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ERTUGLIFLOZIN, PFIZER

THERAPEUTIC CLAIM Treatment of type 2 diabetes
CHEMICAL NAMES
1. β-L-Idopyranose, 1,6-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-5-C-(hydroxymethyl)-
2. (1S,2S,3S,4R,5S)-5-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

PF-04971729, MK 8835

M. Wt: 436.88
Formula: C22H25ClO7
CAS No:. 1210344-57-2

Diabetes looms as a threat to human health worldwide. As a result, considerable research efforts are devoted to identify new and efficacious anti-diabetic agents lacking the side effects associated with some of the current drugs (hypoglycemia, weight gain).Inhibition of sodium-dependent glucose cotransporter 2 (SGLT2), a transporter located in the kidney, is a mechanism that promotes glucosuria and therefore, reduction of plasma glucose concentration. Since the mechanism operates in a glucose-dependent and insulin-independent manner, and is associated with weight loss, it has emerged as a very promising approach to the pathophysiologic treatment of type 2 diabetes. Ertugliflozin (PF-04971729), an anti-diabetic agent currently in development (Phase 3 clinical trials) and belonging to a new class of SGLT2 inhibitors bearing a dioxa-bicyclo[3.2.1]octane bridged ketal motif.

SYNTHESIS

WO2010023594A1

Scheme 1 outlines the general procedures one could use to provide compounds of the present invention.

Figure imgf000012_0001

Scheme 1 AIIyI 2,3,4-tιϊ-O-benzyl-D-glucopyranoside (La, where Pg1 is a benzyl group) can be prepared by procedures described by Shinya Hanashima, et al., in Bioorganic & Medicinal Chemistry, 9, 367 (2001 ); Patricia A. Gent et al. in Journal of the Chemical Society, Perkin 1, 1835 (1974); Hans Peter Wessel in the Journal of Carbohydrate Chemistry, 7, 263, (1988); or Yoko Yuasa, et al., in Organic Process Research & Development, 8, 405-407

(2004). In step 1 of Scheme 1 , the hydroxymethylene group can be introduced onto the glycoside by means of a Swern oxidation followed by treatment with formaldehyde in the presence of an alkali metal hydroxide (e.g., sodium hydroxide). This is referred to as an aldol-Cannizzaro reaction. The Swern oxidation is described by Kanji Omura and Daniel Swern in Tetrahedron, 34, 1651 (1978). Modifications of this process known to those of skill in the art may also be used. For example, other oxidants, like stabilized 2- iodoxybenzoic acid described by Ozanne, A. et al. in Organic Letters, 5, 2903 (2003), as well as other oxidants known by those skilled in the art can also be used. The aldol Cannizzaro sequence has been described by Robert Schaffer in the Journal of The American Chemical Society, 81 , 5452 (1959) and Amigues, E.J., et al., in Tetrahedron, 63,10042 (2007).

In step 2 of Scheme 1 , protecting groups (Pg2) can be added by treating intermediate (MD) with the appropriate reagents and procedures for the particular protecting group desired. For example, p-methoxybenzyl (PMB) groups may be introduced by treatment of intermediate (MD) with p-methoxybenzyl bromide or p-methoxybenzyl chloride in the presence of sodium hydride, potassium hydride, potassium te/t-butoxide in a solvent like tetrahydrofuran, 1 ,2-dimethoxyethane or Λ/,Λ/-dimethylformamide (DMF). Conditions involving para-methoxybenzyltrichloroacetimidate in presence of a catalytic amount of acid (e.g., trifluoromethanesulfonic acid, methanesulfonic acid, or camphorsulfonic acid) in a solvent such as dichloromethane, heptane or hexanes can also be used. Benzyl (Bn) groups may be introduced by treatment of intermediate (MD) with benzyl bromide or benzyl chloride in the presence of sodium hydride, potassium hydride, potassium te/t-butoxide in a solvent like tetrahydrofuran, 1 ,2-dimethoxyethane or Λ/,Λ/-dimethylformamide. Conditions involving benzylthchloroacetimidate in presence of a catalytic amount of acid (e.g., trifluoromethanesulfonic acid, methanesulfonic acid, or camphorsulfonic acid) in a solvent such as dichloromethane, heptane or hexanes can also be used. In step 3 of Scheme 1 , the allyl protection group is removed (e.g., by treatment with palladium chloride in methanol; cosolvent like dichloromethane may also be used; other conditions known by those skilled in the art could also be used, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ) to form the lactol (Ld).

