Inhibitors of the gastric H+, K+-atpase with enhanced therapeutic properties
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Abstract
Chemical syntheses and medical uses of novel inhibitors of the gastric H+, K+-ATPase for the treatment and/or management of duodenal ulcers, heartburn, acid reflux, other conditions mediated by gastric acid secretion and/or psoriasis are described.
487 Citations
35 Claims
- 1. A compound of Formula 1
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6. A compound selected from the group consisting of:
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7. A compound selected from the group consisting of:
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8. A compound selected from the group consisting of:
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13. An effervescent dosage form comprising a first component and a second component, wherein said first component is one or more effervescent excipients, and said second component is a mixture comprising a compound of Formula 1, a beta blocking agent, and optionally a pharmaceutically acceptable excipients;
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wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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14. An oral multiple unit tablet pharmaceutical composition comprising a first component and a second component, wherein said first component comprises one or more antibacterial agent with similar or different activities, and said second component is a compound of Formula 1, in the form of pellets covered with an enteric coating polymer layer;
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wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, and C1-6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-C6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. - View Dependent Claims (15, 16)
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17. An oral multiple unit tablet pharmaceutical composition comprising a first component, a second component, and an optional third component, wherein said first component is a compound of Formula 1 in the form of pellets covered with an enteric coating polymer layer, said second component comprises at least one non steroidal anti-inflammatory drug (NSAID), and said optional third component comprises a pharmaceutically acceptable excipients, wherein said second component is separated from said first component by said enteric coating layer covering said first component;
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wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. - View Dependent Claims (18)
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19. An extended release pharmaceutical dosage form comprising a compound of Formula 1, a hydrophilic or hydrophobic matrix, a water-soluble separating layer, an enteric coating layer, and optionally one or more pharmaceutically acceptable excipients;
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wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, and C1-6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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20. An enteric coated pharmaceutical dosage form comprising a compound of Formula 1, a disruptable semi-permeable membrane and one or more swellable substances, wherein the dosage form comprises an instant inhibitor-releasing part and at least one delayed inhibitor-releasing part, and is capable of giving a discontinuous release of a compound of Formula 1, in the form of at least two consecutive pulses separated in time from about 0.1 up to about 24 hours;
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wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-C6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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21. A stable pharmaceutical dosage form for oral administration to mammalian subjects which comprises a compound of Formula 1, and optionally one or more pharmaceutical adjuvants, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer;
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wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-C6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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22. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H+, K+-ATPase inhibitor comprising a compound of Formula 1 so as to affect decreased inter-individual variation in plasma levels of said compound or a metabolite thereof during treatment of gastric acid related diseases as compared to the non-isotopically enriched compound;
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wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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23. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H+, K+-ATPase inhibitor comprising a compound of Formula 1 so as to affect increased average plasma levels of said compound or decreased average plasma levels of at least one metabolite of said compound per dosage unit as compared to the non-isotopically enriched compound;
-
wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, and C1-6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-C6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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24. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H+, K+-ATPase inhibitor comprising a compound of Formula 1 wherein said amount of said gastric H+, K+-ATPase inhibitor affects a less pronounced increase in gastrin levels in mammalian subjects during treatment of gastric acid related diseases as compared to the non-isotopically enriched compound;
-
wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-C6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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25. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H+, K+-ATPase inhibitor comprising a compound of Formula 1 wherein said amount of said gastric H+, K+-ATPase inhibitor affects a decreased inhibition of at least one cytochrome P450 isoform in mammalian subjects during treatment of gastric acid related diseases as compared to the non-isotopically enriched compound;
-
wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, and C1-6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-C6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. - View Dependent Claims (26)
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27. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H+, K+-ATPase inhibitor comprising a compound of Formula 1 so as to elicit an improved antisecretory effect during the treatment of gastric acid related diseases as compared to the non-isotopically enriched compound;
-
wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, and C1-6 alkyloxy;
R5 is selected from the group consisting of—
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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28. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H+, K+-ATPase inhibitor comprising a compound of Formula 1 wherein said amount of said gastric H+, K+-ATPase inhibitor elicits an improved clinical effect comprising accelerated rate of healing and accelerated rate of symptom relief during the treatment of gastric related diseases as compared to the non-isotopically enriched compound;
-
wherein said compound of Formula 1 has the structure or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.
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29. A method for treatment of a bacterial infection caused or mediated by Helicobacter pylori, comprising administering to a mammalian subject in need thereof an effective amount of a nitric oxide-releasing non-steroidal anti-inflammatory drug (NSAID) and a compound of Formula 1;
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wherein said compound of Formula 1 has the structure. or a single enantiomer, a mixture of the (+)-enantiomer and the (−
)-enantiomer, a mixture of about 90% or more by weight of the (−
)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−
)-enantiomer, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt, solvate, or prodrug thereof wherein;
R1, R4, R9 and R10 are each independently hydrogen or deuterium;
R2, R3, R6, and R8 are each independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, and C1-6 alkyloxy;
R5 is selected from the group consisting of —
CH2—
, —
CHD- and —
CD2-; and
R7 is selected from the group consisting of hydrogen, deuterium, —
NO2, C1-C6 alkyl, and C1-6 alkyloxy;
provided that said compound of Formula 1 contains at least one deuterium atom; and
provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. - View Dependent Claims (30)
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31. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H+, K+-ATPase inhibitor comprising a compound of Formula 1 wherein said compound of Formula 1 has the structure
- 32. A process for preparing a compound of formula 3 comprising contacting a compound of formula 2 with deuterium oxide under conditions to produce compound of formula 3,
- 34. A process for preparing a compound of formula 5 comprising contacting a compound of formula 4 with deuterium oxide under conditions to produce compound of formula 5,
Specification
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Current AssigneeAuspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
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Original AssigneeAuspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
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InventorsSarshar, Sepehr, Gant, Thomas
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/338
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CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 17/06 AntipsoriaticsA61P 29/00 Non-central analgesic, anti...A61P 31/04 Antibacterial agentsA61P 43/00 Drugs for specific purposes...C07D 401/12 linked by a chain containin...
