CA2410939A1 - Materials and methods for the treatment of gastroesophageal reflux disease - Google Patents
Materials and methods for the treatment of gastroesophageal reflux disease Download PDFInfo
- Publication number
- CA2410939A1 CA2410939A1 CA002410939A CA2410939A CA2410939A1 CA 2410939 A1 CA2410939 A1 CA 2410939A1 CA 002410939 A CA002410939 A CA 002410939A CA 2410939 A CA2410939 A CA 2410939A CA 2410939 A1 CA2410939 A1 CA 2410939A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- 4alkyl
- amino
- group
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
Abstract
The subject invention provides novel compounds and compositions for the safe and effective treatment of gastroesophageal reflux and related conditions. I n 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 effec ts include, but are not limited to, diarrhea, abdominal cramping and elevations of blood pressure and heart rate.
Claims (32)
1. A method for treating a disease state which can be improved by stimulating the motility of the gastrointestinal system 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 axe, 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-C n H2n-X-C m H2m-(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 H, C1-14 alkyl or 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.
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 axe, 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-C n H2n-X-C m H2m-(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 H, C1-14 alkyl or 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.
2. The method, according to claim 1, wherein said disease state is selected from the group consisting of gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo-obstruction.
3. The method, according to claim 2, wherein said disease state is gastroesophageal reflux disease.
4. The method, according to claim 1, wherein said individual is a human.
5. The method, according to claim 1, wherein R4, R5, and R6 are, independently, selected from the group consisting of halo, amino, mono- and dialkylamino, and lower alkyloxy.
6. The method, according to claim 1, wherein R4 is methoxy, R5 is amino or methylamino, and R6 is chloro, in the 2-, 4-, and 5- position of the phenyl ring, respectively.
7. The method, according to claim 1, wherein said compound is selected from the group consisting of:
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
8. The method, according to claim 1, wherein R1=OCH3; R2=H; X=O or N (if X=N, then R3=H); R4, R5, and R6 are methoxy, amino, and chlorine at the 2, 4, and 5-position of the phenyl ring, respectively.
9. The method, according to claim 1, wherein both asymmetric centers are in the cis-configuration.
10. A pharmaceutical composition comprising a compound, or an analog 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 -C1-4a1ky1NR7R8 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 -C n H2n-X-C m H2m(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 H, C1-14 alkyl or 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, C1-4allcoxy, hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, -COOH, or-COOC1-4alkyl.
wherein:
R1 is H, C1-4 alkyl, OH, OC1-4alkyl, -COOH, -COOC1-4alkyl, -O(C=O)OC1-4alkyl, -O(C=O)C1-4alkyl, or -C1-4a1ky1NR7R8 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 -C n H2n-X-C m H2m(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 H, C1-14 alkyl or 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, C1-4allcoxy, hydroxy, cyano, amino, alkylamino, dialkylamino, trifluoromethyl, -COOH, or-COOC1-4alkyl.
11. The pharmaceutical composition, according to claim 10, wherein R4, R5, and are, independently, selected from the group consisting of halo, amino, mono-and dialkylamino, and lower alkyloxy.
12. The pharmaceutical composition, according to claim 10, wherein R4 is methoxy, R5 is amino or methylamino, and R6 is chloro, in the 2-, 4-, and 5- position of the phenyl ring, respectively.
13. The pharmaceutical composition, according to claim 10, wherein said compound is selected from the group consisting of:
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
14. The pharmaceutical composition, according to claim 10, wherein R1=OCH3;
R2=H; X=O or N (if X=N, then R3=H); R4, R5, and R6 are methoxy, amino, and chlorine at the 2, 4, and 5-position of the phenyl ring, respectively.,
R2=H; X=O or N (if X=N, then R3=H); R4, R5, and R6 are methoxy, amino, and chlorine at the 2, 4, and 5-position of the phenyl ring, respectively.,
15. The pharmaceutical composition, according to claim 10, wherein both asymmetric centers are in the cis-configuration.
16. 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 -C n H2n-X-C m H2m-(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 H, C1-14 alkyl or 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.