In step 4 of Scheme 1 , oxidation of the unprotected hydroxyl group to an oxo group (e.g., Swern oxidation) then forms the lactone (l-e).

In step 5 of Scheme 1 , the lactone (Le) is reacted with Λ/,O-dimethyl hydroxylamine hydrochloride to form the corresponding Weinreb amide which may exist in equilibrium in a closed/opened form, (l-f/l-g). The “Weinreb amide” (LgJ can be made using procedures well known to those of skill in the art. See, Nahm, S., and S. M. Weinreb, Tetrahedron Letters. 22 (39), 3815-1818 (1981 ). For example, intermediate (l-f/l-α) can be prepared from the commercially available Λ/,O-dimethylhydroxylamine hydrochloride and an activating agent (e.g., trimethylaluminum). In step 6 of Scheme 1 , the arylbenzyl group (Ar) is introduced using the desired organometallic reagent (e.g., organo lithium compound (ArLi) or organomagnesium compound (ArMgX)) in tetrahydrofuran (THF) at a temperature ranging from about -780C to about 2O0C followed by hydrolysis (upon standing in protic conditions) to the corresponding lactol (N) which may be in equilibrium with the corresponding ketone (Ni). The bridged ketal motif found in (A) and (B) can be prepared by removing the protecting groups (Pg2) using the appropriate reagents for the protecting groups employed. For example, the PMB protecting groups may be removed by treatment with trifluoroacetic acid in the presence of anisole and dichloromethane (DCM) at about O0C to about 230C (room temperature). The remaining protecting groups (Pg1) may then be removed using the appropriate chemistry for the particular protecting groups. For example, benzyl protecting groups may be removed by treating with formic acid in the presence of palladium (Pd black) in a protic solvent (e.g., ethanol/THF) at about room temperature to produce the final products (A) and (B). When R1 is CN, the use of a Lewis acid like boron trichloride at a temperature ranging from about -780C to about room temperature in a solvent like dichloromethane or 1 ,2-dichloroethane may also be used to remove benzyl protective and/or para- methoxybenzyl protective groups. When R1 is CN and R2 is (Ci-C4)alkoxy in intermdediate (l-i) or in products (A) or (B), upon treatment with a Lewis acid such as boron trichloride or boron tribomide, partial to complete de-alkylation to the corresponding phenol may occur to lead to the corresponding compound (A) or (B) where R1 is CN and R2 is OH. If this occurs, the (d- C4)alkoxy group may be re-introduced via selective alkylation using a (CrC4) alkyl iodide under mildly basic conditions, for example, potassium carbonate in acetone at a temperature ranging from about room temperature to about 56 degrees Celsius.

When R1 and/or R2 is (CrC4)alkyl-SO2- it is understood by one skilled in the art that the organometallic addition step 6 (Scheme 1 ) will be carried out on the corresponding (d- C4)alkyl-S- containing organometallic reagent. The thio-alkyl is then oxidized at a later stage to the corresponding sulfone using conventional methods known by those skilled in the art.

The compounds of the present invention may be prepared as co-crystals using any suitable method. A representative scheme for preparing such co-crystals is described in Scheme 2.

Figure imgf000016_0001

Scheme 2

In Scheme 2, wherein Me is methyl and Et is ethyl, in step 1 , 1-(5-bromo-2- chlorobenzyl)-4-ethoxybenzene is dissolved in 3:1 , toluene: tetrahydrofuran followed by cooling the resulting solution to <-70°C. To this solution is added hexyllithium while maintaining the reaction at <-65°C followed by stirring for 1 hour. (3R,4S,5R,6R)-3,4,5- ths(thmethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (ll-a) is dissolved in toluene and the resulting solution is cooled to -150C. This solution is then added to the – 7O0C aryllithium solution followed by stirring for 1 hour. A solution of methanesulfonic acid in methanol is then added followed by warming to room temperature and stirring for 16 to 24 hours. The reaction is deemed complete when the α-anomer level is < 3%. The reaction is then basified by the addition of 5 M aqueous sodium hydroxide solution. The resulting salts are filtered off followed by concentration of the crude product solution. 2- methyltetrahydrofuran is added as a co-solvent and the organic phase is extracted twice with water. The organic phase is then concentrated to 4 volumes in toluene. This concentrate is then added to a 5:1 , heptane: toluene solution causing precipitate to form. The solids are collected and dried under vacuum to afford a solid.

