Pfizer’s PF 04937319 glucokinase activators for the treatment of Type 2 diabetes

PF 04937319
N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide
MW 432.43

MF C₂₂ H₂₀ N₆ O₄

CAS 1245603-92-2

2-​Pyrimidinecarboxamid​e, N,​N-​dimethyl-​5-​[[2-​methyl-​6-​[[(5-​methyl-​2-​pyrazinyl)​amino]​carbonyl]​-​4-​benzofuranyl]​oxy]​-

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide

Pfizer Inc. clinical candidate currently in Phase 2 development.

CLINICAL TRIALS

A trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of PF-04937319 in subjects with type 2 diabetes mellitus (NCT01044537)

Multiple dose study of PF-04937319 in patients with type 2 diabetes (NCT01272804)

Phase 2 study to evaluate safety and efficacy of investigational drug – PF04937319 in patients with type 2 diabetes (NCT01475461)

SYNTHESIS

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.


Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type Il diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM. As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.
It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity. Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type 2 diabetes and the metabolic syndrome” Nature 414; 821 -827, (2001 )): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents. Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.
Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication No’s. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus

Jeffrey A. Pfefferkorn,*^a   et al

*Corresponding authors

^aPfizer Worldwide Research & Development, Eastern Point Road, Groton
E-mail: jeffrey.a.pfefferkorn@pfizer.com
Tel: +860 686 3421

Med. Chem. Commun., 2011,2, 828-839

DOI: 10.1039/C1MD00116G

http://pubs.rsc.org/en/content/articlelanding/2011/md/c1md00116g/unauth#!divAbstract
http://www.rsc.org/suppdata/md/c1/c1md00116g/c1md00116g.pdf

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as an early development candidate.

N,N-Dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)-benzofuran-4- yloxy)pyrimidine-2-carboxamide (28). To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethoxyethane (315 mL) in a 3-neck flask equipped with overhead stirring and a condenser at 0 o C was added Me2AlCl (1 M solution in hexanes) (715 mL). The mixture was warmed to room temperature and stirred for 1.5 h. In a separate flask, 26 (52.6 g, 142.5 mmol) was dissolved in dimethoxyethane (210 mL). This mixture was then added to the amine mixture. A gum precipitated and upon scratching the flask it dissipated into a solid. The reaction was refluxed for 3.5 h. Aq. Rochelle’s salt (5 L) and 2-MeTHF (2 L) was added to the mixture and this was allowed to stir with overhead stirring for 14 h, after which time, a yellow solid precipitated. The solid was collected by filtration, washing with 2-MeTHF. The resulting solid was dried in a vacuum oven overnight to afford the desired material (50.0g) in 81% yield.
1 H NMR (400MHz, CDCl3) δ 9.54 (d, J = 1.56 Hz, 1H), 8.50 (s, 2H), 8.37 (s, 1H), 8.14 (d, J = 0.78 Hz, 1H), 7.88 – 7.92 (m, 1H), 7.52 (d, J = 1.37 Hz, 1H), 6.28 (t, J = 0.98 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 2.55 (s, 3H), 2.49 (d, J = 1.17 Hz, 3H);
MS(ES+ ): m/z 433.4 (M+1), MS(ES- ): m/z 431.3 (M-1).

PAPER

http://pubs.rsc.org/en/content/articlelanding/2013/md/c2md20317k#!divAbstract

PAPER
Bioorganic & Medicinal Chemistry Letters (2013), 23(16), 4571-4578
http://www.sciencedirect.com/science/article/pii/S0960894X13007452

Figure 1.

Glucokinase activators 1 and 2.

PATENT

Pfizer Inc.
WO 2010103437
https://www.google.co.in/patents/WO2010103437A1?cl=en
Scheme I outlines the general procedures one could use to provide compounds of the present invention having Formula (I).

Preparations of Starting Materials and Key Intermediates
Preparation of Intermediate (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but- 3-enoic acid (I- 1a):

(Ma) To a vigorously stirred solution of 5-methyl-2-furaldehyde (264 ml_, 2650 mmol) and diethyl succinate (840 ml_, 5050 mmol) in ethanol (1.820 L) at room temperature was added sodium ethoxide (0.93 L of a 21 weight % solution in ethanol) in one portion. The reaction mixture was then heated at reflux for 13 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was partitioned between ethyl acetate (1 L) and hydrochloric acid (1 L of a 2M aqueous solution). After separation, the aqueous layer was extracted with ethyl acetate (2 x 1 L). The combined organic extracts were then extracted with sodium hydrogen carbonate (2 x 1 L of a saturated aqueous solution). These aqueous extracts were combined and adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give desired (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (J₁ Ia: 34.34 g, 5%). The original organic extract was extracted with sodium hydroxide (2 L of a 2M aqueous solution). This aqueous extract was adjusted to pH 2 with hydrochloric acid (2M aqueous solution) then extracted with ethyl acetate (2 x 1 L). These organic extracts were combined and concentrated in vacuo to give additional desired materials (395.2 gram, 63%) as red liquid. ¹H NMR (CDCI₃, 300 MHz) δ ppm 7.48 (s, 1 H), 6.57 (d, 1 H), 6.09 (d, 1 H), 4.24 (q, 2H), 3.87 (s, 2H), 2.32 (s, 3H), 1.31 (t, 3H).
Preparation of Intermediate ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (1-1 b):

