NOVEL BENZAMIDE DERIVATIVES AND PROCESS FOR THE PREPARTION THEREOF
First Claim
Patent Images
1. A compound represented by formula 1:
- wherein;
R1 is hydrogen or C1-6 alkyl;
R2 is hydrogen or C1-6 alkyl;
R3, R4 and R5 are independently hydrogen, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, nitro, or halogen; and
L is wherein m is an integer of 1 to 5;
X is —
(C═
O)—
, —
(C═
S)—
, or —
SO2—
;
R6 is C1-10 alkyl, C1-10 alkenyl, C1-10 alkoxy, C1-10 thioalkoxy, or NR7R8 wherein R7 and R8, which are identical or different, are independently hydrogen or C1-10 alkyl;
Q is pyrrole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, or benzofuran, each of which being optionally substituted by C3-10 cycloalkyl, C1-6 alkyl or nitro; and
R9 and R10, which are identical or different, are independently pyridine, indole, or quinoline, each of which being optionally substituted by hydrogen or C1-6 alkyl;
or an isomer, a pharmaceutically acceptable salt or a hydrate thereof.
1 Assignment
0 Petitions
Accused Products
Abstract
The present invention provides a novel benzamide derivative represented by formula 1 and an isomer, a pharmaceutically acceptable salt or hydrate thereof, and a composition for activating a 5-HT<sb>4</sb> receptor comprising the same, as an active ingredient. Benzamide derivatives of the present invention has superior affinity for 5-HT<sb>4</sb> receptors, capability to reduce the gastric evacuation time, capability to alleviate ventricular tachycardia, ventricular fibrillation, torsades de pointes and QT prolongation, and low toxicity. Therefore, benzamide derivatives of the present invention are therapeutically effective for digestive system diseases.
-
Citations
22 Claims
-
1. A compound represented by formula 1:
-
wherein; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3, R4 and R5 are independently hydrogen, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, nitro, or halogen; and L is wherein m is an integer of 1 to 5;
X is —
(C═
O)—
, —
(C═
S)—
, or —
SO2—
;
R6 is C1-10 alkyl, C1-10 alkenyl, C1-10 alkoxy, C1-10 thioalkoxy, or NR7R8 wherein R7 and R8, which are identical or different, are independently hydrogen or C1-10 alkyl;
Q is pyrrole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, or benzofuran, each of which being optionally substituted by C3-10 cycloalkyl, C1-6 alkyl or nitro; and
R9 and R10, which are identical or different, are independently pyridine, indole, or quinoline, each of which being optionally substituted by hydrogen or C1-6 alkyl;
or an isomer, a pharmaceutically acceptable salt or a hydrate thereof.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 19, 20, 21, 22)
-
8. The compound according to claim 1, wherein L is
-
9. The compound according to claim 1, wherein L is
-
10. The compound according to claim 1, wherein the compound is selected from the group consisting of:
-
ethyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, ethyl 4-[((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, ethyl 4-[2-(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl]piperidine-1-carboxylate, ethyl 2-[2-(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)ethyl]piperidine-1-carboxylate, methyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, propyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, butyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, isopropyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, isobutyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, allyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, 2-ethylhexyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, 3-methyl-pentyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, 4-methyl-pentyl 4-[(cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carboxylate, cis-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, (3S,4R)-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-propionylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(2-(1-propionylpiperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-propionylpiperidin-3-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-butyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(1-butyrylpiperidin-3-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-pentanoylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-hexanoylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(2-methylpentanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(3-methylbutanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(3,3-dimethylbutanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(4-methylpentanoyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-acetylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(2-methylpropanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-ethanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-propanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-pentanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-hexanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-butanethioylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(3-methylbutanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(4-methylpentanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(1-(2,2-dimethylpropanethioyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, S-ethyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate, S-propyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate, S-butyl 4-[cis-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)methyl]piperidine-1-carbothioate, cis-4-amino-5-chloro-N-[1-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, (3S,4R)-4-amino-5-chloro-N-[1-(1-(methylsulfonyl)piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, (3S,4R)-4-amino-5-chloro-N-[1-(3-(1H-1,2,4-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-(1H-tetrazol-2-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-(1H-1,2,3-triazol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-(1H-pyrrol-1-yl)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(2-(bicyclo[2.2.1]heptan-2-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(benzofuran-2-ylmethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, (3S,4R)-4-amino-5-chloro-N-[1-(2-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-oxo-3-(quinolin-5-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-oxo-3-(quinolin-6-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(6-oxo-6-(quinolin-5-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-oxo-3-(4,6-dimethylpyridin-2-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(6-oxo-6-(4,6-dimethylpyridin-2-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(3-oxo-3-(1H-indol-5-ylamino)propyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(6-oxo-6-(1H-indol-5-ylamino)hexyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, 4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide, 4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid dimethylamide, (3R,4S)-4-amino-5-chloro-N-[1-((1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide, cis-4-amino-5-chloro-N-[1-(1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide hydrochloride, cis-4-amino-5-chloro-N-[1-(1-isobutyrylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide maleate, cis-4-amino-5-chloro-N-[1-(1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide hydrochloride, cis-4-amino-5-chloro-N-[1-(1-pivaloylpiperidin-4-yl)methyl)-3-methoxypiperidin-4-yl]-2-methoxybenzamide maleate, 4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide hydrochloride, and 4-[cis-4-(4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide maleate.