In step 2 of Scheme 2, to (ll-b) in methylene chloride is added imidazole followed by cooling to O0C and then addition of trimethylsilylchlohde to give the persilylated product.

The reaction is warmed to room temperature and quenched by the addition of water, and the organic phase is washed with water. This crude methylene chloride solution of (ll-c) is dried over sodium sulfate and then taken on crude into the next step.

In step 3 of Scheme 2, the crude solution of (ll-c) in methylene chloride is concentrated to low volume and then the solvent is exchanged to methanol. The methanol solution of (ll-c) is cooled to O0C, then 1 mol% of potassium carbonate is added as a solution in methanol followed by stirring for 5 hours. The reaction is then quenched by addition of 1 mol% acetic acid in methanol, followed by warming to room temperature, solvent exchange to ethyl acetate, and then filtration of the minor amount of inorganic solids. The crude ethyl acetate solution of (ll-d) is taken directly into the next step.

In step 4 of Scheme 2, the crude solution of (ll-d) is concentrated to low volume, then diluted with methylene chloride and dimethylsulfoxide. Triethylamine is added followed by cooling to 1O0C and then sulfur trioxide pyridine complex is added in 3 portions as a solid at 10 minute intervals. The reaction is stirred an additional 3 hours at 1O0C before quenching with water and warming to room temperature. The phases are separated followed by washing the methylene chloride layer with aqueous ammonium chloride. The crude methylene chloride solution of (ll-e) is taken directly into the next step.

In step 5 of Scheme 2, the crude solution of (ll-e) is concentrated to low volume and then the solvent is exchanged to ethanol. Thirty equivalents of aqueous formaldehyde is added followed by warming to 550C. An aqueous solution of 2 equivalents of potassium phosphate, tribasic is added followed by stirring for 24 hours at 550C. The reaction temperature is then raised to 7O0C for an additional 12 hours. The reaction is cooled to room temperature, diluted with te/t-butyl methyl ether and brine. The phases are separated followed by solvent exchange of the organic phase to ethyl acetate. The ethyl acetate phase is washed with brine and concentrated to low volume. The crude concentrate is then purified by silica gel flash chromatography eluting with 5% methanol, 95% toluene. Product containing fractions are combined and concentrated to low volume.

Methanol is added followed by stirring until precipitation occurs. The suspension is cooled and the solids are collected and rinsed with heptane followed by drying. Product (ll-f) is isolated as a solid.

In step 6 of Scheme 2, compound (ll-f) is dissolved in 5 volumes of methylene chloride followed by the addition of 1 mol% SiliaBonc/® tosic acid and stirring for 18 hours at room temperature. The acid catalyst is filtered off and the methylene chloride solution of (ll-g) is taken directly into the next step co-crystallization procedure.

In step 7 of Scheme 2, the methylene chloride solution of (ll-g) is concentrated and then the solvent is exchanged to 2-propanol. Water is added followed by warming to 550C. An aqueous solution of L-pyroglutamic acid is added followed by cooling the resulting solution to room temperature. The solution is then seeded and granulated for 18 hours. After cooling, the solids are collected and rinsed with heptane followed by drying. Product (ll-h) is isolated as a solid.

An alternative synthesis route for compounds (A) of the present invention is depicted in Scheme 3 and described below.

Figure imgf000019_0001

Scheme 3

The synthesis of (lll-a), where R3 is an alkyl or fluoro substituted alkyl (except for the carbon adjacent to the oxygen atom) can be prepared in a similar way as described in step 1 of Scheme 2. In step 1 of Scheme 3, the primary hydroxyl group is selectively protected by an appropriate protective group. For example, a trityl group (Pg3 = Tr) can be introduced by treatment of intermediate (lll-a) with chlorotriphenylmethane in presence of a base like pyridine in a solvent like toluene, tetrahydrofuran or dichloromethane at a temperature ranging from about 0 degrees Celsius to about room temperature. Additional examples of such protective groups and experimental conditions are known by those skilled in the art and can be found in T. W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991.