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 -C n H2n-X-C m H2m-(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 H, C1-14 alkyl or 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.
17. The compound, according to claim 16, wherein R4, R5, and R6 are, independently, selected from the group consisting of halo, amino, mono- and dialkylamino, and lower alkyloxy.
18. The compound, according to claim 16, wherein R4 is methoxy, R5 is amino or methylamino, and R6 is chloro, in the 2-, 4-, and 5- position of the phenyl ring, respectively.
19. The compound, according to claim 16, wherein said compound is selected from the group consisting of:
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
20. The compound, according to claim 16, wherein R1=OCH3. R2=H; X=O or N (if X=N, then R3=H); R4, R5, and R6 are methoxy, amino, and chlorine at the 2, 4, and 5-position of the phenyl ring, respectively.
21. The compound, according to claim 16, wherein both asymmetric centers are in the cis-configuration.
22. A method for treating a condition which is susceptible to treatment by modulation of serotonergic systems 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 -C1-4a1ky1NR7R8 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 -C nH2n-X-C mH2m-(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 0or 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 H, C1-14 alkyl or 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, -COON, or-COOC1-4alkyl.
wherein:
R1 is H, C1-4 alkyl, OH, OC1-4alkyl, -COOH, -COOC1-4alkyl, -O(C=O)OC1-4alkyl,-O(C=O)C1-4alkyl, or -C1-4a1ky1NR7R8 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 -C nH2n-X-C mH2m-(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 0or 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 H, C1-14 alkyl or 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, -COON, or-COOC1-4alkyl.
23. The method, according to claim 22, wherein said condition is selected from the group consisting of 1) cognitive disorders, 2) behavioral disorders, 3) mood disorders, and 4) disorders of control of autonomic function.
24. The method, according to claim 23, wherein said cognitive disorder is Alzheimer's disease.
25. The method, according to claim 23, wherein said behavioral disorder is selected from the group consisting of schizophrenia, mania, obsessive-compulsive disorder, and psychoactive substance use disorders.
25. The method, according to claim 23, wherein said mood disorder is selected from the group consisting of depression and anxiety.
25. The method, according to claim 23, wherein said mood disorder is selected from the group consisting of depression and anxiety.
26. The method, according to claim 23, wherein said disorder of control of autonomic function is selected from the group consisting of essential hypertension and sleep disorders.
27. The method, according to claim 22, wherein said individual is a human.
28. The method, according to claim 22, wherein R4, R5, and R6 are, independently, selected from the group consisting of halo, amino, mono- and dialkylamino, and lower alkyloxy.
29. The method, according to claim 22, wherein R4 is methoxy, R5 is amino or methylamino, and R6 is chloro, in the 2-, 4-, and 5- position of the phenyl ring, respectively.
30. The method, according to claim 22, wherein said compound is selected from the group consisting of:
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
where IIIa and IIIb are mirror images of each other (enantiomers), and where L
is defined as shown in Formula (II):
where n=1 to 4, m=0 to 4, X is a direct bond and Y is hydrogen, lower alkyl, or substituted aryl.
31. The method, according to claim 22, wherein R1=OCH3; R2=H; X=O or N (if X=N, then R3=H); R4, R5, and R6 are methoxy, amino, and chlorine at the 2, 4, and 5-position of the phenyl ring, respectively.
