U.S. patent application number 09/767373 was filed with the patent office on 2001-10-25 for ring opening metathesis of alkenes.
Invention is credited to Cao, Jingrong, Cuny, Gregory D., Hauske, James R..
Application Number | 20010034341 09/767373 |
Document ID | / |
Family ID | 25224931 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010034341 |
Kind Code |
A1 |
Cuny, Gregory D. ; et
al. |
October 25, 2001 |
Ring opening metathesis of alkenes
Abstract
Methods for performing ring-opening cross-metathesis reactions
on solid support are disclosed. Substituted cyclic compounds,
libraries of the compounds, and methods of using the compounds to
treat bacterial infections are also disclosed.
Inventors: |
Cuny, Gregory D.; (Hudson,
MA) ; Cao, Jingrong; (Belmont, MA) ; Hauske,
James R.; (Hopkinton, MA) |
Correspondence
Address: |
FOLEY, HOAG & ELIOT, LLP
PATENT GROUP
ONE POST OFFICE SQUARE
BOSTON
MA
02109
US
|
Family ID: |
25224931 |
Appl. No.: |
09/767373 |
Filed: |
January 23, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09767373 |
Jan 23, 2001 |
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08818197 |
Mar 14, 1997 |
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6177464 |
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Current U.S.
Class: |
514/184 |
Current CPC
Class: |
A61P 31/04 20180101;
C07D 295/185 20130101; C07D 307/93 20130101; C07C 235/40 20130101;
C07C 2601/08 20170501; C07D 221/04 20130101; C07D 295/205 20130101;
C07C 271/20 20130101; C07D 491/04 20130101; C07D 207/26 20130101;
C07D 207/27 20130101 |
Class at
Publication: |
514/184 |
International
Class: |
A61K 031/555 |
Claims
What is claimed is:
1. A compound represented by the formula (Formula I): 26in which X
is a direct bond or a moiety selected from the group consisting of
O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q; Y is a moiety selected from
the group consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2Q; Q is
independently for each occurrence a direct bond or a moiety
selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2; R.sub.1 and R.sub.2 are each independently for
each occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S; R'.sub.1 and R'.sub.2 are each
independently for each occurrence hydrogen, halogen, or substituted
or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
or R.sub.1 and R.sub.2 taken together are O or S; R.sub.3 and
R.sub.4 are each independently hydrogen, halogen, cyano, nitro,
boronato, stannyl, silyl, or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or
aminocarbonyloxy; R.sub.5 is independently for each occurrence
hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminoc arbonyl or heterocyclyl; or a first occurrence of R.sub.1 or
R.sub.2, taken together with a second occurrence of R.sub.1 or
R.sub.2, and the carbon atoms to which they are attached, form a
carbocyclic or heteroyclic ring; or at least one of R.sub.1,
R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5 is a linker group to a
solid support; or a salt thereof; with the proviso that if none of
R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5 is a linker group
to a solid support: if X is CH.sub.2 or O, and Y is methylene, then
R.sub.3 and R.sub.4 are different; and if X is CH.sub.2 or O, and Y
is methylene, then R.sub.1 and R.sub.2 are different; and if X is a
direct bond, and Y is CR.sub.1R.sub.2Q, then Q is not
CR.sub.1R.sub.2; and if X is CH.sub.2 or O, and Y is NR.sub.5 or
CR.sub.1R.sub.2Q, and Q is a direct bond, then at least one of
R.sub.3 and R.sub.4 is aryl; and if X is O, and one of R.sub.3 and
R.sub.4 is aryl, the other of R.sub.3 and R.sub.4 is not alkyl.
2. The compound of claim 1, in which one of R.sub.3 and R.sub.4 is
aryl.
3. The compound of claim 1, in which X is CH.sub.2.
4. The compound of claim 1, in which X is O.
5. The compound of claim 1, in which at least one of R.sub.1,
R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5 is a linker group to a
solid support.