In step 2 of Scheme 3, the secondary hydroxyl groups can be protected by the appropriate protecting groups. For example, benzyl groups (Pg4 is Bn) can be introduced by treatment of intermediate (lll-b) with benzyl bromide or benzyl chloride in the presence of sodium hydride, potassium hydride, potassium te/t-butoxide in a solvent like tetrahydrofuran, 1 ,2-dimethoxyethane or Λ/,Λ/-dimethylformamide at a temperature ranging from about 0 degrees Celsius to about 80 degrees Celsius. Acetyl or benzoyl groups (Pg4 = Ac or Bz) may be introduced by treatment of intermediate (lll-b) with acetyl chloride, acetyl bromide or acetic anhydride or benzoyl chloride or benzoic anhydride in the presence of a base like triethylamine, Λ/,Λ/-diisopropylethylamine or 4-

(dimethylamino)pyridine in a solvent like tetrahydrofuran, 1 ,2-dimethoxyethane or dichloromethane at a temperature ranging from about 0 degrees Celsius to about 80 degrees Celsius.

In step 3 of Scheme 3, the primary hydroxyl group is deprotected to lead to intermediate (lll-d). When Pg3 is Tr, intermediate (lll-c) is treated in the presence of an acid like para-toluenesulfonic acid in a alcoholic solvent like methanol at a temperature ranging from about -20 degrees Celsius to about room temperature to provide intermediate (lll-d). Cosolvents like chloroform may be used.

In step 4 of Scheme 3, a hydroxymethylene group is introduced through a process similar to the one already described in Scheme 1 (step 1 ) and Scheme 2 (steps 4 and 5).

Other sources of formaldehyde, like paraformaldehyde in a solvent like ethanol at a temperature ranging from about room temperature to about 70 degrees Celsius in the presence of an alkali metal alkoxide can also be used in this step. When Pg4is Bn, this step provides intermediate (lll-e) and when Pg4 is Ac or Bz, this step provides intermediate (lll-f).

In step 5 of Scheme 3, intermediate (lll-e) is treated with an acid like trifluoroacetic acid or an acidic resin in a solvent like dichloromethane at a temperature ranging from about -10 degrees Celsius to about room temperature to produce intermediate (lll-g).

In step 6 of Scheme 3, the remaining protecting groups (Pg4) may then be removed using the appropriate chemistry for the particular protecting groups. For example, benzyl protecting groups may be removed by treating with formic acid in the presence of palladium (Pd black) in a protic solvent (e.g., ethanol/THF) at about room temperature to produce the final product (A).

In step 7 of Scheme 3, intermediate (lll-f) is treated with an acid like trifluoroacetic acid or an acidic resin in a solvent like dichloromethane at a temperature ranging from about -10 degrees Celsius to about room temperature to produce the final product (A). Another alternative scheme for synthesizing product (A) is depicted in Scheme 4 and described below.

Figure imgf000021_0001

Scheme 4 In step 1 of Scheme 4, intermediate (lll-a) is treated with the appropriate arylsulfonyl chloride R4SO2CI or arylsulfonic anhydride R4S(O)2OS(O)2R4 (wherein R4 is an optionally substituted aryl group, such as found in the arylsulfonyl chlorides 4-methyl-benzenesulfonyl chloride, 4-nitro-benzenesulfonyl chloride, 4-fluoro-benzenesulfonyl chloride, 2,6-dichloro- benzenesulfonyl chloride, 4-fluoro-2-methyl-benzenesulfonyl chloride, and 2,4,6-trichloro- benzenesulfonyl chloride, and in the arylsulfonic anhydride, p-toluenesulfonic anhydride) in presence of a base like pyridine, triethylamine, Λ/,Λ/-diisopropylethylamine in a solvent like tetrahydrofuran, 2-methyltetrahydrofuran at a temperature ranging from about -20 degrees Celsius to about room temperature. Some Lewis acids like zinc(ll) bromide may be used as additives. In step 2 of Scheme 4, intermediate (IV-a) is submitted to a Kornblum-type oxidation

(see, Kornblum, N., et al., Journal of The American Chemical Society, 81 , 4113 (1959)) to produce the corresponding aldehyde which may exist in equilibrium with the corresponding hydrate and/or hemiacetal form. For example intermediate (IV-a) is treated in the presence of a base like pyridine, 2,6-lutidine, 2,4,6-collidine, Λ/,Λ/-diisopropylethylamine, A- (dimethylamino)pyridine in a solvent like dimethyl sulfoxide at a temperature ranging from about room temperature to about 150 degrees Celsius. The aldehyde intermediate produced is then submitted to the aldol/Cannizzaro conditions described for step 1 (Scheme 1 ) and step 5 (Scheme 2) to produce intermediate (IV-b). In step 3 of Scheme 4, intermediate (IV-b) is treated with an acid like thfluoroacetic acid or an acidic resin in a solvent like dichloromethane at a temperature ranging from about -10 degrees Celsius to about room temperature to produce the final product (A).

