USRE48842EActiveUtilityPatentIndex 60
Pyrimido-pyrrolo-oxazine-dione compound inhibitors of the cystic fibrosis transmembrane conductance regulator protein and uses therefor
Est. expiryMay 27, 2031(~4.9 yrs left)· nominal 20-yr term from priority
C07D 498/14C07D 487/14
60
PatentIndex Score
0
Cited by
68
References
52
Claims
Abstract
Provided herein are benzopyrimido-pyrrolo-oxazine-dione (BPO) compounds and pyrimido-pyrrolo-quinoxalinedione (PPQ) compounds, and compositions comprising these compounds, that inhibit cystic fibrosis transmembrane conductance regulator (CFTR) mediated ion transport and that are useful for treating diseases and disorders associated with aberrantly increased CFTR chloride channel activity, such as polycystic kidney disease and secretory diarrheas. The compounds and compositions comprising the compounds described herein may be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.
Claims
exact text as granted — not AI-modifiedWe claim the following:
1. A compound having the following structure (I):
as an isolated enantiomer or a racemic mixture of enantiomers, or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide, thereof, wherein:
m is 1, 2, 3, or 4;
n is 1, 2, 3, 4 or 5;
p is an integer from 0 to 4;
q is an integer from 1 to 4;
R 1 at each occurrence is the same or different and independently H, halo, haloalkyl, C 1 -C 6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 1a at each occurrence is the same or different and independently H, halo, haloalkyl, C 1 -C 6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 2a and R 2b are each the same or different and independently H, or C 1 -C 6 alkyl;
R 4a is —OR 7 , —NR 7 R 8 , —O(CH 2 ) q —OC(O)R 7 , or an amino acid residue;
R 7 and R 8 are each the same or different and independently H, C 1 -C 20 alkyl, a saccharide, or an amino acid residue; and
Z is aryl or heteroaryl,
wherein the amino acid residue is selected from residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic gamma-aminobutyric acid, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
2. The compound of claim 1 , wherein R 2a and R 2b are each methyl, and Z is optionally substituted furanyl or optionally substituted thienyl, and the compound has the following structure (IA) or (IB), respectively:
as an isolated enantiomer or a racemic mixture of enantiomers, or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein:
m is 1, 2, 3, or 4;
n is 1, 2, 3, 4 or 5;
p is an integer from 0 to 4;
q is an integer from 1 to 4;
R 1 at each occurrence is the same or different and independently H, halo, haloalkyl, C 1-6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 1a at each occurrence is the same or different and independently H, halo, haloalkyl, C 1-6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 4a is —OR 7 , —NR 7 R 8 , —O(CH 2 ) q —OC(O)R 7 , or an amino acid residue;
R 5 is H, halo, or C 1-6 alkyl;
R 6 is H, halo, C 1-6 alkyl, or C 1-6 haloalkyl; and
R 7 and R 8 are each the same or different and independently H, C 1-20 alkyl, a saccharide, or an amino acid residue,
wherein the amino acid residue is selected from residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic gamma-aminobutyric acid, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
3. The compound of claim 1 , wherein R 2a and R 2b are each methyl, p is 0, R 4a is —OR 7 is Z is optionally substituted furanyl, n is 1 and R 1 is meta to the linking carbon and the compound has the following structure (IA1):
wherein:
R 1 is H, halo, or C 1-6 alkyl;
R 2 and R 3 are each the same or different and independently H, halo, —NO 2 , C 1-6 alkyl, tetrazolyl, —S(O) 2 OR 7 , or —C(═O)OR 7 ;
R 5 is H, halo, or C 1-6 alkyl;
R 6 is halo, C 1 -C 6 alkyl, or C 1-6 haloalkyl; and
R 7 is H, C 1-6 alkyl, a saccharide, or an amino acid residue, selected residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic gamma-aminobutyric acid, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
4. The compound of claim 1 , wherein R 2a and R 2b are each methyl, p is 0, R 4a is —OR 7 , Z is optionally substituted thienyl, n is 1 and R 1 is meta to the linking carbon, and the compound has the following structure (IB1):
wherein:
R 1 is H, halo, or C 1-6 alkyl;
