Substituted arylalkanoic acid derivatives and use thereof
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a technology of arylalkanoic acid and derivatives, which is applied in the field of substituted arylalkanoic acid derivatives, can solve the problems of increased production of leukotrienes, side effects, and small difference between effective dose and dose inducing side effects
Inactive Publication Date: 2009-03-05
ASAHI KASEI PHARMA
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Benefits of technology
[0196]The compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an action of suppressing the production of both of prostaglandins and leukotrienes, and said compound has characteristic features that, when administered to a human or animal, the compound exerts superior prophylactic and / or therapeutic effect on diseases or pathological conditions in which a prostaglandin and / or leukotriene is involved, and the compound has extremely low toxicity. The compounds (II) and (III) of the present invention are synthetic intermediates useful for the production of the compound (I) of the present invention. Furthermore, it was confirmed that a type 4 PLA2 inhibitor is useful as a prophylactic and / or therapeutic agent for fibrosis, in particular, pulmonary fibrosis, especially drug-induced pulmonary fibrosis, which was induced as a side effect of a medicament.
Problems solved by technology
However, the class of NSAIDS suppress only production of prostaglandins, and as a result, they increase amounts of production of leukotrienes, and exhibit side effects such as asthmatic attack and gastrointestinal injury as well as renal disturbance.
Furthermore, a difference between an effective dose and a dose inducing the side effects is small in these NSAIDS, and no satisfactory agent is available from a viewpoint of therapeutic effect.
However, since the agent causes side effects such as hepatic disorder, its dosage is limited, and the agent is not satisfactory also from a viewpoint of therapeutic effect.
However, their actions are not limited to the lipid mediator production-suppressing action, and they exhibit severe side effects such as induction and exacerbation of infectious diseases due to the immunosuppression action, growth retardation due to normal cell antiproliferative activity, anetoderma and peptic ulcer.
Therefore, their uses are limited.
Method used
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examples
[0621]The present invention will be further specifically explained with reference to examples. However, the scope of the present invention is not limited to the following examples. In the examples, for thin layer chromatography (TLC), Precoated Silica Gel 60 F254 (produced by Merck, product number: 5715-1M)) was used. After development with chloroform:methanol (1:0 to 1:1), acetonitrile:acetic acid:water (200:1:1 to 100:4:4) or ethyl acetate:hexane (1:0 to 0:1), spots were observed by UV irradiation (254 nm) or color development with ninhydrine or dinitrophenylhydrazine solution in hydrochloric acid. For drying organic solvent, anhydrous magnesium sulfate or anhydrous sodium sulfate was used. As for column chromatography, the indication of “Quad” means use of Quad 1 preparative chromatography system (produced by Biotage), and one or several columns selected from cartridge columns KP-Sil-12M, 40S and 40M produced by the same manufacturer were used depending on the amount of sample. F...
example a-1
Synthesis of methyl 3-(4-hydroxyphenyl)propionate (Intermediate 1)
[0627]A solution obtained beforehand by adding thionyl chloride (18.3 ml, WAKO) dropwise to methanol (250 ml) and mixing the mixture under ice cooling was added dropwise with a solution of 3-(4-hydroxyphenyl)propionic acid (16.6 g, TCI) in methanol (50 ml) under ice cooling, stirred for 30 minutes, warmed to room temperature, and further stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then extracted with diethyl ether (200 ml). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate 1, 17.95 g).
Synthesis of methyl 3-(4-cyclopentylmethyloxyphenyl)propionate (Intermediate 2)
[0628]A solution of cyclopentane methanol (4.05 ml, Ald) in anhydrous tetrahydrofuran (a...
example a-2
Synthesis of 3-(3-bromo-4-methoxyphenyl)propionic acid (Intermediate 3)
[0630]According to the procedure described in the synthesis method of Compound No. A-1 provided that the reaction was carried out under ice cooling for 30 minutes and at room temperature for 3 hours, 3-(4-methoxyphenyl)propionic acid (27.0 g, TCI) and NBS (29.4 g) were reacted and treated to obtain the title compound (Intermediate 3, 38.1 g).
Synthesis of 3-(3-bromo-4-hydroxyphenyl)propionic acid (Intermediate 4)
[0631]According to a procedure described in a literature (Carreno, M. C., J. Org. Chem., 1995, vol. 60, p. 5328), a 1 M solution of boron tribromide in methylene chloride (200 ml, Fluka) was added dropwise with a solution of Intermediate 4 (23.5 g) in methylene chloride (200 ml) at −78° C., warmed to room temperature after 30 minutes, and further stirred for 1.5 hours. The reaction mixture was poured into ice water (750 ml), and stirred at room temperature for 1 hour. The reaction mixture was added with di...
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Abstract
A compound represented by the formula (I):[In the formula, Link represents a saturated or unsaturated straight hydrocarbon chain having 1 to 3 carbon atoms, C2 to C6 in the aromatic ring (E) independently represent a ring-constituting carbon atom, one of the ring-constituting carbon atoms may be replaced with V, V represents nitrogen atom, or carbon atom substituted with Zx, Zx represents a saturated alkyl group having 1 to 4 carbon atoms and the like, Rs represents -D-Rx etc., D represents a single bond, oxygen atom and the like, Rx represents a saturated alkyl group having 3 to 8 carbon atoms and the like, AR represents a partially unsaturated or completely unsaturated condensed bicyclic carbon ring or a heterocyclic ring, and Y represents hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms and the like] or a salt thereof. A compound having prostaglandin production-suppressing action and leukotriene production-suppressing action is provided.
Description
[0001]This application is a Divisional of co-pending application Ser. No. 10 / 568,185 filed on Feb. 13, 2006 and for which priority is claimed under 35 U.S.C. § 120. application Ser. No. 10 / 568,185 is the national phase of PCT International Application No. PCT / JP2004 / 011953 filed on Aug. 13, 2004 under 35 U.S.C. § 371. This application also claims priority to U.S. Provisional Application No. 60 / 495,734, filed Aug. 18, 2003 under 35 U.S.C. § 119(e) and JP2003-293590, filed in Japan on Aug. 14, 2003 under 35 U.S.C. § 119(a). The entire contents of each of the above-identified applications are hereby incorporated by reference.FIELD OF THE INVENTION[0002]The present invention relates to a novel substituted arylalkanoic acid derivative. More specifically, the present invention relates to a substituted arylalkanoic acid derivative having an action as a medicament and a synthetic intermediate of said compound.BACKGROUND ART[0003]Various kinds of prostaglandins and various kinds of leukotrie...
Claims
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Patent Type & Authority Applications(United States)
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