Substituted oxygen alicyclic compounds, including methods...

Details Substituted oxygen alicyclic compounds, including methods... Substituted oxygen alicyclic compounds, including methods...

2001-10-02

2002-08-13

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S266000, C549S273000, C549S295000, C549S323000, C549S324000

Reexamination Certificate

active

06433197

ABSTRACT:

BACKGROUND
1. Field of the Invention
The present invention provides new methods for preparation of various oxygen ring compounds (oxygen as an alicyclic ring member) including 2,5-disubstituted-tetrahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. The invention further provides novel compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.
2. Background
Leukotrienes are recognized potent local mediators, playing a significant role in inflammatory and allegeric responses, including arthritis, asthma, psoriasis and thrombotic disease. Leukotrienes are produced by the oxidation of arachidonic acid by lipoxygenase. More particularly, arachidonic acid is oxidized by 5-lipooxygenase to the hydroperoxide 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), that is converted to leukotriene A
4
, that in turn can be converted to leukotriene B
4
, C
4
, or D
4
. The slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C
4
, D
4
and E
4
, all of which are potent bronchoconstrictors.
Efforts have been made to identify receptor antagonists or inhibitors of leukotriene biosynthesis, to prevent or minimize pathogenic inflammatory responses mediated by leukotrienes.
For example, European Patent Application Nos. 901171171.0 and 901170171.0 report indole, benzofuran, and benzothiophene lipoxygenase inhibiting compounds.
Various 2,5-disubstituted tetrahydrofurans have exhibited significant biological activity, including as lipoxygenase inhibitors. See U.S. Pat. Nos. 5,703,093; 5,681,966; 5,648,486; 5,434,151; and 5,358,938.
While such compounds are highly useful therapeutic agents, current methods for synthesis of least some of the compounds require lengthy routes, and reagents and protocols that are less preferred in larger scale operations, such as to produce kilogram quantities.
It thus would be desirable to have improved methods to substituted tetrahydrofurans and other cyclic oxygen compounds, particularly new syntheses that facilitate larger scale production of such compounds.
SUMMARY OF THE INVENTION
We have now found new methods for preparation of cyclic oxygen compounds, including 2,5-disubstituted tetrahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. These methods utilize reagents and synthetic protocols that facilitate large scale manufacture, and provide increased yields relative to prior approaches.
The methods of the invention are suitable for preparation of a variety of cyclic oxygen-containing compounds (i.e., alicyclic compounds having an oxygen ring member), including compounds of the following Formula I:
wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;
each R
1
, X and Y is independently hydrogen or a non-hydrogen substituent such as halogen, hydroxyl, optionally substituted alkyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkenyl preferably having from 2 to about 20 carbon atoms, optionally substituted alkynyl preferably having from 2 to about 20 carbon atoms, optionally substituted alkoxy preferably having from 1 to about 20 carbon atoms, optionally substituted alkylthio preferably having from 1 to about 20 carbon atoms, optionally substituted alkylsulfinyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkylsulfonyl preferably having from 1 to about 20 carbon atoms, optionally substituted aminoalkyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkanoyl preferably having from 1 to about 20 carbon atoms, optionally substituted carbocyclic aryl having at least about 6 ring carbons, or substituted or unsubstituted aralkyl having at least about 6 ring carbons, and the like;
Z is a chemical bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkylene, or a hetero atom such as O, S, S(O), S(O)
2
, or NR
1
wherein R
1
is the same as defined immediately above;
n is an integer from 1 to 11, and preferably is 1 to 9, more preferably 1 to 7;
p is an integer from 0 (where the &agr; and &bgr; ring positions are fully hydrogen-substituted) to 4; and pharmaceutically acceptable salts thereof.
The methods of the invention are particularly suitable for synthesis of substituted tetrahydrofurans, including compounds of the following Formula II:
wherein Ar is optionally substituted aryl or heteroaryl;
m is 0 or 1; n is 1-6;
W is —AN(OM)C(O)N(R
3
)R
4
, —N(OM)C(O)N(R
3
)R
4
, —AN(R
3
)C(O)N(OM)R
4
, —N(R
3
)C(O)N(OM)R
4
, —AN(OM)C(O)R
4
, —N(OM)C(O)R
4
, —AC(O)N(OM)R
4
, —C(O)N(OM)R
4
, or —C(O)NHA; and A is lower alkyl, lower alkenyl, lower alkynyl, alkylaryl or arylalkyl, wherein one or more carbons optionally can be replaced by N, O or S, however —Y—A—, —A—, or —AW— should not include two adjacent heteroatoms;
M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;
X and Y are each independently O, S, S(O), S(O)
2
, NR
3
or CHR
5
;
Z is O, S, S(O), S(O)
2
, or NR
3
;
R
1
and R
2
are each independently hydrogen, lower alkyl, C
3-8
cycloalkyl, halolower alkyl, halo or —COOH;
R
3
and R
4
are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, C
1-6
alkoxy-C
1-10
alkyl, C
1-6
alkylthio-C
1-10
alkyl, heteroaryl, or heteroarylalkyl;
R
5
is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkaryl, —AN(OM)C(O)N(R
3
)R
4
, —AN(R
3
)C(O)N(OM)R
4
, —AN(OM)C(O)R
4
, —AC(O)N(OM)R
4
, —AS(O)
x
R
3
, —AS(O)
x
CH
2
C(O)R
3
, —AS(O)
x
CH
2
CH(OH)R
3
, or —AC(O)NHR
3
, wherein x is 0-2; and pharmaceutically acceptable of such compounds.
Compounds of Formula II have been disclosed in U.S. Pat. No. 5,703,093. As disclosed in that patent, preferred compounds of Formula II include compounds where Ar is substituted by halo (including but not limited to fluoro), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), W (as defined above in Formula II), cyano, or R
3
(as defined above in Formula II). Those substituents are also preferred Ar group substituents for compounds of other formulae disclosed herein. Specifically suitable Ar groups for the above Formula II as well as the other formulae disclosed herein include phenyl, trimethoxyphenyl, dimethoxyphenyl, fluorophenyl (specifically 4-fluorophenyl), difluorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidazolyl, and thienyl. Additionally, in Formula II as well as other formulae disclosed herein, W suitably is lower alkyl, such as a branched alkyl group, e.g. —(CH2)
n
C(alkyl)H—, wherein n is 1-5, and specifically —(CH
2
)
2
C(CH
3
)H—, or lower alkynyl such as of the formula —C≡C—CH(alkyl)-, including —C≡C—CH(CH
3
)—.
In particularly preferred aspect, methods of the invention are employed to synthesis the following compound 1, 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran:
It has been found that biological activity, particularly 5-lipoxygenase activity, can vary among optically active isomers of compounds of the invention, and therefore a single optical isomer of a compound may be preferred. Accordingly, the synthetic methods of the invention include preparation of enantiomerically enriched compounds of the invention.
In a first preferred aspect, substituted tetrahydrofuran compounds are provided by reacting a hydroxy substituted aryl compound with an epoxide having a reactive carbon, e.g. a glycidyl compound substituted at the C3 position with an electron-withdrawing group such as halo (e.g. epichlorohydrin, epibromohydrin), mesyl or tosyl (glycidyl mesylate and glycidyl tosylate), etc., to form an epoxyarylether or epoxyoarylether in the presence of base and preferably at or above about 0° C. (As used herein, the term “aryl” refers to both carbocyclic aryl and heteroaromatic or heteroaryl groups, which terms are further discussed below). That epoxyether is then r

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