4-thio coumarins

Details 4-thio coumarins 4-thio coumarins

2003-05-13

2004-03-09

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S285000

Reexamination Certificate

active

06703514

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel 4-thio substituted coumarin derivatives and coumarin dimers, and processes for their preparation. The invention provides a synthetic process for the preparation of 4-thio substituted coumarin derivatives using mild reaction conditions, which provides a high substituent tolerance and is appropriate for use in solid phase syntheses for producing a library of 4-thio substituted coumarin derivatives for biological screening.
BACKGROUND OF THE INVENTION
Strategies in new drug discovery often look to natural products for leads in finding new chemical compounds with therapeutic properties. One of the recurring problems in drug discovery is the availability of organic compounds derived from natural sources. Techniques employing combinatorial chemistry attempt to overcome this problem by allowing the high throughput synthesis and testing of hundreds or thousands of related synthetic compounds, called a chemical library. In designing the synthesis of a prospective therapeutic compound or a chemical library, one often looks to natural chemical motifs which are known to have broad biological activity. Of particular interest are materials which have structural components, such as coumarins, flavones, and isoflavones, which are similar to secondary metabolites from plant extracts.
Coumarins are widely distributed in the plant kingdom. Approximately 50 naturally occurring coumarin derivatives have been identified. Derivatives of coumarin posses a range of biological activities. Of particular interest to researchers are modification at the 3- and 4-position of the coumarin scaffold and synthesis of symmetrical and unsymmetric dimers of coumarin compounds for biological evaluations. To avoid confusion, the coumarin derivatives described herein are numbered according to the following convention:
Unfortunately, the preparation of such coumarin derivatives has suffered from multiple difficulties. This is particularly true of 4-substituted thiol derivatives of coumarin. Although certain 4-thio coumarins have been prepared, their synthesis has involved harsh conditions (such as the use of stoichiometric amounts of strong bases or toxic reagents, often under high temperatures), multiple synthetic steps, and poor substituent tolerance. For example, Parfenov et al. discussed a route for synthesis of 4-coumarinyl sulfides derivatives from 4-tosyl coumarin using harsh reaction conditions or from 4-chloro coumarin, which was generated under acidic conditions and high temperature. Parfenov et al.,
Khim. Gererotsikl. Soedin
., 1991, 8, 1032. It is known that the selectivity of the reaction of 4-hydroxycoumarin with chlorinating reagents such as PCl
5
and POCl
3
is low, because a considerable amount of 4-chloro-3,4,3′,4″-tercoumarin will be formed as a by-product. Also reported with regard to substituted 4-thio coumarin derivatives, is a paper by Martin Kov
{haeck over (c)}, in ARKIVOC, 2001, part (vi), which utilizes 4-chlorocoumarin as an intermediate to synthesize 4-ethylthiocoumarin under basic conditions at elevated temperature (reflux) using sodium ethanethiol. Although a high yield of product was obtained by this methodology, it is not applicable to the production of a large variety of 4-thiol substituted derivatives with a diverse substitution pattern because of the harsh reaction conditions (both acidic and basic) used to arrive at the product. Extension of this route to solid supported synthesis for production of a combinatorial library is limited due to the acid sensitivity of many common solid support linkers.
SUMMARY OF THE INVENTION
The present invention is directed to certain 4-thio substituted coumarin derivatives of the formula I
wherein
R
1
is selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C
1
-C
8
acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C
1
-C
8
acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy;
R
3
is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R
3
is a group of the formula
Z—(CH
2
)
a
—Y
b
—(CH
2
)
c
—Q
d
—(CH
2
)
e
—
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from H, —CO
2
R, —OR, —SR, —NR
2
,
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R
3
may occupy two adjacent positions to form a fused aromatic ring, n is selected from values between 0 and 4;
R
5
is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, and lower aralkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, lower alkyl, and lower alkoxy, thio-lower alkyl, C
1
-C
8
acyl, lower alkyl ester, amide, and lower alkyl amide; or R
5
may be a group of the formula
wherein
R
2
is selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C
1
-C
8
acyl, lower alkyl ester, amide, and lower alkyl amide;
a substituted or unsubstituted aralkyl group, wherein the substituted aralkyl group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C
1
-C
8
acyl, lower alkyl ester, amide, and lower alkyl amide;
an unsubstituted or substituted alkyl group, wherein the substituted alkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy; and
an unsubstituted or substituted cycloalkyl group, wherein the substituted cycloalkyl group may be substituted with one or more halogen, hydroxy, and lower alkoxy;
R
4
is selected from halogen, hydroxy, amino, lower alkyl, lower alkoxy, lower alkenyl, and lower alkynyl, wherein the lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl may be unsubstituted or may be substituted with one or more of halogen, hydroxy, and lower alkoxy; or R
4
is a group of the formula
Z-(CH
2
)
a
—Y
b
—(CH
2
)
c
—Q
d
—(CH
2
)
e
—
wherein Y and Q are independently selected from an aromatic group, O, S, —CR═CR—,
each R is independently selected from H or lower alkyl,
Z is selected from
a, c and e are independently selected from values from 0 to 10;
b and d are independently selected from 0 and 1, provided that when a=0 then b=0, and when c=0 then d=0;
or R
4
may occupy two adjacent positions to form a fused aromatic ring, and, m is selected from values between 0 and 4.
Therefore, the present invention provides for symmetrical and unsymmetrical dimeric forms of 4-thio-substituted coumarin derivatives of the formula II:
wherein
R
1
and R
2
are independently selected from
an unsubstituted or substituted aromatic group, wherein the substituted aromatic group may be substituted with one or more of halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, thio-lower alkyl, C
1
-C
8
acyl, lower alkyl ester, amide, and lower alky

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