Biphenyl-5-alkanoic acid derivatives and use thereof

Details Biphenyl-5-alkanoic acid derivatives and use thereof Biphenyl-5-alkanoic acid derivatives and use thereof

2000-06-08

2002-04-23

Carr, Deborah D. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S567000, C514S532000, C514S533000, C514S534000, C514S539000, C514S561000, C514S564000, C514S570000, C562S469000, C562S429000, C562S435000, C562S473000, C562S492000, C560S021000, C560S037000, C560S042000, C560S051000, C560S053000, C560S059000

Reexamination Certificate

active

06376546

ABSTRACT:

This application is a 371 of PCT JP/98/04456 Oct. 2, 1998
FILED OF THE INVENTION
This invention relates to novel biphenyl-5-alkanoic acid derivatives or salt thereof and a pharmaceutical composition containing the same as an active ingredient, especially IgE antibody production suppressor and drugs for treatment and prevention of allergic diseases characterized by IgE antibody suppressive action.
PRIOR ARTS
Allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis and anaphylaxis are classified into type I allergic reaction. The type I allergic reaction consists of, generally, the following three steps during the process of generation. Namely, these are: (1) the first step: antigen is entered into the body, and immunoglobulin E (IgE) is produced as a result of interaction with antigen-presenting cells such as macrophage, T cells and B cells, then the IgE antibody is bound with receptor on the cell membrane of mast cells and basophils to establish sensitization; (2) the second step: the reentry of antigen results to bind with IgE which is bound with the receptor, to generate degranulation of mast cells or basophils by antigen-antibody reaction to release chemical mediators such as histamine and SRS-A; and (3) the third step: the released chemical mediators induce contraction of the smooth muscle, capillary hyperpermeability and increase in mucous secretion to lead allergic reaction.
As above explained, the type I allergic reaction has known to be induced by IgE antibody production, and, in fact, serum or tissue levels of IgE antibody in patients with the aforementioned allergic diseases showed, in most cases, higher than those of the healthy subjects. Consequently, a compound, which selectively suppresses IgE antibody production, might be a useful agent for causal therapy of allergic diseases, and development of such a compound and its pharmaceutical product has been desired.
The known example of compound, which has similar structure of the compound of the present invention, is, for example, 3-(2-methoxy-1,1′-biphenyl-5-yl)propionic acid (J. Am. Chem. Soc., 75:2334, 1953) as choleretic agent. The said compound has different structure from the compound of the present invention in the ether moiety in phenolic hydroxy group in its structure, and in addition, no information on an action of IgE antibody production is disclosed. The same report discloses 3-(3-phenyl-4-methoxybenzoyl)propionic acid, however the said compound is different from the compound of the present invention in the ether moiety, furthermore a part of an oxo group in methylene moiety between biphenyl moiety and carboxy group is different in each other.
In the reference, Chem. Pharm. Bull. 35(5):1755, 1987, discloses methyl 3-(4′-allyloxy-2-benzyloxy-1,1′-biphenyl-5-yl)propionate is disclosed, however it is different from ether moiety from the compound of the present invention. In addition, the said compound was synthesized as an intermediate of a natural compound magaldehyde and no pharmacological action was disclosed. Further, in the said reference, on page 1762, methyl 3-(2,4′-dihydroxy-1,1′-biphenyl-5-yl)propionate and methyl 3-(4′-allyloxy-2-hydroxy-1,1′-biphenyl-5-yl)propionate were reported, however it was different in its ether moiety from the compound of the present invention, furthermore no pharmacological action has reported.
DE-4019307 and Japanese Patent Unexamined Publication No. Hei 4-230252 disclose methyl 2-methoxyimino-3-(4′-chloro-2-methoxy-1,1′-biphenyl-5-yl)propionate as harmful organisms preventive agent. The said compound is different from the compound of the present invention in the structure on the points having different structure in the ether moiety and having methoxyimino group in methylene moiety between biphenyl moiety and carboxy group. In addition, no action about IgE antibody production is disclosed.
