Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-12-20
1997-12-23
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546301, 546302, 546339, 546340, 5462764, C07D21330, C07D21332, C07D21355, C07D21365
Patent
active
057009430
DESCRIPTION:
BRIEF SUMMARY
SCOPE OF THE INVENTION
The field of this invention is that of a process for making certain thioethers by coupling a chloromethyl pyridyl compound with thiophenols and related mercaptans. The products of this coupling, the thioethers and their related sulfoxides and sulfones are useful for treating diseases arising from or related to leukotrienes, particularly leukotriene B.sub.4. As such there utility lies in antagonizing the affects of leukotrienes.
BACKGROUND OF THE INVENTION
A series of thioethers represented by the general formula ##STR2## have been discovered to be useful in treating diseases involving the leukotriene cascade, particularly those diseases believed to be associated with or caused by the dihydroxyleukotrienes (leukotriene B.sub.4). These thioethers can be found in certain publications, particularly PCT application Ser. No. PCT/US91/03772. A method for preparing those novel therapeutic agents is disclosed therein along with a description of utility and the background of the family of bioactive lipids known as the leukotrienes.
This invention relates to a process for making these compounds and other compounds of a similar nature where a chloromethylpridine is coupled with a thiophenol or benzylic mercaptan.
SUMMARY OF THE INVENTION
This invention covers a method for making a compound of formula I ##STR3## where R.sub.1 contains an .alpha.,.beta.-unsaturated carbonyl group and the designation (R).sub.n indicates hydrogen or one or more non-hydrogen radicals capable of being covalently bonded on the pyridyl and phenyl rings and m is 0-5; which method comprises coupling a chloromethylpyridine of formula II with a thiol of formula III in the presence of temperature between about ambient and 100.degree. C. for a period sufficient to effect the coupling. ##STR4## where R.sub.1 is defined above and (R).sub.n is hydrogen or one or more radicals which can be substituted on either the pyridyl or phenyl ring and m is 0-5.
GENERAL EMBODIMENTS
The following definitions are used in describing this invention.
An .alpha.,.beta.-unsaturated carbonyl group is illustrated by --CH.dbd.CH--C(.dbd.O)-- or --C.tbd.C--C(.dbd.O)--. The undefined carbonyl function valence can be a carbon--carbon bond, a carbon-heteroatom bond wherein the heteroatom is oxygen, nitrogen, sulfur or the like, including phosphorus. This invention is intended to cover all the enventualities where a thiol of the type illustrated is reacted with a pyridyl derivative which has an .alpha.,.beta.-unsaturated carbonyl system at the 2-position which can undergo a Michael addition reaction with the thiol.
The (R).sub.n designation is used here to indicate that one or more groups may be present on either the pyridyl ring or the phenyl ring. This invention also includes the case where each of these R groups is hydrogen. It is expected that any number and combination of substituents may be present on either ring. The only limitation envisioned is that the one of these groups must not interfere with the coupling reaction to a degree as to render the reaction impractical, ie, it does not occur at all, the yield is vanishing small, the wrong product is obtained in an undesirable amount. It should be understood that a given group may be in protected form, for example a carboxylate function may be present in the form of an ester, the acid being regenerated by hydrolytic, catalytic or enzymatic means once the coupling reaction is completed. The invention is that of the use of DBU to affect the coupling of the chloro and the thiol to achieve the thioether and is to be viewed as only so limited.
As for other terms, "aliphatic" is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination. The phrase "lower alkyl" means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. "Lower alkoxy" means the group lower alkyl-O--. "Acyl-lower alkyl" refers to
REFERENCES:
Journal of Organic Chemistry, vol. 3, Issued 1988, Trost et al., "Tetra-n-butylammonium Oxone. Oxidations under Anhydrous Conditions", pp. 532-537, esp. p. 535.
Kanagy James M.
Lentz Edward
Rotman Alan L.
SmithKline Beecham Corporation
Venetianer Stephen
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