When R2 is (C2-C4)alkynyl the process may be performed using Scheme 5, wherein R6 is H or (CrC2)alkyl.

Figure imgf000022_0001

Scheme 5

In step 1 of Scheme 5, which provides intermediate (V-i), the organometallic addition step is carried out in a similar way to the one described in Schemel , step 6, using the organometallic reagent derived from (V-a), where Pg5 is a suitable protective group for the hydroxyl group. For instance Pgs can be a te/t-butyldimethylsilyl group (TBS) (see

US2007/0054867 for preparation of for instance {4-[(5-bromo-2-chloro-phenyl)-methyl]- phenoxy}-te/t-butyl-dimethyl-silane).

In step 2 of Scheme 5, when Pg2 = PMB, intermediate (V-i) is treated with an acid like trifluoroacetic acid, methanesulfonic acid or an acidic resin in presence of anisole in a solvent like dichloromethane at a temperature ranging from about -10 degrees Celsius to about room temperature to produce intermediate (V-j).

In step 3 of Scheme 5, protecting groups (Pg5) and (Pg1) can be removed to provide (V-k). Typically (Pg5) is TBS and Pg1 is Bn. In this circumstance, the protecting groups are removed by sequential treatment of (V-j) with 1 ) tetrabutylammonium fluoride in a solvent like tetrahydrofuran or 2-methyltetrahydrofuran at a temperature ranging from 0 degrees

Celsius to about 40 degrees Celsius and 2) treatment with formic acid in the presence of palladium (Pd black) in a protic solvent (e.g., ethanol/THF) at about room temperature. In this sequence, the order of the 2 reactions is interchangeable.

In step 4 of Scheme 5, intermediate (V-k) is treated with N,N-bis- (trifluoromethanesulfonyl)-aniline in presence of a base like triethylamine or 4- dimethyaminopyridine in a solvent like dichloromethane or 1 ,2-dichloroethane at a temperature ranging from 0 degrees Celsius to about 40 degrees Celsius to produce intermediate (V-I).

In step 5 of Scheme 5, intermediate (V-I) is subjected to a Sonogashira-type reaction (see, Sonogashira, K. Coupling Reactions Between sp2 and sp Carbon Centers. In

Comprehensive Organic Synthesis (eds. Trost, B. M., Fleming, I.), 3, 521-549, (Pergamon, Oxford, 1991 )).

WO2010023594A1

Figure imgf000006_0001

IS ERTUGLIFLOZIN

WO2010023594A1

Example 4

(1 S.2S.3S.4R.5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-Dhen yll- 1 -h vdroxymeth yl-6.8-dioxa- bicvclo[3.2.1loctane-2,3Λ-triol (4A) and (1S,2S,3SΛS,5S)-5-[4-chloro-3-(4-ethoxy- benzvD-phen yll- 1 -h vdroxymeth yl-6, 8-dioxa-bicvclo[3.2.1 loctane-2, 3, 4-triol (4B):

Figure imgf000067_0001

To a solution of {(2S,3S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8- dioxa-bicyclo[3.2.1]oct-1-yl}-methanol (l-4k: 335 mg) in ethanol/tetrahydrofuran (10 ml_, 4/1 volume) was added successively formic acid (420 microL, 22 equivalents) and palladium black (208 mg, 4 equivalents) and the resulting mixture was stirred at room temperature. After 1 hour, additional formic acid (420 microL, 22 equivalents) and palladium black (208 mg, 4 equivalents) were added and the mixture was allowed to stir for an additional hour at room temperature. The palladium was filtered and the crude mixture obtained after evaporation of solvent was purified by HPLC preparative.

HPLC preparative: reverse phase C18 Gemini column 5 micrometer 30 x 100 mm, 40 mL/minute, gradient of acetonitrile/0.1 % formic acid : water/0.1 % formic acid; 25 to 50% of acetonitrile/0.1 % formic acid over 18 minutes; UV detection: 220 nm. The HPLC indicated a ratio of diastereomers of 1.1 :1 (4A:4B).

4A: (60 mg, 29% yield); Rt = 12.4 minutes; the fractions containing the product were concentrated under reduced pressure. The crude material was precipitated from ethyl acetate and heptane. The resulting white solid was washed with heptane 2 times and dried under reduced pressure.