R 2 and R 3 are each the same or different and independently H, halo, —NO 2 , C 1-6 alkyl, tetrazolyl, —S(O) 2 OR 7 , or —C(═O)OR 7 ;
R 5 is H, halo, or C 1-6 alkyl;
R 6 is halo, C 1-6 alkyl, or C 1-6 haloalkyl; and
R 7 is H, C 1-6 alkyl, a saccharide, or an amino acid residue selected from residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic gamma-aminobutyric acid, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
5. The compound of claim 1 , wherein R 2a and R 2b are each methyl, and Z is optionally substituted phenyl, and the compound has the following structure (IC):
as an isolated enantiomer or a racemic mixture of enantiomers, or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein:
m is 1, 2, 3, or 4;
n is 1, 2, 3, 4 or 5;
p is an integer from 0 to 4;
q is an integer from 1 to 4;
t is 1, 2, 3, 4 or 5;
R 1 at each occurrence is the same or different and independently H, halo, haloalkyl, C 1-6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 1a at each occurrence is the same or different and independently H, halo, haloalkyl, C 1-6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 1b at each occurrence is the same or different and independently H, halo, —OH, —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, or C 1-6 alkoxy;
R 4a is —OR 7 , —NR 7 R 8 , —O(CH 2 ) q —OC(O)R 7 , or an amino acid residue;
R 7 and R 8 are each the same or different and independently H, C 1-20 alkyl, a saccharide, or an amino acid residue,
wherein the amino acid residue is selected from residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic gamma-aminobutyric acid, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
6. The compound of claim 1 , wherein R 2a and R 2b are each methyl, p is 0, R 4a is —OR 7 , n is 1, and R 1 is meta to the linking carbon and the compound has the following structure:
wherein:
R 1 is H, halo, or C 1 -C 6 alkyl;
R 2 and R 3 are each the same or different and independently H, halo, —NO 2 , C 1-6 alkyl, tetrazolyl, —S(O) 2 OR 7 , or —C(═O)OR 7 ;
t is 1, 2, 3, 4 or 5;
R 1b at each occurrence is the same or different and independently H, halo, —OH, —NO 2 , C 1-6 alkoxy, or C 1-6 alkyl; and
R 7 is H, C 1-6 alkyl, a saccharide, or an amino acid residue selected from residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic gamma-aminobutyric acid, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
7. A compound having the following structure (II):
as an isolated enantiomer or a racemic mixture of enantiomers, or as a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein:
m is 1, 2, 3, or 4;
n is 1, 2, 3, 4 or 5;
p is an integer from 0 to 4;
q is an integer from 1 to 4;
X is O or S;
R 1 at each occurrence is the same or different and independently H, halo, haloalkyl, C 1-6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 1a at each occurrence is the same or different and independently H, halo, haloalkyl, C 1-6 alkyl, —(CH 2 ) p —C(O)—R 4a , —S(O) 2 R 4a , —NO 2 , or tetrazolyl;
R 2a and R 2b are each the same or different and independently H or C 1-6 alkyl;
R 4a is —OR 7 , —NR 7 R 8 , —O(CH 2 ) q —OC(O)R 7 , an amino acid residue;
R 4 is H, —N(═O), C 1-6 alkyl, or haloalkyl;
R 5 is H, halo, or C 1-6 alkyl;
R 6 is halo; and
R 7 and R 8 are each the same or different and independently H, C 1 -C 20 alkyl, a saccharide, or an amino acid residue;
wherein the amino acid residue is selected from residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic acid gamma-aminobutyric, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
8. The compound of claim 7 , wherein R 2a and R 2b are each methyl, p is 0, R 4a is —OR 7 , n is 1 and R 1 is meta to the linking carbon, and the compound has the following structure (IIA):
wherein:
X is O or S;
R 1 is H, halo, or C 1-3 alkyl;
R 2 is H, halo, —NO 2 , or —C(═O)OR 7 ;
R 3 is H or —NO 2 ;
R 4 is —N(═O), C 1-3 alkyl, or H;
R 5 is H or C 1-3 alkyl;
R 6 halo; and
R 7 is H, C 1-6 alkyl, a saccharide, an amino acid residue of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine desmosine, isodesmosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic gamma-aminobutyric acid, cirtulline citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, proparagylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated glycosylated serine, and glycosylated asparagine.
