Claims for Patent: 8,080,580

Summary for Patent: 8,080,580

Title:	Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
Abstract:	Compounds of Formula (I) are described herein and the uses thereof for the treatment of diseases, conditions and/or disorders mediated by sodium-glucose transporter inhibitors (in particular, SGLT2 inhibitors). ##STR00001##
Inventor(s):	Mascitti; Vincent (Groton, CT), Collman; Benjamin M. (Ledyard, CT)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	12/546,306
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,080,580
Patent Claims:	1. A compound of Formula (A) or Formula (B) ##STR00051## wherein R.sup.1 is H, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, Cl, F, cyano, fluoro-substituted (C.sub.1-C.sub.2)alkyl, (C.sub.1-C.sub.4)alkyl-SO.sub.2--, or (C.sub.3-C.sub.6)cycloalkyl; and R.sup.2 is (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, (C.sub.2-C.sub.4)alkynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, Cl, F, cyano, fluoro-substituted (C.sub.1-C.sub.2)alkyl, (C.sub.1-C.sub.4)alkyl-SO.sub.2--, (C.sub.3-C.sub.6)cycloalkyl, or a (C.sub.5-C.sub.6)heterocycle having 1 or 2 heteroatoms each independently selected from N, O, or S. 2. The compound of claim 1 wherein said compound is a compound of Formula (A). 3. The compound of claims 1 or 2 wherein R.sup.1 is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, F, Cl, cyano, --CF.sub.3, cyclopropyl, or cyclobutyl; and R.sup.2 is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, F, Cl, cyano, --CF.sub.3, --CF.sub.2CH.sub.3, ethynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, or cyclopropyl. 4. The compound of claim 3 wherein R.sup.1 is H, methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl, cyano, --CF.sub.3, or cyclopropyl; and R.sup.2 is methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl, cyano, --CF.sub.3, --CF.sub.2CH.sub.3, ethynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, or cyclopropyl. 5. The compound of claim 4 wherein R.sup.1 is H, methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, --CF.sub.3, or cyclopropyl; and R.sup.2 is methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, --CF.sub.3, --CF.sub.2CH.sub.3, ethynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, or cyclopropyl. 6. The compound of claim 5 wherein R.sup.1 is methyl, ethyl, F, Cl, cyano, CF.sub.3, or cyclopropyl; and R.sup.2 is methoxy, or ethoxy. 7. A compound selected from the group consisting of: (1S,2S,3S,4R,5S)-1-hydroxymethyl-5-[3-(4-methoxy-benzyl)-4-methyl-phenyl]- -6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4R,5S)-5-[3-(4-ethoxy-benzyl)-4-methyl-phenyl]-1-hydroxymethyl-- 6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl- -6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-- 6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4R,5S)-5-[4-fluoro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl- -6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; 2-(4-methoxybenzyl)-4-((1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(hydroxymethyl- )-6,8-dioxa-bicyclo[3,2,1]oct-5-yl)benzonitrile; 2-(4-ethoxybenzyl)-4-((1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-(hydroxymethyl)- -6,8-dioxa-bicyclo[3,2,1]oct-5-yl)benzonitrile; (1S,2S,3S,4R,5S)-5-[3-(4-ethoxy-benzyl)-4-fluoro-phenyl]-1-hydroxymethyl-- 6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4R,5S)-5-{4-fluoro-3-[4-(tetrahydro-furan-3-yloxy)-benzyl]-phen- yl}-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4R,5S)-5-[3-(4-chlorobenzyl)-4-fluorophenyl]-1-hydroxymethyl-6,- 8-dioxabicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4R,5S)-5-{4-fluoro-3-[4-(oxetan-3-yloxy)-benzyl]-phenyl}-1-hydr- oxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; and (1S,2S,3S,4R,5S)-5-{4-chloro-3-[4-(oxetan-3-yloxy)-benzyl]-phenyl}-1-hydr- oxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol. 8. A compound which is (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-- 6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol. 