Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-29
2002-05-28
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254100, C514S255050, C514S469000, C544S358000, C544S376000, C544S386000, C544S398000, C544S399000, C546S281700, C546S284100, C549S462000, C549S467000, C549S468000
Reexamination Certificate
active
06395738
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to benzofuran derivatives which have phosphodiesterase (PDE) IV inhibitory activity and which are useful as a therapeutic agent for inflammatory allergic diseases such as bronchial asthma, allergic rhinitis and nephritis; autoimmune diseases such as rheumatism, multiple sclerosis, Crohn's diseases, psoriasis and systemic lupus erythematosus; diseases of the central nervous system such as depression, amnesia and dementia; organopathy associated with ischemic reflux caused by cardiac failure, shock and cerebrovascular disease, and the like; insulin-resistant diabetes; wounds; AIDS; and the like.
BACKGROUND ART
Heretofore, it is known that the functions of numerous hormones and neurotransmitters are expressed by an increase in the concentration of adenosine 3′,5′-cyclic monophosphate (cAMP) or guanosine 3′,5′-cyclic monophosphate (cGMP), both of which are the secondary messengers in cells. The cellular concentrations of cAMP and cGMP are controlled by the generation and decomposition thereof, and their decomposition is carried out by PDE. Therefore, when PDE is inhibited, the concentrations of these secondary cellular messengers increase. Up to the present, 7 kinds of PDE isozymes have been found, and the isozyme-selective PDE inhibitors are expected to exhibit pharmaceutical effect based on their physiological significance and distribution in vivo [TiPS, 11, 150 (1990), ibid., 12, 19 (1991)].
It is known that the activation of inflammatory leukocytes can be suppressed by increasing the concentration of the cellular cAMP. The extraordinary activation of leukocytes causes secretion of inflammatory cytokines such as tumor necrosis factor (TNF), and expression of the cellular adhesion molecules such as intercellular adhesion molecules (ICAM), followed by cellular infiltration [J. Mol. Cell. Cardiol., 12 (Suppl. II), S61 (1989)].
It is known that the contraction of a respiratory smooth muscle can be suppressed by increasing the concentration of the cellular cAMP (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O'Donell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). The extraordinary contraction of a respiratory smooth muscle is a main symptom of bronchial asthma. Infiltration of inflammatory-leukocytes such as neutrophils is observed in lesions of organopathy associated with ischemic reflux such as myocardial ischemia. It has been found that the type IV PDE (PDE IV) mainly participates in the decomposition of cAMP in these inflammatory cells and tracheal smooth muscle cells. Therefore, the inhibitors selective for PDE IV are expected to have therapeutic and/or preventive effect on inflammatory diseases, respiratory obstructive diseases, and ischemic diseases.
Further, the PDE IV inhibitors are expected to prevent the progress and spread of the inflammatory reaction transmitted by inflammatory cytokines such as TNF&agr; and interleukin (IL)-8, because the PDE IV inhibitors suppress the secretion of these cytokines by increasing the concentration of cAMP. For example, TNF&agr; is reported to be a factor of insulin-resistant diabetes because it declines the phosphorylating mechanism of insulin receptors in muscle and fat cells [J. Clin. Invest., 94, 1543 (1994)]. Similarly, it is suggested that the PDE IV inhibitors may be useful for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and Crohn's disease because TNF&agr; participates in the onset and progress of these diseases [Nature Medicine, 1, 211 (1995) and ibid., 1, 244 (1995)].
WO97/20833 discloses benzofurancarboxamide derivatives having PDE IV inhibitory activity, but none of compounds having substituted piperazinylcarbonyl bound at the 2-position of the benzofuran ring are specifically disclosed.
WO96/36624 discloses benzofuran derivatives having PDE IV inhibitory activity.
However, the conventional PDE IV inhibitors have a problem of induction of vomiting [TiPS, 18, 164 (1997)].
DISCLOSURE OF THE INVENTION
A novel and useful PDE IV inhibitor is expected to have prophylactic or therapeutic effects on a wide variety of diseases. An object of the present invention is to provide benzofuran derivatives having a superior anti-inflammatory activity and causing no vomiting.
The present invention relates to benzofuran derivatives represented by following formula (I):
wherein R
1
represents lower alkyl, R
2
represents hydrogen or substituted or unsubstituted lower alkyl, R
3
, R
4
, R
5
and R
6
independently represent hydrogen or lower alkyl, X represents CH
2
or C═O, and Y represents CH
2
or NH, or pharmaceutically acceptable salts thereof.
Hereinafter, the compounds represented by the general formula (I) are referred to as Compound (I). The same applies to the compounds of other formula numbers.
In addition, the present invention relates to a therapeutic agent for inflammatory allergic diseases, which comprises Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
Further, the present invention relates to a method for treating inflammatory allergic diseases, which comprises administering an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention relates to a use of Compound (I) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition which is useful for the treatment of inflammatory allergic diseases.
The pharmaceutically acceptable acid addition salt of Compound (I) includes inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, and organic acid salts such as acetate, maleate, fumarate and citrate.
In the definitions of the groups in formula (I), the lower alkyl includes straight-chain or branched C
1
to C
8
alkyl groups such as methyl, ethyl,.propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
The substituted lower alkyl has the same or different 1 to 3 substituents such as hydroxy and substituted or unsubstituted lower alkoxy. The alkyl moiety of the lower alkoxy has the same meaning as the lower alkyl defined above, and the substituted lower alkoxy has the same or different 1 to 3 substituents such as hydroxy.
Among Compound (I), preferred compounds are Compound (I) wherein R
2
is substituted or unsubstituted lower alkyl, and specifically preferred compounds are Compound (I) wherein R
2
is lower alkyl or hydroxy-substituted lower alkyl.
Among Compound (I), preferred compounds are Compound (I) wherein X is CH
2
, and Y is CH
2
; or x is C═O, and Y is CH
2
or NH.
A process for producing Compound (I) is described below.
Process: Compound (I) can be produced according to the following processes.
Process 1
(In the formulae, R
1
has the same meaning as defined above, and R
7
represents lower alkyl.)
In the above formulae, the lower alkyl represented by R
7
has the same meaning as the lower alkyl defined above.
Compound (III) can be produced by subjecting Compound (II) to formylation. Compound (II) as the starting material can be synthesized according to a method described in Bull. Soc. Chim. Fr., 2355 (1973) or a similar method thereto.
Specifically, Compound (III) can be obtained by reacting Compound (II) in an inert solvent with 1 equivalent to a large excess of dichloromethyl methyl ether in the presence of 1 equivalent to an excess of an acid for 5 minutes to 48 hours at a temperature between −50° C. and the boiling point of the solvent used.
Examples of the acid are methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride, aluminum chloride, stannic chloride, titanium tetrachloride, zinc chloride and ferric chloride, among which titanium tetrachloride is preferable.
Examples of the inert solvent are tetrahydrofuran (THF), dioxane, diethyl ether, ethylene glycol, triethylene glycol, glime, diglime, dichloromethane, chloroform, benzene and toluene, among which halogenated hydrocarbons such as dichloromethan
Manabe Haruhiko
Matsuzaki Tohru
Ohshima Etsuo
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
Patel Sudhaker B.
Raymond Richard L.
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