(M b) To a vigorously stirred solution of (E)-3-(ethoxycarbonyl)-4-(5- methylfuran-2-yl)but-3-enoic acid (1-1 a: 326.6 g, 1 .371 mol) in acetic anhydride (1 .77 L, 18.72 mol) at room temperature was added sodium acetate (193 g, 2350 mmol) in one portion. The reaction mixture was then heated at reflux for 2.5 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was suspended in dichloromethane (1 .5 L) and filtered, washing the solids with dichloromethane (3 x 500 ml_). The combined filtrate and washings were then washed with sodium hydrogencarbonate (2 x 1 L of a saturated aqueous solution) and brine (2 L), then concentrated in vacuo to give desired ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (H b: 549.03 g, quantitative). ¹H NMR (CDCI₃, 300 MHz) δ ppm 8.00-7.99 (m, 1 H), 7.64 (d, 1 H), 6.32-6.32 (m, 1 H), 4.38 (q, 2H), 2.47 (d, 3H), 2.37 (s, 3H), 1 .39 (t, 3H).
Preparation of Intermediate ethyl 4-hydroxy-2-methylbenzofuran-6- carboxylate (1- 1 c):

(He) To a stirred solution of ethyl 4-acetoxy-2-methylbenzofuran-6- carboxylate (Hb: 549.03 g, 1 .37 mol) in ethanol (4.00 L) at room temperature was added potassium carbonate (266 g, 1 .92 mol) in one portion. The reaction mixture was then heated at 60⁰C for 3 hours. Potassium carbonate (100 g, 0.720 mol) was then added in one portion and the reaction mixture was heated at 60⁰C for a further 3 hours. After cooling to room temperature the mixture was diluted with dichloromethane (2 L) and the suspension filtered, washing the solids with dichloromethane (2 x 1 L) (all batches were combined at this point). The combined filtrate and washings were then washed with citric acid (2.5 L of a 1 M aqueous solution), then concentrated in vacuo and the resulting residue purified by dry flash chromatography (hexane then 2:1 hexane:ethyl acetate). All fractions containing the desired product were combined and concentrated in vacuo. The resulting residue, which solidified on standing, was slurried with cold toluene and filtered. The solids were then stirred with hot toluene and decolourising charcoal for 1 hour, followed by filtration of the hot mixture through a pad of celite. The filtrate was allowed to cool and the resulting precipitate isolated by filtration to give desired ethyl 4-hydroxy-2- methylbenzofuran-6-carboxylate (1-1 c: 360 g, 90%) as orange powder.
¹H NMR (CDCI₃, 300 MHz) δ ppm 7.73-7.73 (m, 1 H), 7.45 (d, 1 H), 6.51 -6.50 (m, 1 H), 5.85 (s, 1 H), 4.39 (q, 2H), 2.48 (d, 3H), 1.40 (t, 3H). LCMS (liquid chromatography mass spectrometry): m/z 221.06 (96.39 % purity).


Preparation of SM-25-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-
£1:

(SM-2) Oxalyl chloride (47.4g, 369mmol) was added to a suspension of 5-
Bromo-pyrimidine-2-carboxylic acid (5Og, 250mmol) in dichloromethane (821 ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture. The acid dissolved after 30 minutess. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 100%). The 5-Bromo-pyrimidine-2-carbonyl chloride (55g, 250mmol) was dissolved in tetrahydrofuran (828ml) and dimethyl-amine (2M solution in tetrahydrofuran) (373ml, 745mmol) was added portionwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500ml) and washed with H₂O (500ml). The water layer was further extracted with CH₂CI₂ (5x500ml), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated in vacuo and then suspended in methyl-/-butylether (650ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-t-butylether (100ml) the solid was dried in a vacuum oven at 55⁰C for 12 hourrs to afford the title compound 5-bromo-N,N-dimethylpyhmidine-2-carboxamide (SM-2: 44g, 77%) as a pink solid.
¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.94 (s, 3 H) 3.13 (s, 3 H) 8.85 (s, 2 H) m/z (M+1 ) = 232.
Preparation of Intermediate Ethyl 4-(2-(dimethylcarbamoyl)Dyrimidin-5- yloxy)-2-methylbenzofuran-6-carboxylate (l-2a):