9. A compound selected from the group consisting of: (1S,2S,3S,4S,5S)-1-hydroxymethyl-5-[3-(4-methoxy-benzyl)-4-methyl-phenyl]- -6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4S,5S)-5-[3-(4-ethoxy-benzyl)-4-methyl-phenyl]-1-hydroxymethyl-- 6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4S,5S)-5-[4-chloro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl- -6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4S,5S)-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-- 6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4S,5S)-5-[4-fluoro-3-(4-methoxy-benzyl)-phenyl]-1-hydroxymethyl- -6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; (1S,2S,3S,4S,5S)-5-[3-(4-ethoxy-benzyl)-4-fluoro-phenyl]-1-hydroxymethyl-- 6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol; and (1S,2S,3S,4S,5S)-5-[3-(4-chlorobenzyl)-4-fluorophenyl]-1-hydroxymethyl-6,- 8-dioxabicyclo[3.2.1]octane-2,3,4-triol. 10. A crystal comprising a compound having the formula (4A): ##STR00052## 11. The crystal of claim 10 further comprising L-proline or L-pyroglutamic acid. 12. The crystal of claim 10 further comprising L-pyroglutamic acid and having one or more of the following: a) space group of P2(1)2(1)2(1) and unit cell parameters substantially equal to the following: a=7.4907(10) .ANG. .alpha.=90.degree. b=12.8626(15) .ANG. .beta.=90.degree. c=28.029(4) .ANG. .gamma.90.degree.; b) a powder x-ray diffraction pattern comprising 2-theta values of (CuK.alpha. radiation, wavelength of 1.54056 .ANG.) 6.4.+-.0.2, 16.7.+-.0.2, 17.4.+-.0.2 and 21.1.+-.0.2; or c) a solid state .sup.13C NMR spectrum comprising peak positions at 16.5.+-.0.2, 131.1.+-.0.2, 158.7.+-.0.2, and 181.5.+-.0.2 ppm as determined on a 500 MHz spectrometer relative to crystalline adamantine of 29.5 ppm. 13. The crystal of claim 10 further comprising L-pyroglutamic acid wherein the crystal is a co-crystal comprising the compound of formula (4A) and L-pyroglutamic acid in a 1:1 stoichiometric ratio. 14. The crystal of claim 10 further comprising L-pyroglutamic acid and having a) a powder x-ray diffraction pattern comprising a 2-theta value of (CuK.alpha. radiation, wavelength of 1.54056 .ANG.) 6.4.+-.0.2; and b) a solid state .sup.13C NMR spectrum comprising peak positions at 16.5.+-.0.2, 158.7.+-.0.2, and 181.5.+-.0.2 ppm as determined on a 500 MHz spectrometer relative to crystalline adamantine of 29.5 ppm. 15. The crystal of claim 10 further comprising L-proline and having one or more of the following: a) space group of C2 and unit cell parameters substantially equal to the following: a=32.8399(16) .ANG. .alpha.=90.degree. b=7.2457(4) .ANG. .beta.=101.268(5).degree. c=11.8023(6) .ANG. .gamma.=90.degree.; or b) a powder x-ray diffraction pattern comprising 2-theta values of (CuK.alpha. radiation, wavelength of 1.54056 .ANG.) 7.6.+-.0.2, 12.1.+-.0.2, 20.3.+-.0.2 and 28.8.+-.0.2. 16. A pharmaceutical composition comprising (i) a compound of any of claims 1 through 9 or a crystal of any of claims 10-15; and (ii) a pharmaceutically acceptable excipient, diluent, or carrier. 17. A method for treating obesity and obesity-related disorders in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 through 9 or a therapeutically effective amount of a crystal of any one of claims 10 through 15. 18. A method for treating or delaying the progression or onset of Type 2 diabetes and diabetes-related disorders in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 through 9 or a therapeutically effective amount of a crystal of any one of claims 10 through 15. 19. A method for treating obesity and obesity-related disorders in animals comprising the step of administering to an animal in need of such treatment a pharmaceutical composition of claim 16. 20. A method for treating or delaying the progression or onset of Type 2 diabetes and diabetes-related disorders in animals comprising the step of administering to an animal in need of such treatment a pharmaceutical composition of claim 16.