32. The method, according to claim 22, wherein both asymmetric centers are in the cis-configuration.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US20992600P | 2000-06-07 | 2000-06-07 | |
| US60/209,926 | 2000-06-07 | ||
| PCT/US2001/018365 WO2001093849A2 (en) | 2000-06-07 | 2001-06-07 | Treatment of gastroesophageal reflux disease using piperidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2410939A1 true CA2410939A1 (en) | 2001-12-13 |
| CA2410939C CA2410939C (en) | 2010-02-16 |
Family
ID=22780902
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2410939A Expired - Fee Related CA2410939C (en) | 2000-06-07 | 2001-06-07 | Materials and methods for the treatment of gastroesophageal reflux disease |
Country Status (6)
| Country | Link |
|---|---|
| US (3) | US6552046B2 (en) |
| EP (1) | EP1296684A2 (en) |
| JP (1) | JP4584534B2 (en) |
| AU (2) | AU7532601A (en) |
| CA (1) | CA2410939C (en) |
| WO (1) | WO2001093849A2 (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6821285B2 (en) | 1999-06-22 | 2004-11-23 | Ndo Surgical, Inc. | Tissue reconfiguration |
| US8287554B2 (en) * | 1999-06-22 | 2012-10-16 | Ethicon Endo-Surgery, Inc. | Method and devices for tissue reconfiguration |
| US6835200B2 (en) | 1999-06-22 | 2004-12-28 | Ndo Surgical. Inc. | Method and devices for tissue reconfiguration |
| US7846180B2 (en) | 1999-06-22 | 2010-12-07 | Ethicon Endo-Surgery, Inc. | Tissue fixation devices and methods of fixing tissue |
| US6663639B1 (en) | 1999-06-22 | 2003-12-16 | Ndo Surgical, Inc. | Methods and devices for tissue reconfiguration |
| US7049326B2 (en) | 2000-05-12 | 2006-05-23 | The University Of Toledo | Method and compositions for temporarily incapacitating subjects |
| US6750238B1 (en) | 2000-05-12 | 2004-06-15 | The University Of Toledo | Aralkyl ester soft drugs |
| AU2004268641A1 (en) * | 2003-08-29 | 2005-03-10 | Dynogen Pharmaceuticals, Inc. | Compositions useful for treating gastrointestinal motility disorders |
| EP1701951B1 (en) | 2003-12-23 | 2010-02-10 | Serodus AS | Modulators of peripheral 5-ht receptors |
| US8138204B2 (en) | 2004-01-07 | 2012-03-20 | Aryx Therapeutics, Inc. | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
| EP2194053B1 (en) * | 2004-01-07 | 2013-03-27 | Armetheon, Inc. | Methoxy piperidine derivatives for use inr the treatment of gastrointestinal and central nervous system disorders |
| US8524736B2 (en) | 2004-01-07 | 2013-09-03 | Armetheon, Inc. | Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
| MY147756A (en) * | 2005-05-25 | 2013-01-15 | Theravance Inc | Benzimidazole-carboxamide compounds as 5-ht4 receptor agonists |
| CA2620379C (en) | 2005-08-31 | 2015-02-24 | Aryx Therapeutics, Inc. | Synthetic methods and intermediates for stereoisomeric compounds useful for the treatment of gastrointestinal and central nervous system disorders |
| US20080085915A1 (en) * | 2006-06-23 | 2008-04-10 | Cyrus Becker | Compounds and methods for the treatment of gastrointestinal and central nervous system disorders |
| KR100976063B1 (en) * | 2007-03-16 | 2010-08-17 | 동아제약주식회사 | Novel benzamide derivatives and process for the preparation thereof |
| US8852216B2 (en) | 2007-03-23 | 2014-10-07 | Ethicon Endo-Surgery, Inc. | Tissue approximation methods |
| KR20100026641A (en) * | 2008-09-01 | 2010-03-10 | 동아제약주식회사 | Novel benzamide derivative and the preparation thereof |
| WO2012028614A1 (en) * | 2010-09-01 | 2012-03-08 | Janssen Pharmaceutica Nv | 5-ht2b receptor antagonists |