9. The compound of claim 1 , wherein (a) each R 1 is H; (b) at least one R 1 is methyl or ethyl; (c) at least one R 1 is methyl and each remaining R 1 is H; or (d) at least one R 1 is ethyl and each remaining R 1 is H.
10. The compound of claim 1 , wherein m=2 and p=0 and (a) at least one of R 1a is halo, —NO 2 , C 1-3 alkyl, —C(O)—R 4a ; or (b) each of R 1a is H.
11. The compound of claim 5 , wherein (a) each R 1 is H; (b) at least one R 1 is methyl or ethyl; (c) at least one R 1 is methyl and each remaining R 1 is H; or (d) at least one R 1 is ethyl and each remaining R 1 is H.
12. The compound of claim 5 , wherein m=2 and p=0 and (a) at least one of R 1a is halo, —NO 2 , C 1-3 alkyl, —C(O)—R 4a ; or (b) each of R 1a is H.
13. The compound of claim 6 , wherein (a) R 2 is H, halo, —NO 2 , or —C(═O)OR 7 , wherein R 7 is H or C 1 -C 6 alkyl; (b) R 2 is H, halo, —NO 2 , or —C(═O)OR 7 , wherein R 7 is H, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ; (c) R 2 is H, chloro, or —NO 2 ; (d) R 2 is —C(═O)OR 7 , wherein R 7 is H, —CH 3 , or —CH 2 CH 3 ; or (e) R 2 is chloro.
14. The compound of claim 5 , wherein:
(a) t=2 and each R 1b is the same or different and independently H, —OH, halo, —NO 2 , C 1-3 alkyl, or C 1-3 alkoxy; or
(b) t=1 and R 1b is —OH, halo, —NO 2 , C 1-3 alkyl, or C 1-3 alkoxy; or
(c) t=2 and each R 1b is the same or different and independtly independently H, —OH, chloro, fluoro, —NO 2 , methyl or methoxy; or
(d) t=1 and R 1b is —OH, chloro, flouro fluoro, —NO 2 , methyl, or methooxy;
(c)(e) each R 1b is H.
15. The compound of claim 3 wherein (a) R 2 is H, halo, —NO 2 , or —C(═O)OR 7 , wherein R 7 is H or C 1-6 alkyl; (b) R 2 is H, halo, —NO 2 , or —C(═O)OR 7 , wherein R 7 is H, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ; (c) R 2 is H, chloro, or —NO 2 ; (d) R 2 is —C(═O)OR 7 , wherein R 7 is H, —CH 3 , or —CH 2 CH 3 ; or (e) R 2 is chloro.
16. The compound of claim 4 wherein (a) R 2 is H, halo, —NO 2 , or —C(═O)OR 7 , wherein R 7 is H or C 1-6 alkyl; (b) R 2 is H, halo, —NO 2 , or —C(═O)OR 7 , wherein R 7 is H, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ; (c) R 2 is H, chloro, or —NO 2 ; (d) R 2 is —C(═O)OR 7 , wherein R 7 is H, —CH 3 , or —CH 2 CH 3 ; or (e) R 2 is chloro.
17. The compound of claim 2 , wherein (a) each R 1 is H; (b) at least one R 1 is methyl or ethyl; (c) at least one R 1 is methyl and each remaining R 1 is H; or (d) at least one R 1 is ethyl and each remaining R 1 is H.
18. The compound of claim 7 , wherein (a) each R 1 is H; (b) at least one R 1 is methyl or ethyl; (c) at least one R 1 is methyl and each remaining R 1 is H; or (d) at least one R 1 is ethyl and each remaining R 1 is H.
19. The compound of claim 2 , wherein m=2 and p=0 and (a) at least one of R 1a is halo, —NO 2 , C 1 -C 3 alkyl, —C(O)—R 4a ; or (b) each of R 1a is H.
20. The compound of claim 7 , wherein m=2 and p=0 and (a) at least one of R 1a is halo, —NO 2 , C 1-3 alkyl, —C(O)—R 4a ; or (b) each of R 1a is H.
21. The compound of claim 2 , wherein R 6 is chloro, bromo, or iodo.
22. The compound of claim 1 , wherein the compound has any one of the following structures:
23. The compound of claim 7 , wherein the compound has any one of the following structures:
24. The compound of claim 1 , wherein the compound is an isolated enantiomer in R form.
25. The compound of claim 24 wherein the compound is 6R-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo [b]pyrimido[4′,5′:3,4]pyrrolo [1,2-d][1,4]oxazine-2-carboxylic acid.
