Benzoic acid compounds and use thereof as medicaments
First Claim
1. A benzoic acid compound of the formula ##STR72## wherein R1 is a halogen;
- R2 is a lower alkoxy, a substituted lower alkoxy, a cycloalkyloxy or a cycloalkylalkoxy;
m is 1 or 2; and
A is ##STR73## wherein R3 is hydrogen, hydroxy, lower alkyl or lower alkoxy, p is an integer of 1-10, q is 2 or 3, and B is a group of the formula
space="preserve" listing-type="equation">--N(R.sup.4)--X.sup.1 --R.sup.5,
space="preserve" listing-type="equation">--N(R.sup.4)--X.sup.2 --N(R.sup.6)(R.sup.7),
space="preserve" listing-type="equation">--X--N(R.sup.8)(R.sup.9),
space="preserve" listing-type="equation">--Het,
space="preserve" listing-type="equation">--N(R.sup.10)(R.sup.11),
space="preserve" listing-type="equation">--X.sup.3 --R.sup.12 or
space="preserve" listing-type="equation">--X.sup.4 --R.sup.13whereinX1 is CO, CS or SO2, X2 is CO or CS, R4 is hydrogen, lower alkyl, phenyl, substituted phenyl, aralkyl or substituted aralkyl, R5 is lower alkyl, cycloalkyl, crosslinked cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or ##STR74## wherein X5 is halogen, X6 is hydrogen or amino, and X7 is a direct bond, methylene, oxygen atom, NH or N--CH3,R6 and R7 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl, or R6 and R7 optionally form a ring together with the adjacent nitrogen atom, R8 and R9 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl or R8 and R9 optionally form a ring together with the adjacent nitrogen atom, Het is a 5- or 6-membered mono- or bicyclic heterocycle having amide or urea in the ring and having 1 to 5 hetero atom(s) selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, R10 and R11 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, X3 is oxygen atom or sulfur atom, R12 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, X4 is CO, CS, SO or SO2, and R13 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl,an optical isomer thereof or a pharmaceutically acceptable salt thereof.
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Accused Products
Abstract
Benzoic acid compounds of the formula ##STR1## wherein each symbol is as defined in the specification, optical isomers thereof and pharmaceutically acceptable salts thereof; pharmaceutical composition comprising this compound and pharmaceutically acceptable additive; and serotonin 4 receptor agonists, gastrointestinal prokinetic agents and therapeutic agents for various gastrointestinal diseases, which comprise this compound as active ingredient. The compounds of the present invention have high and selective affinity for serotonin 4 receptor, and show agonistic effects thereon. Accordingly, they are useful medications for the prophylaxis and treatment of various gastrointestinal diseases, central nervous disorders, cardiac function disorders, urinary diseases, and the like, as well as useful anti-nociceptors for analgesic use which increase threshold of pain.
62 Citations
48 Claims
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1. A benzoic acid compound of the formula ##STR72## wherein R1 is a halogen;
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R2 is a lower alkoxy, a substituted lower alkoxy, a cycloalkyloxy or a cycloalkylalkoxy; m is 1 or 2; and A is ##STR73## wherein R3 is hydrogen, hydroxy, lower alkyl or lower alkoxy, p is an integer of 1-10, q is 2 or 3, and B is a group of the formula
space="preserve" listing-type="equation">--N(R.sup.4)--X.sup.1 --R.sup.5,
space="preserve" listing-type="equation">--N(R.sup.4)--X.sup.2 --N(R.sup.6)(R.sup.7),
space="preserve" listing-type="equation">--X--N(R.sup.8)(R.sup.9),
space="preserve" listing-type="equation">--Het,
space="preserve" listing-type="equation">--N(R.sup.10)(R.sup.11),
space="preserve" listing-type="equation">--X.sup.3 --R.sup.12 or
space="preserve" listing-type="equation">--X.sup.4 --R.sup.13wherein X1 is CO, CS or SO2, X2 is CO or CS, R4 is hydrogen, lower alkyl, phenyl, substituted phenyl, aralkyl or substituted aralkyl, R5 is lower alkyl, cycloalkyl, crosslinked cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or ##STR74## wherein X5 is halogen, X6 is hydrogen or amino, and X7 is a direct bond, methylene, oxygen atom, NH or N--CH3, R6 and R7 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl, or R6 and R7 optionally form a ring together with the adjacent nitrogen atom, R8 and R9 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl or R8 and R9 optionally form a ring together with the adjacent nitrogen atom, Het is a 5- or 6-membered mono- or bicyclic heterocycle having amide or urea in the ring and having 1 to 5 hetero atom(s) selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, R10 and R11 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, X3 is oxygen atom or sulfur atom, R12 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, X4 is CO, CS, SO or SO2, and R13 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof. - View Dependent Claims (44, 45, 46, 47, 48)
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2. A benzoic acid compound of the formula ##STR75## wherein R1 is a halogen;
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R2 is a lower alkoxy, a substituted lower alkoxy, a cycloalkyloxy or a cycloalkylalkoxy; m is 1 or 2; and A3 is ##STR76## wherein R3 is hydrogen, hydroxy, lower alkyl or lower alkoxy, p3 is an integer of 1-6, q is 2 or 3, and B1 is a group of the formula
space="preserve" listing-type="equation">--N(R.sup.4)--X.sup.1 --R.sup.5,
space="preserve" listing-type="equation">--N(R.sup.4)--X.sup.2 --N(R.sup.6)(R.sup.7),
space="preserve" listing-type="equation">--X.sup.1 --N(R.sup.8)(R.sup.9) or