MS (LCMS) 437.3 (M+H+; positive mode); 481.3 (M+HCO2 ~; negative mode). 1H NMR (400 MHz, methanol-d4) delta 7.43 (d, 1 H, J = 1.9 Hz), 7.36 (dd, 1 H, J = 8.3 and 2Hz), 7.32 (d, 1 H, J = 8.3 Hz), 7.08-7.04 (m, 2H), 6.79-6.75 (m, 2H), 4.12 (d, 1 H, J = 7.5 Hz), 4.00 (s, 2H), 3.96 (q, 2H, J = 7.0 Hz), 3.81 (d, 1 H, J = 12.5 Hz), 3.75 (dd, 1 H, J = 8.3 and 1.3 Hz), 3.65 (d, 1 H, J = 12.5 Hz), 3.63 (t, 1 H, J = 8.2 Hz), 3.57 (dd, 1 H, J = 7.5 and 1.3 Hz), 3.52 (d, 1 H, J = 8.0 Hz), 1.33 (t, 3H, J = 6.9 Hz). HRMS calculated for C22H26O7CI (M+H+) 437.1361 , found 437.1360.

4B: (30 mg, 15% yield); Rt = 13.2 minutes; the fractions containing the product were concentrated under reduced pressure. The crude material was precipitated from ethyl acetate and heptane. The resulting white solid was washed with heptane 2 times and dried under reduced pressure.

MS (LCMS) 437.3 (M+H+; positive mode) 481.3 (M+HCO2 “, negative mode). 1H NMR (400 MHz, methanol-d4) delta 7.48 (d, 1 H, J = 1.9 Hz) 7.40 (dd, 1 H, J = 8.1 and 1.9 Hz), 7.32 (d, 1 H, J = 8.3 Hz), 7.08-7.03 (m, 2H), 6.80-6.74 (m, 2H), 4.04-3.99 (m, 3H), 3.95 (q, 2H, J = 7 Hz), 3.89-3.81 (m, 4H), 3.73 (d, 1 H, J = 12.5 Hz), 3.49 (d, 1 H, J = 7.3 Hz), 1.32 (t, 3H, J = 7 Hz). HRMS calculated for C22H26O7CI (M+H+) 437.1361 , found 437.1358.
Merck & Co., Inc. and Pfizer Enter Worldwide Collaboration Agreement to Develop and Commercialize Ertugliflozin, an Investigational Medicine for Type 2 Diabetes

ERTUGLIFLOZIN

Monday, April 29, 2013 9:23 am EDT

Merck & Co., Inc. (NYSE: MRK), known as MSD outside the United States and Canada (“Merck”), and Pfizer Inc. (NYSE:PFE) today announced that they have entered into a worldwide (except Japan) collaboration agreement for the development and commercialization of Pfizer’s ertugliflozin (PF-04971729), an investigational oral sodium glucose cotransporter (SGLT2) inhibitor being evaluated for the treatment of type 2 diabetes. Ertugliflozin is Phase III ready, with trials expected to begin later in 2013.

“We are pleased to join forces with Merck in the battle against type 2 diabetes and the burden that it poses on global health,” said John Young, president and general manager, Pfizer Primary Care. “Through this collaboration, we believe we can build on Merck’s leadership position in diabetes care with the introduction of ertugliflozin, an innovative SGLT2 inhibitor discovered by Pfizer scientists.”

Under the terms of the agreement, Merck, through a subsidiary, and Pfizer will collaborate on the clinical development and commercialization of ertugliflozin and ertugliflozin-containing fixed-dose combinations with metformin and JANUVIA® (sitagliptin) tablets. Merck will continue to retain the rights to its existing portfolio of sitagliptin-containing products. Pfizer has received an upfront payment and milestones of $60 million and will be eligible for additional payments associated with the achievement of pre-specified future clinical, regulatory and commercial milestones. Merck and Pfizer will share potential revenues and certain costs on a 60/40 percent basis.

“Merck continues to build upon our leadership position in the oral treatment of type 2 diabetes through our own research and business development,” said Nancy Thornberry, senior vice president and Diabetes and Endocrinology franchise head, Merck Research Laboratories. “We believe ertugliflozin has the potential to complement our strong portfolio of investigational and marketed products, and we look forward to collaborating with Pfizer on its development.”

……………….

Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin

David Bernhardson, Thomas A. Brandt, Catherine A. Hulford, Richard S. Lehner, Brian R. Preston, Kristin Price, John F. Sagal, Michael J. St. Pierre, Peter H. Thompson, and Benjamin Thuma
pp 57–65
Publication Date (Web): January 3, 2014 (Article)
DOI: 10.1021/op400289z
Abstract Image

The development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, ertugliflozin, for the treatment of type-2 diabetes is described. Highlights of the chemistry are a concise, four-step synthesis of a structurally complex API from known intermediate 4 via persilylation–selective monodesilylation, primary alcohol oxidation, aldol-crossed-Cannizzaro reaction, and solid-phase acid-catalyzed bicyclic ketal formation. The final API was isolated as the l-pyroglutamic acid cocrystal.

Inline image 1

1= ertugliflozin

Inline image 2

Inline image 3

PF-04971729, a potent and selective inhibitor of the sodium-dependent glucose cotransporter 2, is currently in phase 2 trials for the treatment of diabetes mellitus. Inhibitory effects against the organic cation transporter 2-mediated uptake of [14C] metformin by PF- 04971729 also were very weak (IC50 900μM). The disposition of PF-04971729, an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [14C]-PF-04971729 to healthy human subjects. The absorption of PF-04971729 in humans was rapid with a Tmax at ~ 1.0 h. Of the total radioactivity excreted in feces and urine, unchanged PF-04971729 collectively accounted for ~ 35.3% of the dose, suggestive of moderate metabolic elimination in humans.
References on PF-04971729:
[1]. 1. Amit S. Kalgutkar, Meera Tugnait, Tong Zhu, et al.Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose cotransporter 2 and Clinical Candidate for the Treatment of Type 2 . Diabetes Mellitus Drug Metabolism and Diposition, 2011, 39 (9):. 1609-1619
Abstract
(1S, 2S, 3S, 4R, 5S) -5 – [4-Chloro-3-(4-ethoxybenzyl) phenyl] -1 -hydroxymethyl-6 ,8-dioxabicyclo [3.2.1] octane-2 ,3,4-triol (PF-04971729), a potent and selective inhibitor of the sodium-dependent glucose cotransporter 2, is currently in phase 2 trials for the treatment of diabetes mellitus. This article describes the preclinical species and in vitro human disposition characteristics of PF-04971729 that were used in experiments performed to support the first-in-human study. Plasma clearance was low in rats (4.04 ml · min? 1 · kg? 1) and dogs (1.64 ml · min? 1 · kg? 1), resulting in half-lives of 4.10 and 7.63 h, respectively. Moderate to good bioavailability in rats (69%) and dogs (94%) was . observed after oral dosing The in vitro biotransformation profile of PF-04971729 in liver microsomes and cryopreserved hepatocytes from rat, dog, and human was qualitatively similar;. prominent metabolic pathways included monohydroxylation, O-deethylation, and glucuronidation No human-specific metabolites of PF-04971729 were detected in in vitro studies. Reaction phenotyping studies using recombinant enzymes indicated a role of CYP3A4/3A5, CYP2D6, and UGT1A9/2B7 in the metabolism of PF-04971729. No competitive or time-dependent inhibition of the major human cytochrome P450 enzymes was discerned with PF-04971729. Inhibitory effects against the organic cation transporter 2-mediated uptake of [14C] metformin by PF-04971729 also were very weak (IC50 =? 900 μM). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies after oral administration indicated that the human pharmacokinetics / dose predictions for PF -04971729 were in the range that is likely to yield a favorable pharmacodynamic response.. [2] … Timothy Colin Hardman, Simon William Dubrey Development and potential role of type-2 sodium-glucose transporter Inhibitors for Management of type 2 Diabetes Diabetes Ther 2011 September; 2 (3):. 133-145
Abstract
There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria , which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80-90 g [300-400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances.[3]. Zhuang Miao, Gianluca Nucci, Neeta Amin. Pharmacokinetics, Metabolism and Excretion of the Anti-Diabetic Agent Ertugliflozin (PF-04971729) in Healthy Male the Subjects. Drug Metabolism and Diposition.
Abstract
The Disposition of ertugliflozin (PF-04971729) , an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [14C]-PF-04971729 to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of PF-04971729 in humans was rapid with a Tmax at ~ 1.0 h. Of the total radioactivity excreted in feces and urine, unchanged PF-04971729 collectively accounted for ~ 35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites M4a, M4b and M4c (~ 39.3% of the dose in urine) of which M4c was the major regioisomer (~ 31.7% of the dose). The structure of M4a and M4c were confirmed to be PF-04971729-4-O-β-and-3-O-β-glucuronide , respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl PF-04971729 (M2), which accounted for ~ 5.2% of the dose in excreta. In plasma, unchanged PF-04971729 and the corresponding 4-O-β-(M4a) and 3-O-β-(M4c) glucuronides were the principal components, which accounted for 49.9, 12.2 and 24.1% of the circulating radioactivity. Overall, these data suggest that PF-04971729 is well absorbed in humans, and eliminated largely via glucuronidation.. [4] .. Tristan S. Maurer, Avijit Ghosh, Nahor Haddish-Berhane pharmacodynamic Model of Sodium-Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology AAPS J. 2011; 13 (4): 576-584