6. A compound represented by the formula (Formula Ia): 27in which W
is CH.sub.2 or O; Z is CHC(O)R.sub.8 or NR.sub.5; R.sub.5 is
hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl; R.sub.6 and R.sub.7 taken together
are O, or R.sub.6 is CHC(O)R'.sub.8 and R.sub.7 is hydrogen;
R.sub.8 and R'.sub.8 are each independently hydroxy, alkoxy,
aryloxy, or amino; and one of R.sub.9 and R.sub.10 is hydrogen and
the other of R.sub.9 and R.sub.10 is alkyl or aryl; or a salt
thereof.
7. The compound of claim 6, in which Z is CHC(O)R.sub.8, R.sub.6 is
CHC(O)R'.sub.8 and R.sub.7 is hydrogen.
8. A compound represented by the formula (Formula II): 28in which X
is a direct bond or a moiety selected from the group consisting of
O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q; Q is a direct bond or a
moiety selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2; R.sub.1 and R.sub.2 are each independently for
each occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S; R'.sub.1 and R'.sub.2 are each
independently hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S; R.sub.3 and R.sub.4 are each
independently hydrogen, halogen, cyano, nitro, boronato, stannyl,
silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy; R.sub.5 is
independently for each occurrence hydrogen or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or
heterocyclyl; R.sub.a and R.sub.b are each hydrogen, or R.sub.a and
R.sub.b taken together are O; or a salt thereof.
9. The compound of claim 8, wherein R.sub.4 is a substituted or
unsubstituted aryl.
10. The compound of claim 8, wherein X is O or CH.sub.2.
11. A method for performing a ring opening cross-metathesis
reaction on a solid support, the method comprising the step of
reacting an immobilized bicyclic alkene with an olefin under ring
opening cross-metathesis conditions, such that ring opening
cross-metathesis occurs on a solid support.
12. The method of claim 11, in which the olefin is a terminal aryl
olefin.
13. A method for performing a ring opening cross-metathesis
reaction of a bicyclic alkene with a terminal aryl olefin, the
method comprising the step of reacting a bicyclic alkene with a
terminal aryl olefin under ring opening cross-metathesis
conditions, such that ring opening cross-metathesis occurs.
14. A method for preparing a compound represented by the formula
(Formula I): 29in which X is a direct bond or a moiety selected
from the group consisting of O, S, NR.sub.5, and
CR'.sub.1R'.sub.2Q; Y is a moiety selected from the group
consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2Q; Q is
independently for each occurrence a direct bond or a moiety
selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2; R.sub.1 and R.sub.2 are each independently for
each occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S; R'.sub.1 and R'.sub.2 are each
independently for each occurrence hydrogen, halogen, or substituted
or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
or R.sub.1 and R.sub.2 taken together are O or S; R.sub.3 and
R.sub.4 are each independently hydrogen, halogen, cyano, nitro,
boronato, stannyl, silyl, or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or
aminocarbonyloxy; R.sub.5 is independently for each occurrence
hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl; or a first occurrence of R.sub.1 or
R.sub.2, taken together with a second occurrence of R.sub.1 or
R.sub.2, and the carbon atoms to which they are attached, form a
carbocyclic or heterocyclic ring; or at least one of R.sub.1,
R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5 is a linker group to a
solid support; or a salt thereof; the method comprising the step of
reacting a bicyclic alkene represented by the formula (Formula
III): 30with a compound represented by the formula (Formula IV):
31under ring opening cross-metathesis conditions, such that a
compound of Formula I is prepared.
15. The method of claim 14, in which the bicyclic alkene is
immobilized on a solid support.
16. The method of claim 14, in which the ring opening
cross-metathesis reaction is a regioselective reaction.
