Benzoic acid derivatives, processes for producing the same and drugs containing the same as the active ingredient
First Claim
1. A benzoic acid derivative of formula (I) wherein are each independently, phenyl,D is C1-4 alkylene, G is oxygen or sulfur, E is a bond, oxygen, sulfur, C1-4 alkylene, C1-4 alkyloxy or C1-4 oxyalkyl, R1 is hydroxy, —
- OR9 or —
NR10R11, wherein R9 is C1-6 alkyl, and R10 and R11 are each independently, hydrogen atom or C1-6 alkyl, R2 and R3 are each independently, C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalomethyl, cyano or nitro, R4 is hydrogen or C1-6 alkyl, R5 is a bond, C1-6 alkylene, C1-6 alkylene substituted with C1-4 alkoxy, or C3-5 cycloalkylene, R6 is phenyl or naphthyl, R7 is hydrogen, C1-8 alkyl, C5˜
7 carbocyclic ring or 5-15 membered heterocyclic ring containing nitrogen, sulfur and/or oxygen, m and n are each independently, 0, 1, 2 or 3, the rings represented by R6 and R7 may be substituted with C1-4 alkyl, C1-4 alkoxy, halogen, trihalomethyl, nitro, cyano or oxo, with the proviso that 2-[2-(benzoylamino)phenylmethyl]benzoic acid is excluded, or a non-toxic salt thereof.
1 Assignment
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Accused Products
Abstract
An agent comprising the benzoic acid of formula (I)
wherein A, B, R6, R7 are carbocyclic ring, heterocyclic ring, etc.; R1 is hydroxy etc.; R2, R3, R4 are alkyl etc.; R5, D, E are alkylene, etc.; G is oxygen etc., as active ingredient.
The compound of formula (I) is considered to be useful for the treatment and/or prophylaxis of bone diseases, cancer, systemic granuloma, immunological diseases, allergy, atopy, asthma, gumboil, gingivitis, periodontitis, neurocyte death, Alzheimer'"'"'s diseases, lungs injury, pulmopathy, acute hepatitis, nephritis, myocardial ischemia, Kawasaki disease, ambustion, ulcerative colitis, Crohn'"'"'s disease, multiple organ failure, sleeping disorder, platelet aggregation, etc.
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Citations
13 Claims
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1. A benzoic acid derivative of formula (I)
wherein are each independently, phenyl, D is C1-4 alkylene, G is oxygen or sulfur, E is a bond, oxygen, sulfur, C1-4 alkylene, C1-4 alkyloxy or C1-4 oxyalkyl, R1 is hydroxy, — - OR9 or —
NR10R11, wherein R9 is C1-6 alkyl, and R10 and R11 are each independently, hydrogen atom or C1-6 alkyl,R2 and R3 are each independently, C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalomethyl, cyano or nitro, R4 is hydrogen or C1-6 alkyl, R5 is a bond, C1-6 alkylene, C1-6 alkylene substituted with C1-4 alkoxy, or C3-5 cycloalkylene, R6 is phenyl or naphthyl, R7 is hydrogen, C1-8 alkyl, C5˜
7 carbocyclic ring or 5-15 membered heterocyclic ring containing nitrogen, sulfur and/or oxygen,m and n are each independently, 0, 1, 2 or 3, the rings represented by R6 and R7 may be substituted with C1-4 alkyl, C1-4 alkoxy, halogen, trihalomethyl, nitro, cyano or oxo, with the proviso that 2-[2-(benzoylamino)phenylmethyl]benzoic acid is excluded, or a non-toxic salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
(1) 2-[5-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (2) 2-[2-[2-(1-naphthyl)propanoylamino]phenylmethyl]benzoic acid, (3) 2-[2-[2-(2-naphthyl)propanoylamino]phenylmethyl]benzoic acid, (4) 2-[2-[2-(4-biphenyl)propanoylamino]phenylmethyl]benzoic acid, (5) 2-[3-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (6) 2-[5-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (7) 2-[2-[2-(1-naphthyl)acetylamino]phenylmethyl]benzoic acid, (8) 2-[2-[2-(1-naphthyl)carbonylamino]phenylmethyl]benzoic acid, (9) 2-[3-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (10) 2-[4-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (11) 2-[4-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (12) 2-[6-chloro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (13) 2-[6-methoxy-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (14) 2-[4-fluoro-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (15) 2-[4-trifluoromethyl-2-[2-(1-naphthyl)propanoyl amino]phenylmethyl]benzoic acid, (16) 2-[4-methyl-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (17) 2-[2-[2-(4-benzyloxyphenyl)acetylamino]phenylmethyl]benzoic acid, (18) 2-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, or a methyl ester thereof or a non-toxic salt thereof. -
7. The benzoic acid according to claim 1, which is selected from
(1) 2-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid, (2) 2-[2-[2-(4-benzyloxyphenyl)propanoylamino]phenyl methyl]benzoic acid, (3) 2-[2-[2-(3-benzyloxyphenyl)propanoylamino]phenyl methyl]benzoic acid, (4) 2-[2-[2-(1-naphthyl)butanoylamino]phenylmethyl]benzoic acid, (5) 2-[2-[2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid, (6) 2-[2-[3-methyl-2-(1-naphthyl)butanoylamino]phenyl methyl]benzoic acid, (7) 2-[2-[2-(1,1′ - -biphenyl-2-yl)propanoylamino]phenyl methyl]benzoic acid,