-
-
11. A process for preparing a compound represented by formula 1, comprising:
-
(1) introducing a substituent at the amine of a compound of formula III to form a compound of formula IV; (2) substituting hydroxy of the compound of formula IV by halogen or sulfonate to form a compound of formula V; and (3) reacting the resulting compound of formula V with a piperidine-benzamide compound of formula II to prepare a compound of formula 1-1; wherein L, X, R1, R2, R3, R4, R5, R6, and m are as defined in claim 1, and Y is a halogen atom or sulfonate.
-
-
12. A process for preparing a compound represented by formula 1, comprising:
-
(1) substituting Y2 of a compound of formula VI with Q to form a compound of formula VII; and (2) reacting the resulting compound of formula VII with a piperidine-benzamide compound of formula II to prepare a compound of formula 1-2; wherein L, R1, R2, R3, R4, R5, R6, m and Q are as defined in claim 1, and Y1 and Y2 are independently a halogen atom.
-
-
13. A process for preparing a compound represented by formula 1, comprising:
-
(1) reacting an acid chloride compound of formula VIII or XI with an amine compound of formula X to form an amide compound of formula IX or XII, and (2) reacting the resulting compound of formula IX or XII with a piperidine-benzamide compound of formula II to prepare a compound of formula 1-3; wherein L, R1, R2, R3, R4, R5, R9, R10, and m are as defined in claim 1, and Y is a halogen atom.
-
-
19. A method for treating a disease condition mediated by 5-HT4 receptor activity, comprising administering a compound of claim 1, or an isomer, a pharmaceutically acceptable salt or a hydrate thereof to a mammalian subject in need thereof.
-
20. A method for treating a disease condition, comprising administering a compound of claim 1, or an isomer, a pharmaceutically acceptable salt or a hydrate thereof to a mammalian subject in need thereof, wherein the disease condition is selected from the group consisting of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, post-operative ileus, gastroparesis, dyspepsia, esophagitis, gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer'"'"'s disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, cardiac arrhythmia, diabetes and apnea syndrome.
-
21. A use of a compound of claim 1, an isomer, a pharmaceutically acceptable salt or a hydrate thereof, for the preparation of a medicament for treating a disease condition mediated by 5-HT4 receptor activity in a mammalian subject.
-
22. A use of a compound of claim 1, an isomer, a pharmaceutically acceptable salt or a hydrate thereof, for the preparation of a medicament for treating a disease condition in a mammalian subject, wherein the disease condition is selected from the group consisting of gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, post-operative ileus, gastroparesis, dyspepsia, esophagitis, gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer'"'"'s disease, cognitive impairment, emesis, migraine, neurological disease, pain, cardiovascular disease, heart failure, cardiac arrhythmia, diabetes and apnea syndrome.
-
-
14. A composition for activating a 5-HT4 receptor, comprising a compound represented by formula 1, or an isomer, a pharmaceutically acceptable salt or a hydrate thereof, as an active ingredient.
wherein: -
R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3, R4 and R5 are independently hydrogen, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, nitro, or halogen; and L is wherein m is an integer of 1 to 5;
X is —
(C═
O)—
, —
(C═
S)—
, or —
SO2—
;
R6 is C1-10 alkyl, C1-10 alkenyl, C1-10 alkoxy, C1-10 thioalkoxy, or NR7R8 wherein R7 and R8, which are identical or different, are independently hydrogen or C1-10 alkyl;
Q is pyrrole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, or benzofuran, each of which being optionally substituted by C3-10 cycloalkyl, C1-6 alkyl or nitro; and
R9 and R10, which are identical or different, are independently pyridine, indole, or quinoline, each of which being optionally substituted by hydrogen or C1-6 alkyl.- View Dependent Claims (15, 16, 17, 18)
-
Specification