17. A method for preparing a compound represented by the formula
(Formula II): 32in which X is a direct bond or a moiety selected
from the group consisting of O, S, NR.sub.5, and
CR'.sub.1R'.sub.2Q; Q is a direct bond or a moiety selected from
the group consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2;
R.sub.1 and R.sub.2 are each independently for each occurrence
hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl,
alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy,
aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S; R'.sub.1 and R'.sub.2 are each independently
hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl,
alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy,
aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S; R.sub.3 and R.sub.4 are each independently
hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, or aminocarbonyloxy; R.sub.5 is independently for
each occurrence hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
R.sub.a and R.sub.b are each hydrogen, or R.sub.a and R.sub.b taken
together are O; or a salt thereof; the method comprising the steps
of: reacting a compound represented by the formula (Formula V):
33in which X, R.sub.1, R.sub.2, R.sub.5, R.sub.a and R.sub.b are as
defined above; and P is hydrogen or a protecting group; with a
compound represented by the formula (Formula IV): 34in which
R.sub.3 and R.sub.4 are as defined above; under ring opening
cross-metathesis conditions, such that a cross-metathesis product
is prepared; and cyclizing the cross-metathesis product, such that
a compound of Formula II is prepared.
18. The method of claim 17, in which the bicyclic alkene is
immobilized on a solid support.
19. The method of claim 17, in which the ring opening
cross-metathesis reaction is a regioselective reaction.
20. The method of claim 17, in which the step of cyclizing the
cross-metathesis product includes exposing the cross-metathesis
product to acidic conditions, such that ring closure occurs.
21. A library of compounds represented by the formula (Formula I):
35in which X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q; Y is a moiety
selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2Q; Q is independently for each occurrence a direct
bond or a moiety selected from the group consisting of O, S,
NR.sub.5, and CR.sub.1R.sub.2; R.sub.1 and R.sub.2 are each
independently for each occurrence hydrogen, halogen, or substituted
or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
or R.sub.1 and R.sub.2 taken together are O or S; R'.sub.1 and
R'.sub.2 are each independently for each occurrence hydrogen,
halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy,
carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S; R.sub.3 and R.sub.4 are each independently
hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, or aminocarbonyloxy; R.sub.5 is independently for
each occurrence hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl; or
a first occurrence of R.sub.1 or R.sub.2, taken together with a
second occurrence of R.sub.1 or R.sub.2, and the carbon atoms to
which they are attached, form a carbocyclic or heterocyclic ring;
or at least one of R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5
is a linker group to a solid support; or a salt thereof.
22. The library of claim 21, in which the compound is immobilized
on a solid support.
23. A library of compounds represented by the formula (Formula II):
36in which X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q; Q is a direct
bond or a moiety selected from the group consisting of O, S,
NR.sub.5, and CR.sub.1R.sub.2; R.sub.1 and R.sub.2 are each
independently for each occurrence hydrogen, halogen, or substituted
or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
or R.sub.1 and R.sub.2 taken together are O or S; R'.sub.1 and
R'.sub.2 are each independently hydrogen, halogen, or substituted
or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
or R.sub.1 and R.sub.2 taken together are O or S; R.sub.3 and
R.sub.4 are each independently hydrogen, halogen, cyano, nitro,
boronato, stannyl, silyl, or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or
aminocarbonyloxy; R.sub.5 is independently for each occurrence
hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl; R.sub.a and R.sub.b are each
hydrogen, or R.sub.a and R.sub.b taken together are O; or a salt
thereof.
24. A method for preparing a library of compounds represented by
the formula (Formula I): 37in which X is a direct bond or a moiety
selected from the group consisting of O, S, NR.sub.5, and
CR'.sub.1R'.sub.2Q; Y is a moiety selected from the group
consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2Q; Q is
independently for each occurrence a direct bond or a moiety
selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2; R.sub.1 and R.sub.2 are each independently for
each occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S; R'.sub.1 and R'.sub.2 are each
independently for each occurrence hydrogen, halogen, or substituted
or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl,
alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
or R.sub.1 and R.sub.2 taken together are O or S; R.sub.3 and
R.sub.4 are each independently hydrogen, halogen, cyano, nitro,
boronato, stannyl, silyl, or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or
aminocarbonyloxy; R.sub.5 is independently for each occurrence
hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl; or a first occurrence of R.sub.1 or
R.sub.2, taken together with a second occurrence of R.sub.1 or
R.sub.2, and the carbon atoms to which they are attached, form a
carbocyclic or heterocyclic ring; or at least one of R.sub.1,
R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5 is a linker group; or a
salt thereof; the method comprising the steps of reacting a
bicyclic alkene represented by the formula (Formula III): 38with a
compound represented by the formula (Formula IV): 39under ring
opening cross-metathesis conditions, such that a library of
compounds of Formula I is prepared; wherein at least one of the
bicyclic alkene and the olefin is provided as a variegated
population.