DE-2513157 and Japanese Patent Unexamined Publication No. Sho 50-135050 disclose methyl 4-oxo-4-(2-methoxy-1,1′-biphenyl-5-yl)-2-methylene butyric acid as anti-inflammatory agent. The said compound is different from the compound of the present invention on the point that it has ether moiety and has oxo group and methylene group in the methylene moiety between biphenyl moiety and carboxy group. In addition, no IgE production is disclosed.
In Japanese Patent Unexamined Publication No. Sho 58-55469 describes 3-(3-t-butoxy-2-hydroxy-1,1′-biphenyl-5-yl)propionic acid as a stabilizer for resin. The said compound is different from the compound of the present invention on the point of substituents in the ether moiety and biphenyl moiety. Further, no pharmacological action is disclosed.
J. Med. Chem. 11:1139, 1968, discloses 4-(4-butoxy-1,1′-biphenyl-5-yl)-3-hydroxy butyric acid as anti-inflammatory agent. The said compound is different from the compound of the present invention on the point of position of substituent in ether moiety and having hydroxy group in methylene moiety between biphenyl moiety and carboxy group. Further, no IgE antibody production is disclosed.
In Japanese Patent Unexamined Publications No. Hei 4-95025 and No. Hei 4-95049 disclose biphenyl-5,5′-bis-alkanoic acid derivative as an aldose reductase inhibitor. The said compound is different from the compound of the present invention on the point having alkanoic acid in both of benzene rings in biphenyl moiety. Further, no IgE antibody production is disclosed.
U.S. Pat. No. 5,391,817 and Japanese Patent Unexamined Publication No. Hei 7-223997 disclose biphenyl derivatives as biaryl phospholipase A
2
inhibitor. The said compounds are different from the compound of the present invention on the point of ether moiety and no compound of the present invention is included in their claims. Further, no IgE antibody production is disclosed in these patents.
Problems to be Solved by the Invention
An aspect of the present invention is to provide a compound for treatment and prevention of allergic diseases caused by type I allergic reaction, which is suppressed by selectively suppressing IgE antibody production.
Means for Solving the Problems
In order to solve the above problems, we have extensively studied and found that the novel compound biphenyl-5-alkanoic acid derivatives represented by the general formula shown below have selective and superior suppressive action against IgE antibody production, then completed the present invention.
An object of the present invention is to provide a compound of the general formula (I) or salt thereof.
wherein n is an integer of either 2 or 3, R is straight or branched saturated alkyl of carbon numbers 4 or 5 (a), cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl or —(CH
2
)
m
W, proviso that saturated alkyl (a) may optionally be substituted by hydroxy, oxo or halogen, m is an integer of 1-3, W is carboxy or —CONR
1
R
2
, in which R
1
and R
2
are in together or each separately hydrogen or lower alkyl of C
1-4
, Y is hydroxy or amino, A is hydrogen, hydroxy, methoxy, nitro or —NHZ, in which Z is —CO R
3
or —SO
2
R
4
, in which R
3
is hydrogen, saturated alkyl (b) of C
1-4
or —NR
5
2
, the saturated alkyl (b) may optionally be substituted by hydroxy or halogen, R
4
is saturated alkyl (c) of C
1-4
or —NR
6
2
, the saturated alkyl (c) may optionally be substituted by halogen, R
5
and R
6
are hydrogen or lower alkyl of C
1-4
, and Q is hydrogen, hydroxy or methoxy [hereinafter sometimes designates as “the compound (I)”].
Another object of the present invention is to provide a drug comprising the compound of the above general formula (I) or pharmacologically acceptable salt thereof as an active ingredient.
In the above general formula (I), n is defined as any one of integer of 2 or 3. No effect is obtained wherein n is 1 or 4. Since it is extremely characteristics when n is 2 or 3, ethylene in 2 or trimethylene in 3 is preferable.
A group R is defined as straight or branched saturated alkyl of carbon numbers 4 or 5 (a), cyclopentyl, cyclohexyl, cycl

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