MK-7145,

cas  1255204-84-2

1(3H)-Isobenzofuranone, 5,5′-(1,4-piperazinediylbis((1R)-1-hydroxy-2,1-ethanediyl))bis(4-methyl-

PATENT

WO 2010129379

http://www.google.com/patents/WO2010129379A1?cl=ko

SCHEME 1

SCHEME 2

SCHEME 3

SCHEME 5

SCHEME 6

SCHEME 7

SCHEME 8

14 15

The preparation of compounds 16 can be achieved following the sequence detailed in Scheme 9. Treating epoxide 2-1 with commercially available 1-Boc piperazine at elevated temperatures gives rise to alcohol 2-2 (Nomura, Y. et al. Chemical & Pharmaceutical Bulletin, 1995, 43(2), 241-6). The hydroxyl group of 2-2 can be converted to the fluoride by treatment of such fluorinating reagent as DAST (Hudlicky, M. Organic Reactions, 1988, 35). Removal of the Boc group of 3-1 under acidic conditions such as TFA gives rise to piperazine 3-2. Piperazine 3-2 can be washed with an aqueous base solution followed by extraction with organic solvents to generate the free base form. The free base of 3-2 can be coupled to epoxide 5-1 at elevated temperatures to afford compound 16. The Ar-CHF- and Ar’-CHOH- groups in 16 represent examples of either Z¹ or Z².

SCHEME 9

16 General Procedures.

INTERMEDIATE (Ry-H (free base)

5-\(lR)-l -hγdroxγ-2-piperazio- 1 -ylethyl] -4-methyl-2-benzofuran- 1 f 3/f)-one To a 20 mL microwave tube charged with 4-methyl-5-[(2jS)-oxiran-2-yl]-2-benzofuran-l(3H)-one (1020 mg, 5.40 mmol) and a stir bar was added 1-Boc Piperazine (800mg, 4.3 mmol) and EtOH (15 mL). The tube was sealed and heated in a microwave apparatus to 150 ⁰C for 1 hour. The crude product was adsorbed onto silica gel, and purified by flash chromatography (Hexanes-EtOAc with 10% EtOH: 0 – 100% gradient), and solvent removed to afford terl-butyl~4-[(2R-2-hydroxy-2-(4-methyl-l -oxo-1 ,3-dihydro-2-bers2θfuran-5-yl) ethyl}piperazine-l-carboxylate. LCMS M+l (calc. 377.20, found 377.13). This product was treated with neat TFA for 15 minutes to remove the Boc group. After removal of TFA under reduced pressure, the residue was taken into aq NaHCO₃, and back-extracted with CHCl₃-IPA (3:1). The organic layers were combined, dried over sodium sulfate, and concentrated to afford 5 – [( 1 R)- 1 -hydroxy-2-piperazin- 1 -ylethyl] -4-methyl-2-benzofuran- 1 (3H)-one. ¹H NMR (OMSO-d₆, 500 MHz) δ 7.68 (d, J= 8.0 Hz, IH), 7.65 (d, J= 8.0 Hz, IH)₅ 5.38, 5.35 (AB system, J- 15.4, J= 16.7, 2H), 5.06 (dd₅ J- 3.9 Hz, J= 3.7 Hz, IH), 3.76 (m, IH)₅ 2.72 (m, 4H), 2.42 (m, 4H), 2.34 (d, J= 3.8 Hz₅ IH), 2.32 (d, J= 3.8 Hz, IH), 2.24 (s, 3H); LC/MS: (IE, m/z) [M +I]⁺ = 277.03.

EXAMPLE 2A

5, 5 ‘-{ piperazine- 1 ,4-diylbis[( 1 R)- 1 -hydroxy ethane-2 , 1 -diyl] } bis(4-methyl-2-benzofuran- 1 (3H)-one)

Method 1: To a 20 mL microwave tube charged with 4-methyl-5-[(2i?)-oxiran-2-yl]-2-benzofuran-l(3H)-one (972 mg, 5.11 mmol) and piperazine (200 mg, 2.3 mmol) was added a stir bar and EtOH (16 mL). The tube was sealed and heated in a microwave apparatus to 150 ⁰C for 90 minutes. The crude product was adsorbed onto silica gel, and purified by flash chromatography (MeOΗ-DCM 0 ~ 7% gradient). After removal of solvents, 5_»5′-{piperazine-1 ,4-diyIbi s [( 1 R)- 1 -hydroxyethane-2, 1 -diyl] } bis(4-methyl-2-benzofuran- 1 (3 H)-one) was collected. ¹H-NMR (500 MHz₉ CDCl₃) δ ppm 7.80 (s, 4H), 5.25 (s, 4H), 5.11 (d, J= 10.5 Hz₅ 2H), 4.00 (broad, 2H), 2.90 (broad, 4H)₃ 2.69-2.50 (m, 6H), 2.44 (t, J= 11 Hz, 2H), 2.29 (s, 6H); LCMS M+l (calc. 467, found 467).

