Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-06-06
2004-09-07
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06787653
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a preparation process for biphenylcarboxylic acid amide derivatives or salts thereof which have inhibitory activity against IgE antibody production and are, therefore, useful as a preventive or remedy for allergic immunological diseases.
2. Description of the Background
IgE antibody, which is a kind of immunoglobulin (Ig), is an allergen-specific molecule produced by an IgE antibody producing cell, which has been differentiated from a B cell, triggered by contact of an immunocyte with an allergen in vivo.
IgE antibody is produced in a target organ of an allergy and binds to a receptor on the surface of a mast cell, which is an important effector cell in an allergic reaction, or a basophil (sensitization). After sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injuring enzymes such as tryptase are released from the mast cell, stimulated by an allergen which has invaded in the living body and reacted with the specific IgE antibody. Then, immediate allergic reactions such as increased vascular permeability, smooth muscle contraction and vasodilation are elicited. From the stimulated mast cell, cytokines such as IL-4, which directly activate other immune system cells, are also secreted. As a result, eosinophils, basophils and the like infiltrate into the tissue, and the allergic chemical mediators and tissue injuring proteins such as MBP, which are secreted by these inflammatory cells, induce a late-phase allergic reaction, thereby lingering the allergic symptom and making them serious.
From this, IgE antibody is considered a substance fundamentally taking part in allergic immunological diseases. A number of IgE antibody production inhibitors have been studied with a view to developing an antiallergic agent.
From such a viewpoint, the present inventors found that compounds having a diamide structure with aromatic rings at both ends of the molecule, particularly, 1,3-bis[4-[4-[(substituted)phenyl]benzoyl]-1-piperazinyl]propane which is a biphenylcarboxylic acid amide derivative represented by the following formula (1):
wherein, R
1
, R
2
and R
3
each independently represents a hydrogen atom or a substituent) has excellent inhibitory activity against IgE antibody production and is useful as an anti-allergic, as described in international patent WO 99/42446.
The preparation process for the biphenylcarboxylic acid amide derivatives however comprises 6 steps as shown in the synthesis route described below. Thus, this route requires a large number of steps.
For forming a biphenylcarboxylic acid portion of the compound, a cross-coupling reaction (Suzuki reaction) using a (substituted)phenylboronic acid (3a) in the presence of a palladium catalyst is employed. The necessity of carrying out this reaction in the first step leads to an increase in the amount of expensive boronic acid (3a).
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process for preparing a biphenylcarboxylic acid amide derivative represented by the formula (1) or salt thereof conveniently by a reduced number of steps, at lower cost and in high yield.
With a view to developing a novel preparation process of a biphenylcarboxylic acid amide derivative represented by the formula (1) or salt thereof, the present inventors have carried out an extensive investigation. As a result, it has been found that the biphenylcarboxylic acid amide derivative represented by the formula (1) or salt thereof can be prepared by fewer steps in a high yield by reacting, in the presence of a metal catalyst, 1,3-bis[4-(4-halogenobenzoyl)-1-piperazinyl]propane, which is available from N-(4-halogenobenzoyl)piperazine and 1,3-di(leaving group)propane, with a (substituted)phenyl compound having a leaving group containing an element such as boron, thereby forming the biphenylcarboxylic acid portion of the compound in the final step, leading to the completion of the invention.
The present invention is represented by the following reaction scheme:
wherein X represents a halogen atom, Y represents an leaving group having an element selected from the group consisting of boron, silicon, zinc, tin and magnesium, and R
1
, R
2
and R
3
each independently represents a hydrogen atom or a substituent.
In the present invention, there is thus provided a process for preparing a biphenylcarboxylic acid amide derivative represented by the formula (1) by reacting a halogenobenzoic acid derivative represented by the formula (2) with a compound represented by the formula (3) in the presence of a metal catalyst; or salt thereof.
Accordingly, the present invention provides a process for preparing a biphenylcarboxylic acid amide derivative represented by formula (1) or a salt thereof:
wherein
R
1
, R
2
and R
3
each, independently, represent a hydrogen atom or a substituent selected from the group consisting of a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, amino group, mono(lower alkyl)amino groups, di(lower alkyl)amino groups, lower alkylthio groups, lower alkanoyl groups, and a formyl group,
which comprises reacting, in the presence of a metal catalyst, a halogenobenzoic acid derivative represented by formula (2):
wherein
X represents a halogen atom,
with a compound represented by formula (3):
wherein
R
1
, R
2
and R
3
have the same meanings as defined above, and
Y represents a leaving group having an element selected from the group consisting of boron, silicon, zinc, tin, and magnesium.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following description.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, it is preferred that the halogenobenzoic acid derivative (2) is prepared by reacting a compound represented by the formula (4) with a 1,3-di(leaving group)propane.
As each of R
1
, R
2
and R
3
in the formulas (1) and (3), examples include hydrogen atom, hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, amino group, mono(lower alkyl)amino groups, di(lower alkyl)amino groups, lower alkylthio groups, lower alkanoyl groups and formyl groups. Of these, preferred are hydrogen atom, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, di(lower alkylamino) groups, lower alkylthio groups and lower alkanoyl groups, with lower alkoxy, lower alkanoyl and lower alkylthio groups being more preferred. A protecting group may be introduced as needed and after reaction, it may be removed. The term “lower” as used herein means that the group has 1 to 6 carbon atoms. This range includes all specific values.
As the lower alkyl groups, preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl groups, of which methyl, ethyl, n-propyl and isopropyl groups are especially preferred.
Examples of the lower alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy and t-butoxy, with methoxy, ethoxy, n-propoxy and isopropoxy groups being preferred.
Examples of the lower alkanoyl groups include acetyl, propionyl, butyryl and isobutyryl groups, with acetyl and propionyl groups being preferred.
Examples of the lower alkylthio groups include methylthio, ethylthio, n-propylthio and isopropylthio groups.
Examples of the mono(lower alkyl)amino groups include methylamino, ethylamino, n-propylamino, and isopropylamino groups.
Examples of the di(lower alkyl)amino groups include dimethylamino, diethylamino, di(n-propyl)amino, and diisopropylamino groups.
Examples of the lower alkyl groups substituted by 1 to 3 halogen atoms include chloroethyl and trifluoromethyl.
Examples of the halogen atoms include chlorine, bromine, iodine and fluorine, with chlorine, bromine and fluorine being preferred.
As each of
Ishiwata Hiroyuki
Kabeya Mototsugu
Oda Soichi
Sato Seiichi
Kowa Co. Ltd.
Liu Hong
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Shah Mukund J.
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