Process for preparing 5-lipoxygenase inhibitors

Details Process for preparing 5-lipoxygenase inhibitors Process for preparing 5-lipoxygenase inhibitors

1999-08-24

2001-02-27

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S397000

Reexamination Certificate

active

06194585

ABSTRACT:

BACKGROUND OF THE INVENTION.
This invention relates to the process and intermediates for preparing 5-lipoxygenase inhibitors. The 5-lipoxygenase inhibitors that are prepared in accord with the present invention are disclosed in U.S. Pat. No. 5,883,106 which is a continuation of 08/809,901 filed Jun. 13, 1997 now abandoned. This pending application is entitled “5-lipoxygenase Inhibitors” and is incorporated by reference in its entirety.
The 5-lipoxygenase inhibitors that are prepared in accord with the present invention are selective inhibitors of the action of lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl, which comprises reacting a compound of the Formula
 wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl, with a sulfonic acid in a C
1
-C
5
alkyl alcohol; and precipitating the compound of Formula I by addition of an organic solvent that is less polar than the alcohol.
The acid is methanesulfonic acid and the organic solvent is diisopropyl ether or ethylacetate.
In a further aspect of the present invention, the compound of Formula II is prepared by reacting a compound of Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted, with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl, with a hydroxide in an alcohol solvent.
The hydroxide is potassium hydroxide and the alcohol is tertiary butyl alcohol.
In a further aspect of the present invention, the compound of Formula III is prepared by reacting a compound of Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl, with an organic or mineral acid.
The acid is acetic acid, sulfuric acid, formic acid or p-toluenesulfonic acid. The preferred acid is formic acid.
In a further aspect of the present invention, the compound of Formula IV is prepared by reacting the compound of Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl and wherein X is Cl, Br, I, or OCH
3
with an excess of amino acetaldehyde acetal.
The amino acetaldehyde acetal is aminoacetaldehyde dimethylacetal or aminoacetaldehyde diethyl acetal
In a further aspect of the present invention, the compound of Formula V wherein X is Cl, Br or I is prepared by reacting a compound of Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl, with a phosphorous pentahalide in an inert solvent. The compound of Formula V may also be prepared by reacting a compound of Formula VI with (CH
3
)
3
O
+
BF
4
−
to form an intermediate where x is OCH
3
.
The pentahalide is phosphorous pentachloride, phosphorous pentaiodide or phosphorous pentabromide and the solvent is toluene. The preferred A is CH
3
.
In a further aspect of the present invention, the compound of formula VI is prepared by the reacting of a compound of the Formula
wherein X is Cl, Br or I with an excess of 4-amino-thiopenol with a base in an inert solvent to give a compound of Formula
 and further treating a compound of formula VII by acylation with an acid halide or anhydride.
Another more preferably way of preparing a compound of Formula VI is by reacting a compound of the Formula VIII
wherein X is Cl, Br, or I with an excess of 4-amido-thiopenol with a base in an inert solvent.
The 4-amido thiophenol is 4-acetamido thiophenol The solvent is NMP or DMSO.
The base is sodium carbonate/cesium carbonate.
In a further aspect of the present invention, the compound of Formula VIII can be prepared by reacting a compound of Formula
wherein X is Br, Cl or I with bis 2-chloroethyl ether, an alkaline base and a phase transfer catalyst in an inert solvent.
The phase transfer catalyst is tetrabutyl ammonium hydrogen sulfate. The base is sodium hydroxide.
The inert solvent is a mixture of tetrahydrofuran and water.
The invention also relates to a novel compound of the Formula
The invention also relates to a novel compound of the Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl.
The invention also relates to a novel compound of the Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl and wherein X is I, Br, Cl or OCH
3
.
The invention also relates to a novel compound of the Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl and wherein R is C
1
-C
6
alkyl.
The invention also relates to a novel compound of the Formula
wherein A is C
1
-C
6
alkyl, an aryl, which is mono or disubstituted with F, Cl, Br, OCH
3
, C
1
-C
3
alkyl or benzyl.
A preferred compound is
These novel compounds are used in the preparation of 5-lipoxygenase inhibitors and their pharmaceutical composition useful in the treatment or an alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals.
DETAILED DESCRIPTION OF THE INVENTION
The new process synthesis is shown in the Reaction Scheme 1 below
3-Bromophenyl acetonitrile in tetrahydrofuran is treated with aqueous NaOH, tetra butyl ammonium hydrogen sulfate and bis 2-chloro-ethyl ether to give the aryl bromide compound of Formula VIII.
The aryl bromide compound VIII is treated with either 4-aminothiophenol to give the aniline compound VII followed by acylation or with the 4-amidothiophenol to give the amide compound VI. The imidazole function is incorporated with transformation of the Formula VI amido group by heating compound VI with a phosphorous pentahalide to give the compound V which is treated with aminoacetaldehyde alkylacetal to provide the amidine compound IV. The amidine compound IV exists as a mixture of tautomers which are not isolated and are immediately subjected to acid-induced cyclization to provide the imidazole compound III. Subsequent hydrolysis of the nitrile function of the Imidazole compound III gives the 5-lipoxyygenase inhibitor compound II. The preferred salt form is found by treating compound II with methanesulfonic acid to give compound I.
The new process of the present invention eliminates the previous two expensive palladium (O) coupling reactions to introduce a sulfide linkage to the molecule as described in U.S. Pat. No. 5,883,106 incorporated by reference in its entirety. In addition the above preferred sulfur atom was previously introduced by means of a TIPS-thiol reagent (TIPS IS TRISOPROPYL SILYL), which is prepared from toxic hydrogen sulfide and expensive TIPS-chloride
Compound I where A is CH
3
is the preferred salt form of a 5-lipoxygenase inhibitor that is useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. In particular compound I is of use in the treatment or alleviation of inflammatory diseases.
These useful 5-lipoxygenase inhibitors can be administered in a wide variety of dosages form.
For treatment of the various conditions described above, the compounds and their pharmaceutically acceptable salts can be administered to a human subject either alone, or preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice. The compounds can be administered orally or parenterally in conventional fashion.
When the Compounds are administered to a human subject for the prevention or treatment of an inflammatory disease, the oral dose range will be from about 0.1 to 10 mg/kg, per body weight of the Subject to be treated per day, preferably from about 0.1 to 4 mg/kg, per day in single or divided doses. If parenteral admini

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