AZETIDINYLOXYPHENYLPYRROLIDINE COMPOUNDS

Abstract

The invention provides certain azetidinyloxyphenylpyrrolidine compounds, particularly compounds of formula I, and pharmaceutical compositions thereof. The invention further provides methods of using a compound of formula I to treat overactive bladder.

##STR00001##

Claims

1. A compound of the formula ##STR00043## wherein R is ##STR00044## R.sup.1 is CH.sub.3, CD.sub.3, CN, Cl or CF.sub.3; provided when R.sup.1 is CH.sub.3 it is not attached at the 5 position; or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 of the formula ##STR00045##

3. The compound or salt of claim 1 wherein R is ##STR00046##

4. The compound or salt of claim 3 wherein R.sup.1 is Cl.

5. The compound or salt of claim 1 or 2 wherein R is ##STR00047##

6. The compound which is (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-chloropyridin-2-yl)azetidin-3-yl]oxy }phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol, which can be structurally represented by the formula: ##STR00048##

7. A compound selected from the group consisting of: ##STR00049## ##STR00050## or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 6 or 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

9. A method of treating overactive bladder comprising administrating to a patient in need thereof an effective amount of a compound of claim 6 or 7, or a pharmaceutically acceptable salt thereof.

10. A method of treating overactive bladder comprising administrating to a patient in need thereof an effective amount of a compound of claim 6 or 7, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of tadalafil.

11. (canceled)

12. (canceled)

13. (canceled)

Description

REFERENCE 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

[0060] ##STR00029##

[0061] To a solution of (1R)-1-[(3S,4S)-1- {[(45)-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).

[0062] The following compounds are prepared essentially by the method of Reference Example 1.

TABLE-US-00003 Example MS No. Name Structure (ES+) 2 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- {4-methoxy-3- [(1-pyridin-3- ylazetidin-3- yl)oxy]phenyl}- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- diol [00030] 472 (M + 1) 3 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- {4-methoxy-3- [(1-pyridin-4- ylazetidin-3- yl)oxy]phenyl}- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- diol [00031] 472 (M + 1) 4 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- {4-methoxy-3- [(1-pyrazin-2- ylazetidin-3- yl)oxy]phenyl}- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- diol [00032] 573 (M + 1) 5 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- {4-methoxy-3- [(1-pyrimidin-2- ylazetidin-3- yl)oxy]phenyl}- 3- methylpyrroldiin- 1-yl]-3- oxopropane-1,2- diol [00033] 473 (M + 1) 6 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- (4-methoxy-3- {[1-(5- cyanopyridin-2- yl)azetidin-3- yl]oxy}phenyl)- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- [00034] 497 (M + 1) diol 7 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- (4-methoxy-3- {[1-(4- cyanopyridin-2- yl)azetidin-3- yl]oxy}phenyl)- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- [00035] 497 (M + 1) diol 8 (2S)-3-[(3S,4)S- 3-[(1R)-1- hydroxyethyl]-4- {4-methoxy-3- [(1-(6- chloropyrimidin- 4-yl)azetidin-3- yl)oxy]phenyl}- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- [00036] 507 (M + 1) diol 9 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- (4-methoxy-3- {[1-(4- methylpyridin-2- yl)azetidin-3- yl]oxy}phenyl)- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- [00037] 486 (M + 1) diol 10 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- (4-methoxy-3- {[1-(6- methypyridin-2- yl)azetidin-3- yl]oxy}phenyl)- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- [00038] 486 (M + 1) diol 11 (2S)-3-[(3S,4S)- 3-[(1R)-1- hydroxyethyl]-4- (4-methoxy-3- {[1-(3- cyanopyridin-2- yl)azetidin-3- yl]oxy}phenyl)- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- [00039] 497 (M + 1) diol 12 (2S)-3-[(3S,4S)- 3-[(1R)-1- hdyroxyethyl]-4- (4-methoxy-3- {[1-(5- chloropyridin-2- yl)azetidin-3- yl]oxy}phenyl)- 3- methylpyrrolidin- 1-yl]-3- oxopropane-1,2- [00040] 506 (M + 1) diol

EXAMPLE 13

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

[0063] ##STR00041##

[0064] To of (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(6-chloro-pyrimidin-4-yl)azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol (0.017 g) and 60% Pd/C (water) in methanol is added hydrogen. Hydrogenate overnight at room temperature. LC/MS indicates reaction incomplete. Filter and concentrate and subject residue to hydrogenation conditions. LC/MS indicates starting material is consumed. Filter and concentrate. Purify the resulting residue by conventional means to provide the title compound. MS (ES+)=473.

EXAMPLE 14

Synthesis of (S)-2,3-dihydroxy-1-((3S,4S)-3-((R)-1-hydroxyethyl)-4-(4-methoxy-3-((1-(5-(methyl-D.SUB.3.) pyridin-2-yl)azetidin-3-yl)oxy)phenyl)-3-methylpyrrolidin-1-yl)propan-1-one

[0065] ##STR00042##

[0066] Under a nitrogen atmosphere, (2S)-3-[(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-(4-methoxy-3-{[1-(5-chloropyridin-2-yl]azetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-1-yl]-3-oxopropane-1,2-diol (82 mg), potassium methyl-D.sub.3 trifluoroborate (20 mg, purified by trituration with a 1:1 mixture of methanol and acetone), potassium carbonate (71 mg), methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (13 mg) and 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (11 mg) are added to a 4 mL vial containing a stir bar. Toluene (1.2 mL) and water (0.12 mL) are added, and the vial is capped. The vial is heated with stirring at 75° C. for 110 minutes. The reaction mixture is combined with a second mixture from a reaction performed analogously but starting from 20 mg of (S)-1-((3S,4S)-4-(3-((1-(5-chloropyridin-2-yl)azetidin-3-yl)oxy)-4-methoxyphenyl)-3-((R)-1-hydroxyethyl)-3-methylpyrrolidin-1-yl)-2,3-dihydroxypropan-1-one. The combined material is added to a separatory funnel with chloroform (20 mL) isopropanol (2 mL) and water (10 mL). The mixture is shaken. The organic layer is dried over magnesium sulfate and evaporated. The residue is purified on a 30 g C18 column eluting with a mixture of acetonitrile and water containing 0.1% formic acid. The product-containing eluent is adjusted to pH=10 with sodium carbonate and then extracted with 3×40 mL of chloroform. The combined chloroform extracts are dried over magnesium sulfate and then concentrated to provide 49 mg of the title compound. MS (ES+)=489 (m+1).