Abstract
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are an emerging class of agents for use in the treatment of type 2 diabetes mellitus (T2DM). Inhibition of SGLT2 leads to improved glycemic control through increased urinary glucose excretion (UGE). In this study, a biologically based pharmacokinetic / pharmacodynamic (PK / PD) model of SGLT2 inhibitor-mediated UGE was developed. The derived model was used to characterize the acute PK / PD relationship of the SGLT2 inhibitor, dapagliflozin, in rats. The quantitative translational pharmacology of dapagliflozin was examined through both prospective simulation and direct modeling of mean literature data obtained for dapagliflozin in healthy subjects. Prospective simulations provided time courses of UGE that were of consistent shape to clinical observations, but were modestly biased toward under prediction. Direct modeling provided an improved characterization of the data and precise parameter estimates which were reasonably consistent with those predicted from preclinical data. Overall, these results indicate that the acute clinical pharmacology of SGLT2 inhibitors in healthy subjects can be reasonably well predicted from preclinical data through rational accounting of species differences in pharmacokinetics, physiology, and SGLT2 pharmacology. Because these data can be generated at the earliest stages of drug discovery, the proposed model is useful in the design and development of novel SGLT2 inhibitors. In addition, this model is expected to serve as a useful foundation for future efforts to understand and predict the effects of SGLT2 inhibition under chronic administration and in other patient populations.[5]. Yoojin Kim, Ambika R Babu Clinical potential of sodium-glucose cotransporter 2 Inhibitors in the Management of type 2 Diabetes Diabetes Obes Metab Syndr 2012; 5:…. 313-327
Abstract
Background The Kidney plays an Important role in glucose metabolism, and has been considered a target for therapeutic intervention. The sodium-glucose cotransporter type 2 (SGLT2) mediates most of the glucose reabsorption from the proximal renal tubule. Inhibition of SGLT2 leads to glucosuria and provides a unique mechanism to lower elevated blood glucose levels in diabetes. The purpose of this review is to explore the physiology of SGLT2 and discuss several SGLT2 inhibitors which have clinical data in patients with type 2 diabetes. Methods We performed a PubMed search using the terms “SGLT2″ and “SGLT2 inhibitor” through April 10, 2012. Published articles, press releases, and abstracts presented at national and international meetings were considered. Results SGLT2 inhibitors correct a novel pathophysiological defect, have an insulin-independent action, are efficacious with glycosylated hemoglobin reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used at any stage of diabetes. They are generally well tolerated. However, due to side effects, such as repeated urinary tract and genital infections, increased hematocrit, and decreased blood pressure, appropriate patient selection for drug initiation and close monitoring after initiation will be important. Results of ongoing clinical studies of the effect of SGLT2 inhibitors on diabetic complications and cardiovascular safety are crucial to determine the risk -benefit ratio. A recent decision by the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products , including insulin, and as a monotherapy for metformin-intolerant patients. Clinical research also remains to be carried out on the long-term effects of glucosuria and other potential effects of SGLT2 inhibitors, especially in view of the observed increase in the incidence of bladder and breast cancer SGLT2 inhibitors represent a promising approach for the treatment of diabetes, and could potentially be an addition to existing therapies Keywords:.. sodium-glucose cotransporter type 2, SGLT2, inhibitors, kidney, glucosuria, oral diabetes agent, weight loss.[6]. Clinical Trials with PF-04971729

Example 6 Manufacturing Process for Tablets US20130137646

Figure US20130137646A1-20130530-C00028

2 Comments

  1. larryhbern says:

    Reblogged this on Leaders in Pharmaceutical Business Intelligence and commented:
    Informative. T2DM will hardly go away. We are learning more about long term control.

  2. […] two Phase III ertugliflozin trials whose results were presented at New Orleans in American Diabetes Association meeting showed […]

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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