A mixture of Cs₂CO₃ (62.1 g, 191 mmol), 5-bromo-N,N- dimethylpyrimidine-2-carboxamide (SM-2: 24g, 104mmol) and ethyl 4- hydroxy-2-methylbenzofuran-6-carboxylate (1-1 c: 2Og, 91 mmol); 1 ,10- phenanthroline (1.64g, 9.07mmol) and copper iodide (864mg, 4.54mmol) in dimethylformamide (200ml) was purged with N₂ gas and then heated to 90°C using a mechanical stirrer. The heterogeneous reaction mixture was stirred at this temperature for 18 hours. HPLC indicated near completion. The reaction mixture was cooled to 35⁰C and diluted with ethyl acetate (300ml). The mixture was filtered to remove any cesium carbonate. The filtrate was then partitioned between water (500ml) and ethyl acetate (500ml); however, no separation was observed. Concentrated HCL (20ml) was added to the mixture. When the aqueous phase was about pH1 , the phases separated. The organics were separated and the aqueous layer reextracted with ethyl acetate (2x500ml). All organics were combined and back extracted with water (200ml) and brine (500ml). The organics were separated and treated with activated charcoal (10g) and magnesium sulfate. The mixture was allowed to stir for 10 minutes and then filtered through a plug of celite to afford a crude yellow solution. The filter cake was washed with ethyl acetate (100 ml_). The organics were concentrated in vacuo to afford a crude solid this was dried under high vacuum for 4 days. The dry crude solid was triturated using methanol (80 ml_). The solids were dispersed into a fine light orange crystalline powder with a red liquor. The solids were isolated by filtration and rinsed with methanol (20 ml_). The solid was dried in the vacuum oven at 55⁰C for 12 hours to afford ethyl 4-(2- (dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (J₁ 2a) as a yellow solid (18.2g, 54%)
¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.12 Hz, 3 H) 2.50 (d, J=0.98 Hz, 3 H) 3.00 (s, 3 H) 3.17 (s, 3 H) 4.41 (d, J=7.22 Hz, 2 H) 6.29 (s, 1 H) 7.62 (d, J=1.17 Hz, 1 H) 8.06 (s, 1 H) 8.50 (s, 2 H). m/z (M+1 ) = 370.5
Preparation of Starting material 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3):

(SM-3) Oxalyl chloride (1 .45g, 1 1 .1 mmol) was added to a suspension of 5-
Bromo-pyrimidine-2-carboxylic acid (1 .5g, 7.4mmol) in dichloromethane (50ml) at room temperature followed by 1 -2 drop of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours LCMS in methanol indicated the presence of the methyl ester and some acid. Dimethylformamide (0.2ml) was added to the reaction mixture and all of the acid dissolved after 30 minutes. LCMS showed corresponding methyl ester and no starting material peak was observed. The solvent was removed and dried in vacuo to afford the crude 5-Bromo-pyrimidine-2-carbonyl chloride (1 -6g). 5-Bromo-pyrinnidine-2-carbonyl chloride (1600mg, 7.225mnnol) was dissolved in dichloromethane (25ml) and triethylamine (4.03ml, 28.9mmol) was added followed by ethyl-methyl-amine (0.68 mL, 7.92 mmol). The reaction was stirred at room temperature under nitrogen for 16 ours, after which time, LCMS indicated completion. The mixture was diluted with dichloromethane (50ml) and washed with water (50ml) followed by 10% citric acid (50ml) and brine (50ml). The organic layer was separated and dried over MgSO4, the residue was filtered and the solvent was removed in vacuo to afford the title compound 5-bromo-N-ethyl-N-methylpyrimidine-2- carboxamide (SM-3): (1.4g, 79.4%) as a brown oil.
¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 – 1.31 (m, 3 H) 2.99 (d, J=79.05 Hz, 3 H) 3.19 (q, J=7.22 Hz, 1 H) 3.59 (q, J=7.22 Hz, 1 H) 8.84 (d, J=3.12 Hz, 2 H)
Example 2
Preparation of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2- yl)carbamoyl)-benzofuran-4-yloxy)Dyrimidine-2-carboxamide (2):

(2)
To a solution of the 5-methyl-2-aminopyrazine (38.9 g, 356 mmol) in dimethylether (315 ml_) in a 3-neck flask equipped with overhead stirring and a condensor at O⁰C was added Me2AICI (1 M solution in hexanes) (715 ml_). The mixture was warmed at room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2- methylbenzofuran-6-carboxylate (l-2a: 52.6g, 142.5mmol) was dissolved in dimethylether (210 ml_). This mixture was then added to the complexed amine. A gum precipitated upon scratching the flask and dissipated into a solid. The resultant reaction was refluxed for 3.5 hours HPLC indicated 93% complete. Five liters of Rochelles salt made up in water and 2 liters of 2- methyltetrahydrofuran was added to the mixture. The reaction mixture was then poured into the biphasic system. The mixture was allowed to stir with overhead stirring for 14 hours, after which time, a yellow solid precipitated. The solid was collected through filteration. The solid retained was washed with 2-methyltetrahydrofuran. The resultant solid was dried in vacuo oven overnight to afford the title compound N,N-dimethyl-5-(2-methyl-6-((5- methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyhmidine-2-carboxamide (2): (49.98g, 81 %)
1H NMR (400 MHz, CHLOROFORM-d) d ppm 2.49 (d, J=1 .17 Hz, 3H) 2.55 (s, 3H) 2.98 (s, 3 H) 3.14 (s, 3 H) 6.28 (t, J=0.98 Hz, 1 H) 7.52 (d, J=1 .37 Hz, 1 H) 7.88 – 7.92 (m, 1 H) 8.14 (d, J=0.78 Hz, 1 H) 8.37 (s, 1 H) 8.50 (s, 2 H) 9.54 (d, J=1 .56 Hz, 1 H).
m/z (M+1 ) = 433.4, m/z (M-1 )= 431 .5

