

Step B: (4-Bromo-5-iodo-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine (1-3)

[0540]

[0541]To a stirred solution of compound 1-2 (140 g, 0.34 mol) in DMF (2.8 L), was added NIS (115 g, ...

reference example 2-4

4-[2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-1,1a,6,6a-tetrahydro-3-aza-cyclopropa[a]indene-1-carboxylic acid ethyl ester (2-4)

[0574]

Step A: [2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol (2-2)

[0575]

[0576]To a stirred solution of compound 2-1 (25 g, 120 mmol) in dioxane (400 mL), was added bis(pinacolato)diboron (45 g, 180 mmol), Pd(dppf)Cl2 (4.4 g, 6.0 mmol) and KOAc (23.5 g, 240 mmol). The resulting mixture was heated to 110° C. under N2 overnight. The mixture was then concentrated to afford the crude product, which was purified by column chromatography on silica gel (PE:EA=20:1) to give compound 2-2. MS (ESI) m / z: 253 (M+H+).

Step B: 2-(3-Bromomethyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2-3)

[0577]

[0578]To a stirred solution of compound 2-2 (7 g, 28 mmol) in THF (80 mL), was added PBr3 (7.6 g, 28 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 1 h. H2O (50 mL) was added to the mixtu...

reference example 2-5

[0582]1-NMR (400 MHz, CDCl3) δ: 8.10 (s, 1H), 7.88 (s, 1H), 7.75 (d, 1H, J=4.0 Hz), 753(d, 1H, J=4.0 Hz), 7.37 (t, 1H, J=8.0 Hz), 6.61 (s, 1H), 5.36 (s, 2H), 4.12 (dd, 2H, J=2.0 and 7.2 Hz), 3.23 (dd, 1H, J=6.0 and 12.0 Hz), 2.98 (d, 1H, J=8.8 Hz), 2.88 (d, 1H, J=2.8 Hz), 2.43-2.39 (m, 1H), 1.34 (s, 12H), 1.26-1.23 (m, 4H).

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Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Description

BACKGROUND OF THE INVENTION[0001]Diabetes mellitus is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin is still produced in the body. Patients having Type 2 diabetes have a resistance to the effects of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues. These patients often have normal levels of insulin, and may have hyperinsulinemia (elevated plasma insulin levels), as they compensate for the reduced effectiveness of insulin by secreting increased amoun...

Claims

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Application Information

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IPC IPC(8): C07D221/16A61K31/444A61K45/06C07D401/12A61K31/435
CPCC07D221/16C07D401/12A61K31/435A61K45/06A61K31/444A61K31/4412A61K31/4427A61K31/4433A61K31/4439A61K31/496A61K31/506A61K31/513A61K31/5377A61K31/675A61P3/04A61P3/06A61P3/10C07D401/14C07D405/12C07D409/14C07D417/12C07F9/58
Inventor HAGMANN, WILLIAM K.NARGUND, RAVI P.BLIZZARD, TIMOTHY A.JOSIEN, HUBERTBIJU, PURAKKATTLEPLUMMER, CHRISTOPHER W.DANG, QUNLI, BINGLIN, LINUS S.CUI, MINGXIANGHU, BINHAO, JINGLAICHEN, ZHENGXIA
Owner WUXI APPTEC BVI INC
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