(8) 2-[2-[2-(1,1′
-biphenyl-3-yl)propanoylamino]phenyl methyl]benzoic acid,(9) 2-[2-[2-(4-phenoxyphenyl)propanoylamino]phenyl methyl]benzoic acid, (10) 2-[2-[2-[4-(2-phenylethoxy)phenyl]propanoylamino]phenylmethyl]benzoic acid, (11) 2-[2-[2-[4-(3-phenylpropoxy)phenyl]propanoylamino]phenylmethyl]benzoic acid, (12) 2-[2-[2-methoxy-2-(1-naphthyl)acetylamino]phenyl methyl]benzoic acid, (13) 2-[2-[2-(4-isobutylphenyl)propanoylamino]phenyl methyl]benzoic acid, (14) 2-[2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenyl methyl]benzoic acid, (15) 2-[2-[2-(1-naphthyl)hexanoylamino]phenylmethyl]benzoic acid, (16) 2-[2-[2-[4-(4-phenylbutoxy)phenyl]propanoylamino]phenylmethyl]benzoic acid, (17) 2-[2-[2(R)-(1-naphthyl)propanoylamino]phenylmethyl]benzoic acid, (18) 2-[2-[2(S)-(1-naphthyl)propanoylamino]phenylmethyl]benzoic acid, (19) 2-[4-cyano-2-[4-methyl-2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid, (20) 2-[2-[2-ethoxy-2-(1-naphthyl)acetylamino]phenylmethyl]benzoic acid, (21) 2-[2-[2-(1-naphthyl)heptanoylamino]phenylmethyl]benzoic acid, (22) 2-[2-[4,4-dimethyl-2-(1-naphthyl)pentanoylamino]phenylmethyl]benzoic acid, (23) 2-[2-[2-[4-(3-phenylpropyl)phenyl]propanoylamino]phenylmethyl]benzoic acid, (24) 2-[2-[2-[4-[2-(3-pyridyl)ethoxy]phenyl]propanoyl amino]phenylmethyl]benzoic acid, (25) 2-[2-[2-[4-(2-phenoxyethyl)phenyl]propanoylamino]phenylmethyl]benzoic acid, (26) 2-[2-[4-methoxy-2-(1-naphthyl)butanoylamino]phenyl methyl]benzoic acid, (27) 2-[2-[5-methyl-2-(1-naphthyl)hexanoylamino]phenyl methyl]benzoic acid, (28) 2-[2-[2-[4-(2-phenylethylthio)phenyl]propanoyl amino]phenylmethyl]benzoic acid, (29) 2-[2-[3-methoxy-2-(1-naphthyl)propanoylamino]phenyl methyl]benzoic acid, (30) 2-[4-ethoxy-2-[4-methyl-2-(1-naphthyl)pentanoyl amino]phenylmethyl]benzoic acid, (31) 2-[4-isopropyloxy-2-[4-methyl-2-(1-naphthyl) pentanoylamino]phenylmethyl]benzoic acid, (32) 2-[4-methoxy-2-[4-methyl-2-(1-naphthyl)pentanoyl amino]phenylmethyl]benzoic acid, (33) 2-[2-[2-[4-[2-(pyridin-2-yl)ethoxy]phenyl]propanoyl amino]phenylmethyl]benzoic acid, (34) 2-[2-[2-[4-[2-(pyridin-4-yl)ethoxy]phenyl]propanoyl amino]phenylmethyl]benzoic acid, (35) 2-[4-cyano-2-(4-methyl-2-phenylpentanoylamino)phenyl methyl]benzoic acid, (36) 2-[2-[2-(4-pentylphenyl)propanoylamino]phenylmethyl]benzoic acid, or a methyl ester thereof or a non-toxic salt thereof.
- -biphenyl-2-yl)propanoylamino]phenyl methyl]benzoic acid,
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8. A process for the preparation of a benzoic acid derivative of formula (Ia)
wherein all symbols have the same meaning as above, characterized by subjecting to hydrolysis under alkaline conditions the compound of formula (Ib) wherein R20 is C1-6 alkyl and the other symbols have the same meanings as defined in claim 1. -
9. A process for the preparation of a benzoic acid derivative of formula (Ic)
wherein all symbols have the same meaning as defined in claim 1, characterized by subjecting to amidation reaction the compound of formula (Ia) wherein all symbols have the same meaning as defined in claim 1, and the compound of formula -
10. A process for the preparation of the benzoic acid of formula (Ib)
wherein R20 is C1-6 alkyl and the other symbols have the same meaning as defined in claim 1, characterized by subjecting to a reaction the compound of formula (III) wherein all symbols have the same meaning as defined in claim 1, and the compound of formula (IV) wherein all symbols have the same meaning as defined in claim 1. -
11. A pharmaceutical composition comprising the benzoic acid derivative of formula (I) described in claim 1 or a non-toxic salt thereof as active ingredient.
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12. A method for antagonizing EP4 receptor which comprises administering to a mammal an effective amount of the benzoic acid derivative of formula (I) as claimed in claim 1 or a non-toxic salt thereof as active ingredient.
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13. A method for the treatment and/or prophylaxis of bone diseases, cancer, systemic granuloma, immunological diseases, allergy, atopy, asthma, gumboil, gingivitis, periodontitis, neurocyte death, Alzheimer'"'"'s diseases, pulmonary injury, hepatopathy, acute hepatitis, nephritis, myocardial ischemia, Kawasaki disease, ambustion, ulcerative colitis, Crohn'"'"'s disease, multiple organ failure, sleeping disorder, platelet aggregation, etc., comprising the benzoic acid derivative of formula (I) described in claim 1 or a non-toxic salt thereof as active ingredient.
- OR9 or —
Specification