REFERENCES

Beebe, D.A.; Ross, T.T.; Rolph, T.P.; Pfefferkorn, J.A.; Esler, W.P.
The glucokinase activator PF-04937319 improves glycemic control in combination with exercise without causing hypoglycemia in diabetic rats
74th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 13-17, San Francisco) 2014, Abst 1113-P

Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A.
Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes
Diabetes Obes Metab 2015, 17(8): 751

Study to compare single dose of three modified release formulations of PF-04937319 with immediate release material-sparing-tablet (IR MST) formulation previously studied in adults with type 2 diabetes mellitus (NCT02206607)
OTHERS

///////////Pfizer , PF 04937319,  glucokinase activators,  Type 2 diabetes

Pfizer’s PF 04991532 a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus

PF 04991532
GKA PF-04991532
(S)-6-{3-cyclopentyl-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamido}nicotinic acid
(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid
(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid
MW 396.36, MF C₁₈ H₁₉ F₃ N₄ O₃
CAS 1215197-37-7
3-​Pyridinecarboxylic acid, 6-​[[(2S)​-​3-​cyclopentyl-​1-​oxo-​2-​[4-​(trifluoromethyl)​-​1H-​imidazol-​1-​yl]​propyl]​amino]​-
http://www.biochemj.org/content/441/3/881
Type 2 diabetes mellitus (T2DM) is a rapidly expanding public epidemic affecting over 300 million people worldwide. This disease is characterized by elevated fasting plasma glucose (FPG), insulin resistance, abnormally elevated hepatic glucose production (HGP), and reduced glucose-stimulated insulin secretion (GSIS). Moreover, long-term lack of glycemic control increases risk of complications from neuropathic, microvascular, and macrovascular diseases.
The standard of care for T2DM is metformin followed by sulfonylureas, dipeptidyl peptidase-4 (DPP-IV) inhibitors, and thiazolidinediones (TZD) as second line oral therapies. As disease progression continues, patients typically require injectable agents such as glucagon-like peptide-1 (GLP-1) analogues and, ultimately, insulin to help maintain glycemic control. Despite these current therapies, many patients still remain unable to safely achieve and maintain tight glycemic control, placing them at risk of diabetic complications and highlighting the need for novel therapeutic options.

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia.
While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index.

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose levels. Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. Aggressive control of NIDDM with medication is essential; otherwise it can progress into IDDM.
As blood glucose increases, it is transported into pancreatic beta cells via a glucose transporter. Intracellular mammalian glucokinase (GK) senses the rise in glucose and activates cellular glycolysis, i.e. the conversion of glucose to glucose-6-phosphate, and subsequent insulin release. Glucokinase is found principally in pancreatic β-cells and liver parenchymal cells. Because transfer of glucose from the blood into muscle and fatty tissue is insulin dependent, diabetics lack the ability to utilize glucose adequately which leads to undesired accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia leads to decreases in insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in hepatic parenchymal cells which induces glycogen synthesis, thus preventing the release of glucose into the blood. The GK processes are thus critical for the maintenance of whole body glucose homeostasis.
It is expected that an agent that activates cellular GK will facilitate glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization and potentially inhibit hepatic glucose release. Consequently, a GK activator may provide therapeutic treatment for NIDDM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity.
Several drugs in five major categories, each acting by different mechanisms, are available for treating hyperglycemia and subsequently, NIDDM (Moller, D. E., “New drug targets for Type II diabetes and the metabolic syndrome” Nature 414; 821-827, (2001)): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents.
Ideally, an effective new treatment for NIDDM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially replace insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in combination with tolerable amounts of any of the categories of drugs listed herein.
Substituted heteroaryls, particularly pyridones, have been implicated in mediating GK and may play a significant role in the treatment of NIDDM. For example, U.S. Patent publication No. 2006/0058353 and PCT publication Nos. WO2007/043638, WO2007/043638, and WO2007/117995 recite certain heterocyclic derivatives with utility for the treatment of diabetes. Although investigations are on-going, there still exists a need for a more effective and safe therapeutic treatment for diabetes, particularly NIDDM.