26. The compound of claim 1 , wherein the compound is an isolated enantiomer in S form.
27. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically suitable excipient.
28. A method for inhibiting cyst formation or inhibiting cyst enlargement, said method comprising contacting (a) a cell that comprises CFTR and (b) the pharmaceutical composition of claim 27 , under conditions and for a time sufficient that permit CFTR and the compound to interact, wherein the compound inhibits CFTR-mediated ion transport.
29. A method for treating a disease, condition, or disorder that is treatable by inhibiting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated ion transport, said method comprising administering to a subject the pharmaceutical composition of claim 27 , thereby inhibiting CFTR-mediated ion transport.
30. The method of claim 29 , wherein the disease, condition, or disorder is selected from polycystic kidney disease, aberrantly increased intestinal fluid secretion, and secretory diarrhea.
31. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically suitable excipient.
32. A method for inhibiting cyst formation or inhibiting cyst enlargement, said method comprising contacting (a) a cell that comprises CFTR and (b) the pharmaceutical composition of claim 31 , under conditions and for a time sufficient that permit CFTR and the compound to interact, wherein the compound inhibits CFTR-mediated ion transport.
33. A method for treating a disease, condition, or disorder that is treatable by inhibiting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated ion transport, said method comprising administering to a subject the pharmaceutical composition of claim 31 , thereby inhibiting CFTR-mediated ion transport.
34. The method of claim 33 , wherein the disease, condition, or disorder is selected from polycystic kidney disease, aberrantly increased intestinal fluid secretion, and secretory diarrhea.
35. The compound of claim 22, wherein said compound has the structure:
36. The compound of claim 1, wherein the compound is a racemic mixture of enantiomers.
37. The compound of claim 36, which is a racemic mixture of
6R-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4′,5′:3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylic acid; and 6S-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4′,5′:3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylic acid.
38. A pharmaceutical composition comprising the compound of claim 35 and a pharmaceutically suitable excipient.
39. A pharmaceutical composition comprising the compound of claim 37 and a pharmaceutically suitable excipient.
40. A method for inhibiting cyst formation or inhibiting cyst enlargement, said method comprising contacting (a) a cell that comprises CFTR and (b) the pharmaceutical composition of claim 38, under conditions and for a time sufficient that permit CFTR and the compound to interact, wherein the compound inhibits CFTR-mediated ion transport.
41. A method for treating a disease, condition, or disorder that is treatable by inhibiting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated ion transport, said method comprising administering to a subject the pharmaceutical composition of claim 38, thereby inhibiting CFTR-mediated ion transport.
42. The method of claim 41, wherein the disease, condition, or disorder is selected from polycystic kidney disease, aberrantly increased intestinal fluid secretion, and secretory diarrhea.
43. A method for inhibiting cyst formation or inhibiting cyst enlargement, said method comprising contacting (a) a cell that comprises CFTR and (b) the pharmaceutical composition of claim 39, under conditions and for a time sufficient that permit CFTR and the compound to interact, wherein the compound inhibits CFTR-mediated ion transport.
44. A method for treating a disease, condition, or disorder that is treatable by inhibiting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated ion transport, said method comprising administering to a subject the pharmaceutical composition of claim 39, thereby inhibiting CFTR-mediated ion transport.
45. The method of claim 44, wherein the disease, condition, or disorder is selected from polycystic kidney disease, aberrantly increased intestinal fluid secretion, and secretory diarrhea.
46. The method of claim 44, wherein the disease, condition, or disorder is polycystic kidney disease.
47. The method of claim 44, wherein the disease, condition, or disorder is aberrantly increased intestinal fluid secretion.
48. The method of claim 44, wherein the disease, condition, or disorder is secretory diarrhea.
49. A method for treating polycystic kidney disease, aberrantly increased intestinal fluid secretion, or secretory diarrhea in a subject in need thereof, the method comprising administering to the subject a racemic mixture of 6R-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4′,5′:3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylic acid; and 6S-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4′,5′:3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylic acid.
50. The method of claim 49, for the treatment of polycystic kidney disease.
51. The method of claim 49, for the treatment of aberrantly increased intestinal fluid secretion.
52. The method of claim 49, for the treatment of secretory diarrhea.Cited by (0)
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