25. A method for preparing a library of compounds represented by
the formula (Formula II): 40in which X is a direct bond or a moiety
selected from the group consisting of O, S, NR.sub.5, and
CR'.sub.1R'.sub.2Q; Q is a direct bond or a moiety selected from
the group consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2;
R.sub.1 and R.sub.2 are each independently for each occurrence
hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl,
alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy,
aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S; R'.sub.1 and R'.sub.2 are each independently
hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl,
alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy,
aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S; R.sub.3 and R.sub.4 are each independently
hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, or aminocarbonyloxy; R.sub.5 is independently for
each occurrence hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
R.sub.a and R.sub.b are each hydrogen, or R.sub.a and R.sub.b taken
together are O; or a salt thereof; the method comprising the steps
of: reacting a compound represented by the formula (Formula V):
41in which X, R.sub.1, R.sub.2, R.sub.5, R.sub.a and R.sub.b are as
defined above; and P is hydrogen or a protecting group; with a
compound represented by the formula (Formula IV): 42in which
R.sub.3 and R.sub.4 are as defined above; under ring opening
cross-metathesis conditions, such that a cross-metathesis product
is prepared; and cyclizing the cross-metathesis product, such that
a compound of Formula II is prepared; wherein at least one of the
compounds of Formula V and Formula IV is provided as a variegated
population.
26. The method of claim 25, in which the step of cyclizing the
cross-metathesis product includes exposing the cross-metathesis
product to acidic conditions, such that ring closure occurs.
27. A pharmaceutical composition comprising a compound of claim 1
in a pharmaceutically acceptable vehicle.
28. A pharmaceutical composition comprising a compound of claim 7
in a pharmaceutically acceptable vehicle.
29. A method for treating a bacterial infection, the method
comprising the step of administering to a subject in need thereof
an effective amount of a compound of claim 1, such that the
bacterial infection is treated.
Description
BACKGROUND OF THE INVENTION
[0001] The need for new classes of chemical compounds for use in
pharmaceutical and agricultural applications has received much
attention. For example, modern synthetic chemical methods for
producing regio- and stereochemically defined compounds have made
possible drugs with previously unattainable activity and
specificity. Nevertheless, many currently-available drugs have been
designed to avoid structural complexity, due to the traditionally
difficult task of economically developing compounds with dense and
diverse functional arrays. Thus, new methods for the production of
functionally and stereochemically diverse compounds have the
potential to exploit this heretofore underexplored area.
[0002] Transition-metal mediated olefin metathesis has been
recognized as an effective means for carbon-carbon bond formation
(see, e.g., Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
(1995) 28:446; Schmalz, H. -G. Angew. Chem. Int. Ed Engl. (1995)
34(17):1833). Ring closing-metathesis has been extensively utilized
for the synthesis of macrocycles, carbocycles and heterocycles (see
(a) Fu, G. C. Grubbs, R. H. J. Am. Chem. Soc. (1992) 114:5426. (b)
Fu, G. C. Grubbs, R. H. J. Am. Chem. Soc. (1992) 114:7324. (c) Fu,
G. C.; Grubbs, R. H. J. Am. Chem. Soc. (1993) 115:3800. (d) Fu, G.
C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. (1993) 115:9856.
(e) Fujimura, O.; Fu. G. C.; Grubbs, R. H. J. Org. Chem. (1994)
59:4029. (i) Kim, S. -H.; Bowden, N.; Grubbs, R. H. J. Am. Chem.
Soc. (1994) 116:10801. (g) Miller, S. J.; Kim, S. -H.; Chen, Z. -R;
Grubbs, R. H. J. Am. Chem Soc. (1995)117:2108. (h) Miller, S. J.;
Grubbs, R. H. J. Am. Chem. Soc. (1995) 117:5855. (i) Martin, S. F.;
Liao, Y.; Rein, T. Tetrahedron Lett.. (1994) 35:691. (j) Borer, B.
