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US 6,355,823 B1Granted
Inhibitors of intestinal apical membrane na/phoshate co-transportation
AssigneeBoard of Regents, The University of Texas System
InventorBrian E. Peerce
Life of this patent
Estimating the term…
Abstract
The compounds of formula (I) are hydrophilic aryl phosphate, thiophosphate, and aminophosphate intestinal apical membrane Na-mediated phosphate co-transportation inhibitors. The compounds can be administered orally, where they act to inhibit Na-dependent phosphate uptake in the intestines, or internally, where they interact with the phosphate control functions of the kidneys and parathyroid. They are therefore useful for inhibiting sodium-mediated phosphate uptake, reducing serum PTH, calcium, calcitriol, and phosphate, and treating renal disease in an animal, including a human.
Claims57
A compound of formula (I):
- where:
- A1 and A2 are the same or different aryl groups collectively bearing at least one hydrophilic substituent;
- E1 and E2 are the same or different and are O, S, or NR2 (where R2 is H or a linear or branched C1-C20 carbon containing group);
- M is H or a pharmaceutically acceptable monovalent cation;
- R1 is a linear or branched, saturated or unsaturated, C1-C20 carbon containing group;
- Z is a single bond, a carbonyl, CE3E4, or CR3E41, where E3 and E4 are the same or different and are OR4, SR41, and NR42, where
- R3 is a linear or branched C1-C20 carbon containing group, and
- R4 is H or a linear or branched C1-C20 carbon containing group;
- and
- n is 0 or 1, or a pharmaceutically acceptable salt thereof,
- provided that, when E1 is O and when Z is a carbonyl and when A1 is a phenyl ring and when E1 is at the 2-position of the phenyl ring A1, A1 is not further substituted in the 4- and 6-positions of the phenyl ring A1 with OR5 groups (where R5 is a carbon containing group having between 1 and 4 carbon atoms);
- and
- further provided that the compound is not 4′-phosphophloretin or a pharmaceutically acceptable salt thereof.
10 more elements
A medication comprising a carrier and a therapeutically effective amount of a compound of formula (I):
- where:
- A1 and A2 are the same or different aryl groups collectively bearing at least one hydrophilic substituent;
- E1 and E2 are the same or different and are O, S, or NR2 (where R2 is H or a linear or branched C1-C20 carbon containing group);
- M is H or a pharmaceutically acceptable monovalent cation;
- R1 is a linear or branched, saturated or unsaturated, C1-C20 carbon containing group;
- Z is a single bond, a carbonyl, CE3E4, or CR3E4, where E3 and E4 are the same or different and are OR4, SR4, and NR42, where
- R3 is a linear or branched C1-C20 carbon containing group, and
- R4 is H or a linear or branched C1-C20 carbon containing group;
- and
- n is 0 or 1, or a pharmaceutically acceptable salt thereof,
- provided that, when E1 is O and when Z is a carbonyl and when A1 is a phenyl ring and when E1 is at the 2-position of the phenyl ring A1, A1 is not further substituted in the 4- and 6-positions of the phenyl ring A1 with OR5 groups (where R5 is a carbon containing group having between 1 and 4 carbon atoms).
8 more elements
A method of inhibiting sodium-mediated phosphate uptake, reducing serum PTH, calcium, calcitriol, or phosphate, or treating renal disease, said method comprising administration of a compound of formula (I):
- where:
- A1 and A2 are the same or different aryl groups collectively bearing at least one hydrophilic substituent;
- E1 and E2 are the same or different and are O, S, or NR2 (where R2 is H or a linear or branched C1-C20 carbon containing group);
- M is H or a pharmaceutically acceptable monovalent cation;
- R1 is a linear or branched, saturated or unsaturated, C1-C20 carbon containing group;
- Z is a single bond, a carbonyl, CE3E4, or CR3E4, where E3 and E4 are the same or different and are OR4, SR4, and NR42, where
- R3 is a linear or branched C1-C20 carbon containing group, and
- R4 is H or a linear or branched C1-C20 carbon containing group;
- and
- n is 0 or 1, or a pharmaceutically acceptable salt thereof.
7 more elements
A process for preparing a compound of Formula I:
- where:
- A1 and A2 are the same or different aryl groups collectively bearing at least one hydrophilic substituent;
- E1 and E2 are the same or different and are O, S, or NR2 (where R2 is H or a linear or branched C1-C20, carbon containing group);
- M is H or a pharmaceutically acceptable monovalent cation;
- R1 is a linear or branched, saturated or unsaturated, C1-C20 carbon containing group;
- Z is a single bond, a carbonyl, CE3E4, or CR3E4, where E3 and E4 are the same or different and are OR4, SR4, and NR42, where
- R3 is a linear or branched C1-C20 carbon containing group, and
- R4 is H or a linear or branched C1-C20 carbon containing group;
- and
- n is 0 or 1, or a pharmaceutically acceptable salt thereof,
- provided that the compound is not 4′-phosphophloretin or a pharmaceutically acceptable salt thereof,
- said process comprising:
- (a) phosphorylating a compound of the formula E1—A1—Z-R1—A2—(E)n and which either contains or does not contain one or more protecting groups to yield any one of the compounds (I) through (Ig);
- or
- (b) if R1 is an unsaturated group, hydrogenating it;
- or
- (c) cleaving any protecting groups in a compound of Formula I to liberate free hydroxyl or phosphate groups;
- or
- (d) converting a compound of Formula I to a pharmaceutically acceptable salt;
- or
- (e) converting a salt of a compound of Formula I to a compound of Formula I;
- or
- (f) converting a salt of a compound of Formula I to a pharmaceutically acceptable salt of a compound of Formula I;
- or
- (g) converting a substituent in A1 or A2 to another substituent.
22 more elements
Dependencies are inferred from the claim text.