Materials and methods for the treatment of gastroesophageal reflux disease
AssigneeARYx Therapeutics, Inc.
InventorsPascal Druzgala, Peter G. Milner, Jürg Pfister, Cyrus Becker
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Abstract
The subject invention provides novel compounds and compositions for the safe and effective treatment of gastroesophageal reflux and related conditions. In a preferred embodiment, the compositions of the subject invention comprise esterified cisapride derivatives. These compositions possess potent activity in treating gastroesophageal reflux disease and substantially reduce adverse effects associated with the administration of cisapride. These adverse effects include, but are not limited to, diarrhea, abdominal cramping and elevations of blood pressure and heart rate.
Claims33
A method for treating a disease state by stimulating the motility of the gastrointestinal system, and wherein said disease state is selected from the group consisting of gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction, wherein said method comprises administering, to an individual in need of such a treatment, a compound, or an analog or salt thereof, wherein said compound has the following structure:
- wherein:
- R1 is H, C1-4 alkyl, OH, OC1-4alkyl, —COOH, —COOC1-4alkyl, —O(C═O)OC1-4alkyl, —O(C═O)C1-4alkyl, or —C1-4alkylNR7R8 where R7 and R8 are, independently, H or C1-4 alkyl;
- R2 is H, C1-4 alkyl, —OC1-4alkyl, —COOH, or —(C═O)OC1-4alkyl;
- X is O or N;
- R3 is H or C1-3 alkyl (if X is an oxygen atom, then R3 does not exist);
- R4, R5, and R6 are each, independently, selected from the group consisting of hydrogen, C1-4 alkyl, —OC1-4alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono- and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino, alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy, aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthio and mercapto;
- and
- wherein L has the formula —CnH2nX—CmH2m—(CR9R10)p—(C═O)O—Y, wherein
- n is an integer from 1 to 4 inclusive;
- X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;
- m is an integer from 0 to 4 inclusive;
- p is 0 or 1;
- R9 and R10 are, independently, H, C1-4 alkyl, or R9R10 are linked and together form a 5- or a 6-membered cycloalkyl ring;
- and
- Y is cycloalkyl optionally substituted by 1 or more heteroatoms selected from the group consisting of O;
- N;
- S;
- or aryl or heteroaryl optionally substituted by 1 or more halogen atoms, C1-4 alkyl, C1-4alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC1-4alkyl.
A pharmaceutical composition comprising a therapeutically-effective amount of a compound, or a salt thereof, wherein said compound has the following structure:
- wherein:
- R1 is H, C1-4 alkyl, OH, OC1-4alkyl, —COOH, —COOC1-4alkyl, —O(C═O)OC1-4alkyl, —O(C═O)C1-4alkyl, or —C1-4alkylNR7R8 where R7 and R8 are, independently, H or C1-4 alkyl;
- R2 is H, C1-4 alkyl, —OC1-4alkyl, —COOH, or —(C═O)OC1-4alkyl;
- X is O or N;
- R3 is H or C1-3 alkyl (if X is an oxygen atom, then R3 does not exist);
- R4, R5, and R6 are each, independently, selected from the group consisting of hydrogen, C1-4 alkyl, —OC1-4alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono- and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino, alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy, aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthio and mercapto;
- and
- wherein L has the formula —CnH2n—X—CmH2m—(CR9R10)p—(C═O)O—Y, wherein
- n is an integer from 1 to 4 inclusive;
- X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;
- m is an integer from 0 to 4 inclusive;
- p is 0 or 1;
- R9 and R10 are, independently, H, C1-4 alkyl, or R9R10 are linked and together form a 5- or a 6-membered cycloalkyl ring;
- and
- Y is cycloalkyl optionally substituted by 1 or more heteroatoms selected from the group consisting of O;
- N;
- S;
- or aryl or heteroaryl optionally substituted by 1 or more halogen atoms, C1-4 alkyl, C1-4alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC1-4alkyl.
A compound, or salt thereof, wherein said compound has the following structure:
- wherein:
- R1 is H, C1-4 alkyl, OH, OC1-4alkyl, —COOH, —COOC1-4alkyl, —O(C═O)OC1-4alkyl, —O(C═O)C1-4alkyl, or —C1-4alkylNR7R8 where R7 and R8 are, independently, H or C1-4 alkyl;
- R2 is H, C1-4 alkyl, —OC1-4alkyl, —COOH, or —(C═O)OC1-4alkyl;
- X is O or N;
- R3 is H or C1-3 alkyl (if X is an oxygen atom, then R3 does not exist);
- R4, R5, and R6 are each, independently, selected from the group consisting of hydrogen, C1-4 alkyl, —OC1-4alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono- and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino, alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy, aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthio and mercapto;
- and
- wherein L has the formula —CnH2n—XCmH2m—(CR9R10)p—(C═O)O—Y, wherein
- n is an integer from 1 to 4 inclusive;
- X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;
- m is an integer from 0 to 4 inclusive;
- p is 0 or 1;
- R9 and R10 are, independently, H, C1-4 alkyl, or R9R10 are linked and together form a 5- or a 6-membered cycloalkyl ring;
- and
- Y is cycloalkyl optionally substituted by 1 or more heteroatoms selected from the group consisting of O;
- N;
- S;
- or aryl or heteroaryl optionally substituted by 1 or more halogen atoms, C1-4 alkyl, C1-4alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC1-4alkyl.
A method for treating a condition selected from the group consisting of 1) cognitive disorders, 2) behavioral disorders, 3) mood disorders, and 4) disorders of control of autonomic function wherein said method comprises administering to an individual in need of such treatment, an effective amount of a compound, or an analog or salt thereof, wherein said compound has the following structure:
- wherein:
- R1 is H, C1-4 alkyl, OH, OC1-4alkyl, —COOH, —COOC1-4alkyl, —O(C═O)OC1-4alkyl, —O(C═O)C1-4alkyl, or —C1-4alkylNR7R8 where R7 and R8 are, independently, H or C1-4 alkyl;
- R2 is H, C1-4 alkyl, —OC1-4alkyl, —COOH, or —(C═O)OC1-4alkyl;
- X is O or N;
- R3 is H or C1-3 alkyl (if X is an oxygen atom, then R3 does not exist);
- R4, R5, and R6 are each, independently, selected from the group consisting of hydrogen, C1-4 alkyl, —OC1-4alkyl, halogen atom, hydroxy, cyano, nitro, amino, mono- and di(lower alkyl)amino, aminocarbonyl, arylcarbonylamino, alkylcarbonylamino, lower-alkyl carbonyl, lower-alkyl carbonyloxy, aminosulfonyl, lower-alkylsulfinyl, lower-alkylsulfonyl, lower-alkylthio and mercapto;
- and
- wherein L has the formula —CnH2n—X—CmH2m—(CR9R10)p—(C═O)O—Y, wherein
- n is an integer from 1 to 4 inclusive;
- X is —CH(OH)—, —NH—, —S—, —O—, or a direct bond;
- m is an integer from 0 to 4 inclusive;
- p is 0 or 1;
- R9 and R10 are, independently, H, C1-4 alkyl, or R9R10 are linked and together form a 5- or a 6-membered cycloalkyl ring;
- and
- Y is cycloalkyl optionally substituted by 1 or more heteroatoms selected from the group consisting of O;
- N;
- S;
- or aryl or heteroaryl optionally substituted by 1 or more halogen atoms, C1-4 alkyl, C1-4alkoxy, hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, —COOH, or —COOC1-4alkyl.
Dependencies are inferred from the claim text.