C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett.
(1994) 35:3191. (k) Martin, S. F.; Liao, Y.; Chen. H. J.; Patzel,
M.; Ramser, M. N. Tetrahedron Lett. (1994) 35:6005. (1) Martin, S.
F.; Wagman, A. S. Tetrahedron Lett. (1995) 36:1169. (m) Houri, A.
F.; Xu, Z.; Cogan, D.; Hoveyda, A. J. Am. Chem. Soc. (1995)
117:2943. (n) Kim, S. -H.; Zuercher, W. J.; Bowden, N. B.; Grubbs,
R. H. J. Org. Chem. (1996) 61:1073. (o) Furstner, A.; Langemann, K.
J. Org. Chem. (1996) 61:3942. (p) Crimmins, M. T.; King, B. W. J.
Org. Chem. (1996) 61:4192. (q) Zuercher, W. J.; Hashimoto, M.;
Grubbs, R. H. J. Am. Chem. Soc. (1996) 118:6634). However, the
application of intermolecular ring opening cross-metathesis (ROM)
for the convergent synthesis of small organic molecules has
remained relatively unexplored. Recently, solution-phase ROM of
fused and bicyclic olefin systems with aliphatic alkenes yielding
cyclopentane and tetrahydrofuran derivatives was reported (see (a)
Schneider, M. F.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1996)
35: 411. (b) Randall, M. L.; Tallarico, J. A.; Snapper, M. L. J.
Am. Chem. Soc. (1995) 117:9610. (c) Schneider, M. F.; Lucas, N.;
Velder, J.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1997) 36:
257). (d) Snapper et al. J. Am. Chem. Soc. 119:1478 (1997)). For
unsymmetrically substituted substrates only slight regioselectivity
was generally observed. In addition, other reaction pathways, such
as ring opening metathesis polymerization of the bicyclic or fused
olefins competed with the desired cross-metathesis reactions.
[0003] Terminal aryl olefins have been shown to participate in
selective cross-metathesis reactions utilizing a molybdenum
alkylidene catalyst (see Crowe, W. E.; Zhang, Z. J. J. Am. Chem.
Soc. (1993) 115:10998). The cross-metathesis of norbornene and
styrene in the presence of Ru.sub.2(OAC).sub.4 and
ethyldiazoacetate has also been reported (see Noels, A. F.;
Demonceau, A.; Carlier, E.; Hubert A. J.; Mrquez-Silva, R. -L.;
Sanchez-Delgado, R. A. J. Chem. Soc., Chem. Commun. (1988) 783).
However, an extensive utilization of aryl olefins in ROM has been
absent.
[0004] Thus, previously reported ROM methods suffer from drawbacks
which can render them undesirable for the synthesis of highly
complex chemical compounds.
SUMMARY OF THE INVENTION
[0005] The invention relates to ring-opening cross-metathesis
reactions, and to substituted cyclic compounds, libraries of
compounds, and methods of preparing and using the compounds.
[0006] In one aspect, the invention provides a compound represented
by the formula (Formula I): 1
[0007] in which
[0008] X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q;
[0009] Y is a moiety selected from the group consisting of O, S,
NR.sub.5, and CR.sub.1R.sub.2Q;
[0010] Q is independently for each occurrence a direct bond or a
moiety selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2;
[0011] R.sub.1 and R.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0012] R'.sub.1 and R'.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0013] R.sub.3 and R.sub.4 are each independently hydrogen,
halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
or aminocarbonyloxy;
[0014] R.sub.5 is independently for each occurrence hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl;
[0015] or a first occurrence of R.sub.1 or R.sub.2, taken together
with a second occurrence of R.sub.1 or R.sub.2, and the carbon
atoms to which they are attached, form a carbocyclic or
heterocyclic ring;
[0016] or at least one of R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, or
R.sub.5 is a linker group to a solid support;
[0017] or a salt thereof.