PATENT

US 20100063063
http://www.google.com/patents/US20100063063
SYNTHESIS CONSTRUCTION

6-aminonicotinic acid


BENZYL BROMIDE


FIRST KEY INTERMEDIATE

SECOND SERIES FOR NEXT INTERMEDIATE 

(R)-2-amino-3-cyclopentylpropanoic acid


(R)-methyl 3-cyclopentyl-2-hydroxypropanoic acid (I-1a)


(R)-methyl 3-cyclopentyl-2-hydroxypropanoate (I-1b)

Trifluoromethanesulfonic acid anhydride



(R)-methyl 3-cyclopentyl-2-(trifluoromethylsulfonyloxy)propanoate (I-1c)


CONDENSED WITH

4-Trifluoromethyl-1H-imidazole
TO  GIVE PRODUCT SHOWN BELOW


(S)-methyl 3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)




(S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoic acid (I-8b)



CONVERTED TO ACID CHLORIDE, (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoyl chloride (I-8c)
AND CONDENSED WITH

WILL GIVE BENZYL DERIVATIVE AS BELOW


THEN DEBENZYLATION TO FINAL PRODUCT


Intermediate: (R)-methyl 3-cyclopentyl-2-hydroxypropanoic acid (I-1a)

To a stirred solution of (R)-2-amino-3-cyclopentylpropanoic acid (5.0 grams; Chem-Impex International, Inc., Wood Dale, Ill.) and 1 M H₂SO₄ (45.1 mL) at 0° C., was added a solution of NaNO₂ (3.12 g) in H₂O (15.6 mL) drop wise over 10 minutes. The reaction mixture was stirred for 3 hours at 0° C., then for 2 hours at room temperature. The solution was then extracted (3 times) with diethyl ether. The combined organic extracts were dried over MgSO₄, filtered, and the filtrate concentrated to afford 2.36 g of (I-1a). ¹H NMR (400 MHz, CDCl₃) δ 4.26-4.28 (1H), 1.99-2.07 (1H), 1.76-1.81 (4H), 1.60-1.62 (4H), 1.12-1.16 (2H); LCMS for C₈H₁₄O₃ m/z 157.1 (M−H)⁻.
Intermediate: (R)-methyl 3-cyclopentyl-2-hydroxypropanoate (I-1b)

To a stirred solution of 2.36 g of (I-1a) in anhydrous methanol (15 mL) at room temperature was added SOCl₂(1.64 mL). The resulting mixture was heated at reflux for 2 hours. It was then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO₃ solution. The biphasic mixture was separated and the aqueous portion was extracted with ethyl acetate. The combined extracts were dried over MgSO₄, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, heptanes/ethyl acetate) to afford 1.5 g of (I-1b) as a clear oil.¹H NMR (400 MHz, CDCl₃) δ 4.15-4.20 (1H), 3.77 (3H), 2.62-2.63 (1H), 1.97-2.05 (1H), 1.49-1.86 (8H), 1.06-1.17 (2H); LCMS for C₉H₁₆O₃ m/z 171.6 (M)⁺. Intermediate (I-1b) can alternatively be prepared by the method described below.
A 0.2M solution of Li₂CuCl₄ was prepared as follows: Anhydrous CUCl₂ (26.9 g, 200 mol) and anhydrous LiCl (17.0 g, 400 mmol) were dissolved in THF (1000 mL). The mixture required gentle heating to completely dissolve the solids. After cooling the solution is ready for use.
A solution of Li₂CuCl₄ (0.2 M in THF, 125 mL, 25.0 mmol) was added slowly to a suspension of cyclopentylmagnesium bromide (2 M in diethyl ether, 135 mL, 270 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) and THF (500 mL) at −50° C. over 2-3 mins. The pale grey/brown suspension was then allowed to warm slowly to −10° C. over 30 mins, by which time the color had developed to a dark grey. The mixture was re-cooled to −78° C. and (R)-methyl oxirane-2-carboxylate (25.0 g, 245 mmol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added neat via syringe over 90 seconds. The reaction was then stirred at −78° C. for 20 mins, before removing the ice-bath and allowing to warm to approximately −50° C. over 30 mins. Saturated NH₄Cl (aq, 700 mL) was then added and the mixture stirred for 30 mins. The organic layer was collected and the aqueous layer extracted with diethyl ether (2×250 mL). The combined organics were washed with saturated NH₄Cl (aq, 350 mL), dried over MgSO₄, and evaporated. Distillation of the crude residue (68-70° C. at 0.8 mbar) yielded 65-70% of (I-1b) as a pale yellow oil. A small amount of less volatile material remained in the still pot. ¹H NMR (400 MHz; CDCl₃): δ 4.17(1H), 3.76 (3H), 2.67 (1H), 2.01 (1H), 1.48-1.88 (8H), 1.11 (2H).
Intermediate: (R)-methyl 3-cyclopentyl-2-(trifluoromethylsulfonyloxy)propanoate (I-1c)
Intermediate: (R)-methyl 3-cyclopentyl-2-(trifluoromethylsulfonyloxy)propanoate (I-1c
Intermediate (I-1b) (6.37 g, 37.0 mmol) was dissolved in dry dichloromethane (260 mL) and stirred under nitrogen in an ice bath. 2,6-Lutidine (9.0 mL, 77 mmol) was added. Trifluoromethanesulfonic acid anhydride (11 mL, 65 mmol) in dry dichloromethane (75 mL) was added dropwise. The reaction was stirred in the ice bath for 60 minutes, concentrated under reduced pressure, and taken up in 1N HCl and methyl t-butyl ether. The aqueous layer was separated, and the organic layer was washed with additional 1N HCl to insure the removal of all the lutidine. The combined organic layer was then washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford (I-1c) (11.3 g, 37 mmol, 100%), which was used immediately without further purification; ¹H NMR (400 MHz, CDCl₃) δ 5.10-5.14 (1H), 3.82 (3H), 2.02-2.12 (1H), 1.79-1.98 (4H), 1.51-1.66 (4H), 1.08-1.18 (2H).
Intermediate (I-1b) (6.37 g, 37.0 mmol) was dissolved in dry dichloromethane (260 mL) and stirred under nitrogen in an ice bath. 2,6-Lutidine (9.0 mL, 77 mmol) was added. Trifluoromethanesulfonic acid anhydride (11 mL, 65 mmol) in dry dichloromethane (75 mL) was added dropwise. The reaction was stirred in the ice bath for 60 minutes, concentrated under reduced pressure, and taken up in 1N HCl and methyl t-butyl ether. The aqueous layer was separated, and the organic layer was washed with additional 1N HCl to insure the removal of all the lutidine. The combined organic layer was then washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford (I-1c) (11.3 g, 37 mmol, 100%), which was used immediately without further purification; ¹H NMR (400 MHz, CDCl₃) δ 5.10-5.14 (1H), 3.82 (3H), 2.02-2.12 (1H), 1.79-1.98 (4H), 1.51-1.66 (4H), 1.08-1.18 (2H)
Intermediate: (S)-methyl 3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoate (I-8a)