| JP6260531B2 (en) | 2012-05-17 | 2018-01-17 | Jsr株式会社 | Acid diffusion controller, radiation sensitive resin composition, and resist pattern forming method |
| US10570127B1 (en) | 2018-11-05 | 2020-02-25 | Renexxion, Llc | Material and methods for the treatment of gastro-intestinal disorders |
| CN112816528B (en) * | 2021-02-01 | 2024-04-09 | 合肥艾创微电子科技有限公司 | Perception and storage integrated bionic haptic fiber and preparation method thereof |
| CN112966411B (en) * | 2021-02-07 | 2022-05-24 | 华南理工大学 | Medical implant based on body representative unit stress and preparation method and application thereof |
| CN113581374B (en) * | 2021-08-25 | 2023-01-10 | 杭州海斗量海洋仪器有限公司 | Buoy for protecting monitoring equipment |
| CN115935635B (en) * | 2022-11-29 | 2024-02-27 | 上海玫克生储能科技有限公司 | Electrochemical model-based lithium battery road end voltage calculation method, device and medium |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE35550B1 (en) * | 1970-09-03 | 1976-03-18 | Wyeth John & Brother Ltd | Amino-and acylamino-pyridine and -hydropyridine derivatives |
| GB1425706A (en) * | 1972-06-30 | 1976-02-18 | Wyeth John & Brother Ltd | Piperidine derivatives |
| US4962115A (en) | 1981-10-01 | 1990-10-09 | Janssen Pharmaceutica N.V. | Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives |
| US5057525A (en) | 1981-10-01 | 1991-10-15 | Janssen Pharmaceutica N.V. | Novel N-(3-hydroxy-4-piperidinyl) benzamide derivatives |
| CA1183847A (en) * | 1981-10-01 | 1985-03-12 | Georges Van Daele | N-(3-hydroxy-4-piperidinyl)benzamide derivatives |
| CA1317940C (en) * | 1987-09-25 | 1993-05-18 | Georges H. P. Van Daele | Substituted n-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides |
| JP3104142B2 (en) * | 1991-02-15 | 2000-10-30 | 北陸製薬株式会社 | Benzamide derivatives |
| US5395832A (en) | 1991-02-15 | 1995-03-07 | Hokuriku Seiyaku Co., Ltd. | Benzamide derivatives |
| TW213460B (en) | 1991-02-15 | 1993-09-21 | Hokuriku Pharmaceutical | |
| IT1260485B (en) * | 1992-05-29 | 1996-04-09 | PROCEDURE AND DEVICE FOR THE TREATMENT OF THE OBESITY OF A PATIENT | |
| AU680453B2 (en) * | 1992-11-05 | 1997-07-31 | Smithkline Beecham Plc | Piperidine derivatives as 5-HT4 receptor antagonists |
| WO1999002496A1 (en) * | 1997-07-11 | 1999-01-21 | Janssen Pharmaceutica N.V. | (+)-norcisapride useful for 5-ht3 and 5-ht4 mediated disorders |
| JPH11292846A (en) * | 1998-02-10 | 1999-10-26 | Hokuriku Seiyaku Co Ltd | Derivative of benzamide and medicine including the same |
| AR022338A1 (en) * | 1999-02-04 | 2002-09-04 | Hokuriku Pharmaceutical | A BENZAMIDE COMPOUND, A MEDICINAL PRODUCT CONTAINING IT, AND USE FOR THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE TREATMENT OR PREVENTION OF A DIGESTIVE DISEASE OR TO IMPROVE THE MOBILITY OF THE GASTROINTESTINAL TRACT. |
| JP3398111B2 (en) * | 1999-02-04 | 2003-04-21 | 北陸製薬株式会社 | Benzamide derivatives and pharmaceuticals containing them |
| DE19933926A1 (en) * | 1999-07-20 | 2001-01-25 | Boehringer Ingelheim Pharma | Biphenyl derivatives, their preparation and their use as medicines |
| US20040092511A1 (en) * | 1999-12-10 | 2004-05-13 | Billstein Stephan Anthony | Pharmaceutical combinations and their use in treating gastrointestinal and abdominal viscera disorders |
-
2001
- 2001-06-07 JP JP2002501422A patent/JP4584534B2/en not_active Expired - Fee Related
- 2001-06-07 US US09/876,698 patent/US6552046B2/en not_active Ceased
