Crystalline (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol

Abstract

The invention provides crystalline (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol, and pharmaceutical compositions thereof. The invention further provides methods of using this compound to treat overactive bladder.

Claims

1. Crystalline (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol.

2. Crystalline (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol characterized by an X-ray powder diffraction pattern using CuKα radiation having a diffraction peak at diffraction angle 2-theta of 18.5° in combination with one or more of the peaks selected from the group consisting of 16.2°, 20.2°, and 14.4°; with a tolerance for the diffraction angles of 0.2 degrees.

3. A pharmaceutical composition comprising a compound according to claims 1 or 2, and a pharmaceutically acceptable carrier, diluent or excipient.

4. A pharmaceutical composition comprising a first component which is a compound according to claims 1 or 2, and a second component which is tadalafil, and a pharmaceutically acceptable carrier, diluent or excipient.

5. A method of treating overactive bladder comprising administrating to a patient in need thereof an effective amount of a compound according to claims 1 or 2.

6. A method of treating overactive bladder comprising administrating to a patient in need thereof an effective amount of a compound according to claims 1 or 2, in combination with an effective amount of tadalafil.

7. A compound as claimed in claims 1 or 2 for use in therapy.

8. A compound as claimed in claims 1 or 2 for use in the treatment of overactive bladder.

9. A compound as claimed in claims 1 or 2 for simultaneous, separate or sequential use in combination with tadalafil in the treatment of overactive bladder.

Description

EXAMPLE 1

Synthesis of (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-{4-methoxy-3-[(1-pyridin-2-ylazetidin-3-yl)oxy]phenyl}-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol

[0067] ##STR00017##

[0068] To a solution of (1R)-1-[(3S,4S)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-4-(4-methoxy-3-{[1-pyridin-2-ylazetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol (22.1 mg) in tetrahydrofuran (2 mL) is added aqueous 1.0 M HCl (1 mL). Stir overnight at room temperature. Add aqueous 1.0 M HCl (1 mL) and stir for additional 8 hours. Neutralize with aqueous 1.0 M NaOH, extract with ethyl acetate, dry and evaporate to provide the title compound (18.2 mg). MS(ES+)=472 (M+1).

EXAMPLE 2

Synthesis of (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol

[0069] ##STR00018##

[0070] The title compound is prepared essentially by the method of Example 1. MS(ES+)=486 (M+1).

EXAMPLE 3

Preparation of crystalline (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol

[0071] An alternative name of (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol is (S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(5-methylpyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one.

##STR00019##

[0072] Add (1R)-1-[(3S,4S)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol (20 g, 38.05 mmol) to a 5-10° C. solution of 1N hydrochloric acid (120 mL, 120.0 mmol). Warm the solution to 20-25° C. and stir for three hours. Add dichloromethane (400 mL) and separate the resulting layers. Add dichloromethane (400 mL) to the aqueous layer and adjust the pH to 7-8 with 7% aqueous sodium bicarbonate. Separate the layers and back extract the aqueous layer with dichloromethane (200 mL). Wash the combined organic layers with water (100 mL). Concentrate the organic layer to dryness. Add ethanol (8 mL) to the title compound (4.0 g). Stir the mixture for twenty hours at 15-20° C. Filter the slurry and dry the wet cake under vacuum to give the title compound as a crystalline solid (3.5 g).

[0073] Alternative preparation of crystalline (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol.

[0074] Add 1N hydrochloric acid (1800 mL, 1.8 mol) to (1R)-1-[(3S,4S)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol (290 g, 551.7 mmol) at 20-25° C. After stirring for three hours, add dichloromethane (5800 mL) and 10% aqueous sodium carbonate to adjust the pH to 7-8. Add ethanol (1450 mL) and stir the mixture for thirty minutes. Separate the layers and wash the organic layer with water (2900 mL). Concentrate the organic to 2-3 volumes. Add ethanol (1450 mL) and concentrate the organic to 2-3 volumes. Add ethanol (580 mL) and cool the reaction to 15-20° C. Add seed crystals of the title compound (0.1 g) and stir the mixture for twenty-four hours. Filter the slurry and wash the cake with ethanol (290 mL). Dry the cake under vacuum at 55-60° C. for forty hours to yield the title compound (240.0 g, 494.25 mmol): .sup.1H NMR (CDCl.sub.3) δ 0.73 (m, 3H), 1.19 (d, J=6.0 Hz, 3H), 1.8 (brs, 3H), 2.20 (s, 3H), 3.31 (m, 1H), 3.53 (m, 1H), 3.85 (m, 9H), 4.38 (m, 2H), 4.42 (m, 3H), 5.07 (m, 1H), 6.32 (d, J=8.4 Hz, 1H), 6.68 (d, J=6.0 Hz, 1H), 6.84 (m, 2H), 7.33 (m, 1H), 8.02 (m, 1H); and .sup.13C-NMR (CDCl.sub.3) δ (ppm) 17.0, 17.5, 17.6, 19.6, 44.5, 47.4, 48.8, 49.3, 52.7, 55.9, 57.7, 58.2, 64.0, 64.1, 67.5, 67.6, 67.7, 70.5, 71.3, 106.2, 111.3, 111.4, 115.1, 120.7, 122.1, 128.7, 138.5, 138.7, 145.7, 147.3, 148.1, 158.5, 170.9. Rotational isomerization is observed in the .sup.1H and .sup.13C spectrum, which is causing doubling of relevant peaks.

X-Ray Powder Diffraction

[0075] The XRD patterns of crystalline solids are obtained on a Bruker D4 Endeavor X-ray powder diffractometer, equipped with a CuKa source λ=1.54060 Å) and a Vantec detector, operating at 35 kV and 50 mA. The sample is scanned between 4 and 40° in 2θ, with a step size of 0.009° in 2θ and a scan rate of 0.5 seconds/step, and with 0.6 mm divergence, 5.28 fixed anti-scatter, and 9.5 mm detector slits. The dry powder is packed on a quartz sample holder and a smooth surface is obtained using a glass slide. The crystal form diffraction patterns are collected at ambient temperature and relative humidity. It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g., The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature or humidity at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ±0.2 in 2θ will take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks (in units of °2θ), typically the more prominent peaks. The crystal form diffraction patterns, collected at ambient temperature and relative humidity, were adjusted based on NIST 675 standard peaks at 8.853 and 26.774 degrees 2-theta.

[0076] A sample of (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-methylpyridin-2-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol is characterized by an XRD pattern using CuKα radiation as having diffraction peaks (2-theta values) as described in Table 3 below, and in particular having peaks at 18.5° in combination with one or more of the peaks selected from the group consisting of 16.2°, 20.2°, and 14.4°; with a tolerance for the diffraction angles of 0.2 degrees.

TABLE-US-00003 TABLE 3 Example 3 Peak Positions Angle° Relative Intensity Peak (°2-Theta) +/− 0.2° (% of most intense peak) 1 13.1 21.9 2 24.1 22.0 3 25.0 27.0 4 22.3 30.3 5 20.7 32.0 6 19.0 45.2 7 14.4 46.3 8 20.2 50.0 9 16.2 86.5 10 18.5 100.0