4-Trifluoromethyl-1H-imidazole (5.0 g, 37.0 mmol; Apollo Scientific Ltd., Bredbury, Cheshire, UK) was stirred in dry THF (180 mL) under nitrogen at room temperature. Lithium hexamethyldisilazide (1M in THF, 33.4 mL, 33.4 mmol) was added dropwise via addition funnel. The mixture was stirred at room temperature for 50 minutes and then chilled in an ice bath. A solution of (I-1c) (11.3 g, 37 mmol) in dry THF (45 mL), which had been chilled in an ice bath, was added in one portion. The reaction was allowed to warm to room temperature, stirred for 2 hours, quenched with saturated aqueous ammonium chloride solution (20 mL) and allowed to stir overnight. The aqueous layer was separated, and the organic layer was concentrated and then diluted with water and ethyl acetate. The organic layer was washed in series with dilute aqueous phosphoric acid, aqueous 10% potassium carbonate, and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to a brown oil. The crude material, containing the undesired regioisomer as a small impurity, was purified by chromatography on a 330 g pre-packed silica gel column, eluting with 10% ethyl acetate/heptane, linear gradient to 70% ethyl acetate/heptane. The product fractions were located by spotting on a silica TLC plate and visualizing with KMnO₄ stain. TLC (1:1 ethyl acetate/heptane, developed in potassium permanganate) located the pure and mixed fractions. The clean product fractions were combined, evaporated, and dried under high vacuum to afford (I-8a) as a clear oil (6.61 g, 22.4 mmol, 67%). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (1H), 7.38 (1H), 4.71-4.74 (1H), 3.76 (3H), 2.01-2.14 (2H), 1.45-1.79 (7H), 1.03-1.18 (2H); m/z 291.4 (M+H)⁺.
Intermediate: (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoic acid (I-8b
6N HCl (140 mL) was added to (I-8a) (6.61 g, 22.4 mmol) and the mixture was warmed to 95° C. for 16 hours and then allowed to cool. Solid potassium carbonate (58 g) was added in portions to bring the pH to about 4. A precipitate crashed out. Ethyl acetate was added, and the mixture was stirred until everything dissolved. The aqueous layer was extracted once with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford (I-8b) as a clear glass (6.15 g, 21.9 mmol, 98%). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (1H), 7.34 (1H), 6.85-7.15 (1H), 4.66-4.70 (1H), 1.98-2.17 (2H), 1.41-1.75 (7H), 1.01-1.19 (2H); m/z 277.4 (M+H)⁺.
Intermediate: (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoyl chloride (I-8c)

To a suspension of intermediate (I-8b) (0.25 g, 0.9 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.35 g, 2.7 mmol) and N,N-dimethylformamide (1 drop) at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo, and the residue was chased with dichloromethane two times and concentrated in vacuo to afford (I-8c) (0.27 g, 100%) as an oil, which was used in the next step directly.
Intermediate: (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido) nicotinoyl chloride (I-21a)