- 2001-06-07 WO PCT/US2001/018365 patent/WO2001093849A2/en active IP Right Grant
- 2001-06-07 AU AU7532601A patent/AU7532601A/en active Pending
- 2001-06-07 CA CA2410939A patent/CA2410939C/en not_active Expired - Fee Related
- 2001-06-07 AU AU2001275326A patent/AU2001275326C1/en not_active Ceased
- 2001-06-07 EP EP01942028A patent/EP1296684A2/en not_active Ceased
-
2003
- 2003-04-18 US US10/418,842 patent/US20030216387A1/en not_active Abandoned
-
2007
- 2007-12-21 US US11/962,592 patent/USRE42412E1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| USRE42412E1 (en) | 2011-05-31 |
| US20030216387A1 (en) | 2003-11-20 |
| CA2410939C (en) | 2010-02-16 |
| JP2003535128A (en) | 2003-11-25 |
| US6552046B2 (en) | 2003-04-22 |
| JP4584534B2 (en) | 2010-11-24 |
| WO2001093849A2 (en) | 2001-12-13 |
| US20020025970A1 (en) | 2002-02-28 |
| AU2001275326B2 (en) | 2006-02-02 |
| WO2001093849A3 (en) | 2003-01-30 |
| AU2001275326C1 (en) | 2006-09-21 |
| EP1296684A2 (en) | 2003-04-02 |
| AU7532601A (en) | 2001-12-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2410939A1 (en) | Materials and methods for the treatment of gastroesophageal reflux disease | |
| AP1822A (en) | Substituted pyridinones as modulators of P38 MAP kinase. | |
| RU2353616C2 (en) | 2-pyridone derivatives as neutrophil elastase inhibitors and their application | |
| WO2005018557A3 (en) | Substituted pyridinones | |
| JP2003506387A5 (en) | ||
| RU2003134544A (en) | AMRIDES OF ANTRANILIC ACID, METHODS FOR PRODUCING THEM, THEIR APPLICATION AS ANTIARRHYTHMIC MEDICINES, AND ALSO CONTAINING THEIR PHARMACEUTICAL COMPOSITIONS | |
| CA2483752A1 (en) | Tetrahydropyranyl cyclopentyl tetrahydropyridopyridine modulators of chemokine receptor activity | |
| RU2007139700A (en) | Substituted Aminoalkyl and Amidoalkylbenzopyran derivatives | |
| RU2003116123A (en) | AMIDOESTER SUBSTITUTED IMIDAZOCHINOLINS | |
| CA2269994A1 (en) | 7-hetero-bicyclo¬2.2.1|-heptanes | |
| NZ337121A (en) | Pyrazine compounds as good anti-convulsants for the treatment of CNS diseases such as epilepsy | |
| DE69120100D1 (en) | Annealed thiophene derivatives, their preparation and use | |
| CA2355075A1 (en) | Heteroaryl-cyclic acetals | |
| HUP0401009A2 (en) | 1-aryl-or 1-alkylsulfonylbenzole derivatives as 5-hydroxytryptamine-6 ligands, process for their preparation and pharmaceutical compositions containing them | |
| NZ527249A (en) | Purine derivatives as purinergic receptor antagonists | |
| CA2434747A1 (en) | Camptothecin derivatives | |
| JP2005538111A5 (en) | ||
| RU2002133458A (en) | Compounds of piperazine and piperidine | |
| WO2005066166A3 (en) | 3-quinuclidinyl amino-substituted biaryl derivatives | |
| CA2375671A1 (en) | 4-phenyl-pyrimidine derivatives | |
| PL355843A1 (en) | Novel compounds | |
| NZ535833A (en) | Acyl-3-carboxyphenylurea derivatives, processes for preparing them and their use | |
| NO165195C (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE NEW DERIVATIVES OF 4,5-DIHYDRO-OXSAZOLYL-2 - ((2-PYRIDYL) -METHYL-THIO- OR METHYLSULPHINYL) -BENZ- OR TIENOIDID. | |
| NO973342L (en) | Use of 3,4-diphenylchromanes in the preparation of a pharmaceutical composition for the treatment or prophylaxis of cerebral degenerative diseases | |
| HUP9903893A2 (en) | Method of treating heart failure with cyclopentane fused heterocyclic endothelin antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130607 |