Method 2: Piperazine (4.51 g, 52.4 mmol) and 4-methyl-5-[(2Λ)-oxiran-2-yl]-2-benzofuran-1 (3//)-one (20.0 g, 105 mmol) were charged to a 3-neck 500-mL roundbottom flask, equipped with a reflux condensor, under nitrogen. Toluene (80.0 mL, 751 mmol) and N,N-dimethylacetamide (80 mL, 854 mmol) were added to provide a suspension. The reaction mixture was warmed to 110 ⁰C, becoming homogeneous at 25 ⁰C. After stirring for 4.5 h at 110 ⁰C, the temperature was increased to 115 °C to drive the reaction forward. After stirring for 48 h, the reaction mixture was cooled to RT. On cooling, crystallization occurred. Water was added via addition funnel (45 mL), generating a thick slurry. The suspension was filtered and the solids were washed with 4:1 water :DMA (60 mL), followed by water (2 x 35 mL). The solid was dried on the funnel under vacuum with a nitrogen sweep to constant mass. 5,5′-{Piperazine-l,4-diylbis[(li?)-l-hydroxyethane-2,l-diyl]}bis(4-methyl-2-beiizofurari-l(3H)-one) was isolated. ¹H-NMR (500 MHz, CDCl₃) δ ppm 7.80 (s, 4H), 5.25 (s, 4H), 5.11 (d, J- 11 Hz, 2H), 4.30-3.51 (broad, 2H), 2.90 (broad, 4H), 2.69-2.50 (m, 6H), 2.44 (t, J- 11 Hz, 2H), 2.30 (s, 6H).

Compounds of the present invention are amines and can therefore be converted to a variety of salts by treatment with any of a number of acids. For example, the compound of Example 2A can be converted to several different salt forms as shown in the following representative examples. These are selected examples and are not meant to be an exhaustive list; numerous additional salts can be prepared in a similar fashion using a variety of acids. EXAMPLE 2A-1 (di-HCl salt): 5,5^t-{piperazme-l,4-diylbis[(17?)-l-hydroxyethane-2,l- diyl] } bis(4-methyl-2-benzofuran- 1 (3H)-one) dihydrochloride To a 250 mL pear shape flask charged with the free base (1.2 g, 2.6 mmol) and a stir bar was added DCM. The solution was stirred until all solids were gone. To this solution was added 4N HCl in dioxane (2.6 mL, 4.0 eq), and the mixture was allowed to stir for another 15 minutes. The solvent was removed on a rotary evaporator, and the product was left dry on a high vacuum pump until there was no weight change. The product was determined to be 5, 5 ‘-{piperazine- 1,4-diylbis [( 1 R)- 1 ~hydroxyethane-2, 1 -diyl] } bis(4-methyl-2-benzofuran- 1 (3i?)-one) dihydrochloride. EXAMPLE 2A-2 (HCl salt): 5,5’-{piperazine-l,4-diylbis[(l^)-l-hydroxyethane-2,l- diyl] } bis(4-methyl-2-benzofuran- 1 QHVone) hvdrochl oride

To a 20 dram vial charged with the free base (160 mg, 0.34 mmol) and a stir bar was added 0.1 M HCl in IPA. The solution was allowed to stir at RT for 30 minutes, and then heated to 40⁰C for 1 hour. The solvent was removed under vacuum, and the resulting product was left on a high vacuum pump for 16 hours. The product corresponded to 5,5′-{piperazine-l,4-diylbis[(li?)-l-hydroxyethane~2, 1 -diyl] } bis(4-methyl-2-benzofuran- 1 (3 H)-one) hydrochloride.

EXAMPLE 2A-3 (mono-hydrate of the di-HCl salt): 5, 5′- {piperazine- l,4-diylbis[( Ii?)- 1-hydroxyethane-2,l-diyl] Ibis^-niethyl-g-benzofuran-lfS/^-one) dihydrochloride hydrate To a flask charged with the free base (1.0 g, 2.1 rnmol) and a stir bar was added 1 N HCl (50 mL). The mixture was allowed to stir until all solids dissolved. The solvent was removed on a rotary evaporator, and the resulting product was left on a high vacuum pump for 16 hours. The product was determined to be 5,5′-{piperazine-l ,4-diylbis[(li?)-l-hydroxyethane-2,l-diyl]}bis(4-methyl-2-benzofuran-l(3H)-one) dihydrochloride hydrate.

EXAMPLE 2A-4 (H₂SO₄ salt): 5.5′-{piperaziiie-l_>4-diylbis[(lJΪ)-l-hydioxyethane-2,l- diyl] }bis(4-methyl-2-benzofuran-l(3/f)-one) sulfate (salt) To a 100 mL flask charged with a solution of the free base (154 mg, 0.330 mmol) in DMF : MeOH (3 : 1) (20 mL) and a stir bar was added 0.1 M H₂SO₄ (3.3 mL). The solution was allowed to stir at RT for 30 minutes, and then heated to 40 ⁰C for 2 hours. A lot of solids formed during that time. The solvent was removed under vacuum, and the white solids were left on high vacuum for 16 hours to afford 5₎5^l-{piperazine-l,4-diylbis[(lJ?)~l-hydroxyethane-2,l-diyl] }bis(4-methyl-2-benzofuran-l(3H)-one) sulfate (salt).

Paper

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure

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