• 

  Thionyl chloride (225 mg, 1.89 mmol) was added to a solution of the compound of Example 48 (150 mg, 0.387 mmol) in dichloromethane (1.5 mL) and the reaction stirred at room temperature for 1 hour. LCMS of an aliquot in methanol showed ˜67% methyl ester. To the reaction mixture was added another 25 uL of thionyl chloride and this was stirred at room temp for another 30 minutes. Solvents were evaporated to afford 157 mg (100%) of (I-21a) as a grayish-white solid. LCMS in methanol to generate the methyl ester gave m/z 395.9 (M+H)⁺.

(I-8b
Intermediate: (S)-3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanoic acid (I-8b)
6N HCl (140 mL) was added to (I-8a) (6.61 g, 22.4 mmol) and the mixture was warmed to 95° C. for 16 hours and then allowed to cool. Solid potassium carbonate (58 g) was added in portions to bring the pH to about 4. A precipitate crashed out. Ethyl acetate was added, and the mixture was stirred until everything dissolved. The aqueous layer was extracted once with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford (I-8b) as a clear glass (6.15 g, 21.9 mmol, 98%). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (1H), 7.34 (1H), 6.85-7.15 (1H), 4.66-4.70 (1H), 1.98-2.17 (2H), 1.41-1.75 (7H), 1.01-1.19 (2H); m/z 277.4 (M+H)⁺.
(I-28a
Intermediate: benzyl 6-aminonicotinate (I-28a)

To a stirred suspension of 6-aminonicotinic acid (100 g, 0.72 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in N,N-dimethylformamide (700 mL) with brisk mechanical stirring was added potassium carbonate (150 g, 1.08 mol) and the reaction was stirred for 10 min before the portionwise addition of benzyl bromide (95 mL, 0.80 mol). The reaction was stirred at room temperature overnight, then the solids were filtered off and washed thoroughly with ethyl acetate, and the solvent was removed under vacuum. The filter cake was dissolved in water and extracted with ethyl acetate. The residue after evaporation of N,N-dimethylformamide was combined with the ethyl acetate extracts (total volume 2 L of ethyl acetate) and the combined organic extracts washed with brine (5×500 mL), dried (MgSO₄) and the solvent removed under reduced pressure. The crude product was refluxed with 1:1 diethyl ether:hexane for 30 min then the solids filtered off (warm), washed with diethyl ether:hexane (1:1), and dried. This solid was precipitated from hot toluene (hot filtration required to remove dibenzylated material) and dried to afford (I-28a) (107.2 g, 65%) as an off-white solid; ¹H NMR (DMSO-d₆): δ 8.50 (1H), 7.82 (1H), 7.34-7.29 (5H), 6.84 (2H), 6.43 (1H), 5.23 (2H); m/z 229.4 (M+H)⁺.
Example 47
(S)-benzyl 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinate
Formula (1A-4) wherein R⁴ is

To Intermediate (I-8b) (16.28 g, 59.8 mmol) stirring in dry dichloromethane (400 mL) at room temperature under nitrogen was added 2 drops of DMF. Oxalyl chloride (11 mL, 130 mmol) was added dropwise. After the bubbling subsided the reaction was left stirring for 90 minutes and then concentrated under reduced pressure. Two successive portions of 1,2-dichloroethane were added and evaporated to remove all excess oxalyl chloride. The crude acid chloride was taken up in dichloromethane (150 mL) and stirred at room temperature. Intermediate (I-28a) (14.3 g, 62.5 mmol) and pyridine (10 mL, 130 mmol) were stirred in 400 mL dry dichloromethane. This was added to the acid chloride solution, using another 50 mL dry dichloromethane to complete the transfer. The mixture was left stirring at room temperature under nitrogen for 18 hours. The reaction was diluted with dichloromethane and water, and 1M aqueous phosphoric acid was added. The organic layer was separated and washed sequentially with dilute aqueous potassium carbonate, and brine. This was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to a glass, which was taken up in hot ethyl acetate and stirred at room temperature. A precipitate appeared at about 30 minutes. The mixture was stirred for 16 hours and then filtered. The precipitate was washed with ethyl acetate and then diethyl ether and dried under high vacuum at 60° C. to afford the title compound as a white solid (17.8 g, 36.6 mmol, 61%). The mother liquor was evaporated and purified by silica gel chromatography on a 120 g pre-packed column, eluting with 40% ethyl acetate/heptane. The product fractions were combined, concentrated under reduced pressure, dried under high vacuum to a glass, and converted as previously described to additional product (3.5 g, 7.2 mmol, 12%, total yield 73%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (1H), 8.87-8.88 (1H), 8.29-8.32 (1H), 8.12-8.14 (1H), 7.93-7.94 (2H), 7.39-7.46 (2H), 7.30-7.37 (3H), 5.32 (2H), 5.21-5.25 (1H), 2.06-2.19 (2H), 1.26-1.63 (8H), 1.01-1.06 (1H); m/z 487.5 (M+H)⁺.
Example 48
(S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid
Formula (1A-4) wherein R⁴ is