space="preserve" listing-type="equation">--Hetwherein X1 is CO, CS or SO2, X2 is CO or CS, R4 is hydrogen, lower alkyl, phenyl, substituted phenyl, aralkyl or substituted aralkyl, R5 is lower alkyl, cycloalkyl, crosslinked cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or ##STR77## wherein X5 is halogen, X6 is hydrogen or amino, and X7 is a direct bond, methylene, oxygen atom, NH or N--CH3, R6 and R7 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl, or R6 and R7 optionally form a ring together with the adjacent nitrogen atom, R8 and R9 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl or R8 and R9 optionally form a ring together with the adjacent nitrogen atom, and Het is a 5- or 6-membered mono- or bicyclic heterocycle having amide or urea in the ring and having 1 to 5 hetero atom(s) selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, an optical isomer thereof or a pharmaceutically acceptable salt thereof. - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
- 7. The benzoic acid compound of claim 2, wherein B1 is a group of the formula
- space="preserve" listing-type="equation">--NHCOR.sup.5
wherein R5 is as defined in claim 2, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
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- 8. The benzoic acid compound of claim 2, wherein B1 is a group of the formula
- space="preserve" listing-type="equation">--NHCONHR.sup.6 a
wherein R6 a is hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aralkyl or substituted aralkyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
- space="preserve" listing-type="equation">--CONHR.sup.8 a
- space="preserve" listing-type="equation">--NHCOR.sup.5 a ,
space="preserve" listing-type="equation">--NHCONHR.sup.6 b,
space="preserve" listing-type="equation">--CONHR.sup.8 b or ##STR83## wherein R.sup.5 a is aryl, substituted aryl, aralkyl, heteroaryl or substituted heteroaryl, R.sup.6 b is lower alkyl, aryl or substituted aryl, and R.sup.8 b is aryl or substituted aryl,
- space="preserve" listing-type="equation">--NHCOR.sup.5 a or
space="preserve" listing-type="equation">--NHCONHR.sup.6 b
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N-(4-(4-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)piperidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide, 4-amino-5-chloro-2-methoxy-N-(1-(4-(1-naphthoylamino)butyl)-piperidin-4-ylmethyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(1-(4-(2-naphthoylamino)butyl)-piperidin-4-ylmethyl)benzamide, 4-amino-N-(1-(5-benzoylaminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide, 4-amino-5-chloro-N-(1-(5-(3-chlorobenzoylamino)pentyl)piperidin-4-ylmethyl)-2-methoxybenzamide, 4-amino-5-chloro-N-(1-(5-(4-methylbenzoylamino)pentyl)piperidin-4-ylmethyl)-2-methoxybenzamide and N-(5-(4-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)piperidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
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4-amino-5-chloro-2-methoxy-N-(1-(4-(3-n-propylureido)butyl)-piperidin-4-ylmethyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(1-(5-(3-n-propylureido)pentyl)-piperidin-4-ylmethyl)benzamide, and 4-amino-5-chloro-N-(1-(5-(3-(4-chlorophenyl)ureido)pentyl)piperidin-4-ylmethyl)-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof.
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22. A benzoic acid compound of the formula ##STR85## wherein R1 is a halogen;
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R2 is a lower alkoxy, a substituted lower alkoxy, a cycloalkyloxy or a cycloalkylalkoxy; m is 1 or 2; and A4 is ##STR86## wherein R3 is hydrogen, hydroxy, lower alkyl or lower alkoxy, p is an integer of 1-10, q is 2 or 3, and B3 is a group of the formula
space="preserve" listing-type="equation">--N(R.sup.10)(R.sup.11),
space="preserve" listing-type="equation">--X.sup.3 --R.sup.12 or
space="preserve" listing-type="equation">--X.sup.4 --R.sup.13wherein R10 and R11 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, X3 is oxygen atom or sulfur atom, R12 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, X4 is CO, CS, SO or SO2, and R13 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
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23. A benzoic acid compound of the formula ##STR87## wherein R1 is a halogen;
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R2 is a lower alkoxy, a substituted lower alkoxy, a cycloalkyloxy or a cycloalkylalkoxy; m is 1 or 2; and A5 is ##STR88## wherein R3 is hydrogen, hydroxy, lower alkyl or lower alkoxy, p4 is an integer of 1-8, q is 2 or 3, and B4 is a group of the formula
space="preserve" listing-type="equation">--N(R.sup.10)(R.sup.11) or
space="preserve" listing-type="equation">--X.sup.3 --R.sup.12wherein R10 and R11 are the same or different and each is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, X3 is oxygen atom or sulfur atom, and R12 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof. - View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32)
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33. A benzoic acid compound of the formula ##STR92## wherein R1 is a halogen;
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R2 is a lower alkoxy, a substituted lower alkoxy, a cycloalkyloxy or a cycloalkylalkoxy; m is 1 or 2; and A6 is ##STR93## wherein R3 is hydrogen, hydroxy, lower alkyl or lower alkoxy, p is an integer of 1-10, q is 2 or 3, and B5 is a group of the formula
space="preserve" listing-type="equation">--X.sup.4 --R.sup.13wherein X4 is CO, CS, SO or SO2, and R13 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof. - View Dependent Claims (34, 35, 36, 37, 38, 39, 40, 41, 42, 43)
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Specification