The compound of Example 47 (4.07 g, 8.35 mmol) was added to a 500 mL Parr bottle, followed by ethyl acetate (50 mL) and ethanol (100 mL). The mixture was warmed until all of the solid dissolved, and then cooled to room temperature. 10% Pd/C (450 mg) was added, and the mixture was shaken under 50 psi hydrogen for 90 minutes. The reaction was filtered through a microfiber filter. The filtrate was concentrated under reduced pressure and dried under high vacuum at 50° C. to afford product as a glassy solid (3.0 g, 7.75 mmol, 90.6%). The glassy solid was stirred overnight in diethyl ether. The white solid precipitate was filtered, washed with diethyl ether, suction dried, and dried under high vacuum at 50° C. to afford the title compound as a white solid.
¹H NMR (400 MHz, DMSO-d₆) δ 13.10-13.25 (1H), 11.44 (1H), 8.83 (1H), 8.23-8.26 (1H), 8.09-8.12 (1H), 7.94-7.95 (2H), 5.22-5.26 (1H), 2.06-2.17 (2H), 1.29-1.64 (8H), 1.04-1.07 (1H);
m/z 397.3 (M+H)⁺.

THIS NMR IS FROM SUPPORTING INFO OF A JOURNAL



PAPER
Organic Process Research & Development (2012), 16(10), 1635-1645
http://pubs.acs.org/doi/abs/10.1021/op300194c

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid (1)

Pressure Hydrogenation

 1 (89% yield) as a white solid:

mp 187–189 °C;

¹H NMR (400 MHz, d₆-DMSO) δ 13.23 (s, 1H), 11.49 (s, 1H), 8.86 (dd, J = 0.4, 2.4 Hz, 1H), 8.27 (dd, J = 2.4, 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.97–7.99 (m, 2H), 5.27 (dd, J = 5.6, 10.0 Hz, 1H), 2.20 (ddd, J = 6.0, 10.0, 14.0, 1H), 2.10 (ddd, J = 5.6, 8.4, 14.0, 1H), 1.27–1.69 (m, 8H), 1.03–1.12 (m, 1H);

¹³C NMR (100 MHz, d₆-DMSO) δ 168.8, 165.7, 154.3, 149.7, 139.6, 138.8, 129.9 (q, J_CF = 38 Hz), 122.6, 122.0 (q, J_CF = 265 Hz), 120.0 (q, J_CF = 4 Hz), 112.8, 60.0, 37.6, 36.2, 32.0, 30.8, 24.6, 24.4;

¹⁹F NMR (376 MHz, d₆-DMSO) δ −60.7.

HRMS-ESI m/z: [M + H]⁺ calcd for C₁₈H₁₉F₃N₄O₃, 397.1482; found, 397.1481.

Achiral HPLC: rt 4.6 min. Chiral SFC: rt 4.1 min (1), 3.1 min (ent-1).

NMR……..http://pubs.acs.org/doi/suppl/10.1021/op300194c/suppl_file/op300194c_si_001.pdf

PAPER

Journal of Medicinal Chemistry (2012), 55(3), 1318-1333
http://pubs.acs.org/doi/abs/10.1021/jm2014887

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure–activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid (19)

 afford 19 as a white solid (3.22 g, 71%).

¹H NMR (400 MHz, DMSO-d₆) δ 11.47 (s, 1H), 8.86 (d, J = 1.95 Hz, 1H), 8.27 (dd, J = 2.24, 8.68 Hz, 1H), 8.13 (d, J = 8.78 Hz, 1H), 7.97 (d, J = 4.88 Hz, 2H), 5.27 (dd, J = 5.37, 9.66 Hz, 1H), 2.04–2.26 (m, 2H), 1.38–1.72 (m, 7H), 1.26–1.37 (m, 1H), 1.08 (td, J = 7.88, 11.75 Hz, 1H);

LCMS m/z 397.5 (M + H)⁺.

HPLC purity (method A): t_R = 7.690 min, 100%.

PAPER

Bioorganic & Medicinal Chemistry Letters (2013), 23(24), 6588-6592
http://www.sciencedirect.com/science/article/pii/S0960894X13012638

Figure 1.

Structure of Hepatoselective GKA PF-04991532 (1).

References

Drug Metabolism & Disposition (2015), 43(2), 190-198
PLoS One (2014), 9(5), e97139/1-e97139/9,
Journal of Biological Chemistry (2012), 287(17), 13598-13610
Drug Discovery Today (2012), 17(9-10), 528-529
Biochemical Journal (2012), 441(3), 881-887.

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Figure 1. Representative structures of glucokinase activators.