[0018] In another embodiment, the invention provides compounds
represented by the formula (Formula Ia): 2
[0019] in which
[0020] W is CH.sub.2or O;
[0021] Z is CHC(O)R.sub.8 or NR.sub.5;
[0022] R.sub.5 is hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
[0023] R.sub.6 and R.sub.7 taken together are O, or R.sub.6 is
CHC(O)R'.sub.8 and R.sub.7 is hydrogen;
[0024] R.sub.8 and R'.sub.8 are each independently hydroxy, alkoxy,
aryloxy, or amino; and
[0025] one of R.sub.9 and R.sub.10 is hydrogen and the other of
R.sub.9 and R.sub.10 is alkyl or aryl;
[0026] or a salt thereof.
[0027] In another aspect, the invention provides compounds
represented by the formula (Formula II): 3
[0028] in which
[0029] X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q;
[0030] Q is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2;
[0031] R.sub.1 and R.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0032] R'.sub.1 and R'.sub.2 are each independently hydrogen,
halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy,
carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S;
[0033] R.sub.3 and R.sub.4 are each independently hydrogen,
halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
or aminocarbonyloxy;
[0034] R.sub.5 is independently for each occurrence hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl;
[0035] R.sub.a and R.sub.b are each hydrogen, or R.sub.a and
R.sub.b taken together are O;
[0036] or a salt thereof.
[0037] In another aspect, the invention provides a method for
performing a ring opening cross-metathesis reaction on a solid
support. The method includes the step of reacting an immobilized
bicyclic alkene with an olefin under ring opening cross-metathesis
conditions, such that ring opening cross-metathesis occurs on a
solid support.
[0038] In another aspect, the invention provides methods of
preparing a compound of Formula I. The method includes the step of
reacting a bicyclic alkene represented by the formula (Formula
III): 4
[0039] in which
[0040] X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q;
[0041] Y is a moiety selected from the group consisting of O, S,
NR.sub.5, and CR.sub.1R.sub.2Q;
[0042] Q is independently for each occurrence a direct bond or a
moiety selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2;
[0043] R.sub.1 and R.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0044] R'.sub.1 and R'.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0045] R.sub.5 is independently for each occurrence hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl;
[0046] or a first occurrence of R.sub.1 or R.sub.2, taken together
with a second occurrence of R.sub.1 or R.sub.2, and the carbon
atoms to which they are attached, form a carbocyclic or
heterocyclic ring;
[0047] or at least one of R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, or
R.sub.5 is a linker group to a solid support;
[0048] or a salt thereof;
[0049] with a compound of the formula (Formula IV): 5
[0050] in which
[0051] R.sub.3 and R.sub.4 are each independently hydrogen,
halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
or aminocarbonyloxy;
[0052] under ring opening cross-metathesis conditions, such that a
compound of Formula I, Formula Ia, or Formula II is prepared.
[0053] In another aspect, the invention provides libraries of
compounds of Formula I, Formula Ia or Formula II, and methods for
preparing such libraries.
[0054] In another aspect, the invention provides pharmaceutical
compositions. The pharmaceutical compositions include a compound of
Formula I, Formula Ia or Formula II in a pharmaceutically
acceptable vehicle.
[0055] In another aspect, the invention provides a method for
treating a bacterial infection. The method includes the step of
administering to a subject in need thereof an effective amount of a
compound of Formula I or Formula Ia, such that the bacterial
infection is treated.
DETAILED DESCRIPTION OF THE INVENTION
[0056] The invention relates to methods for performing ring opening
cross-metathesis (ROM) reactions on solid supports, and to
compounds and libraries of compounds prepared by such methods.
[0057] Applying solid-phase synthesis techniques to ROM can
effectively isolate the olefin immobilized on the resin, preventing
unwanted olefin polymerization (see Schuster, M.; Pernerstorfer,
J.; Blechert, S. Angew. Chem. Int. Ed. Engl. (1996) 35: 1979). In
addition, a solid-phase methodology can be conveniently
incorporated into combinatorial library strategies (see, e.g., (a)
DeWitt, S. H.; Czamik, A. W. Acc. Chem. Res. (1996) 29:114. (b)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. (1996) 29:123. (c) Ellman, J. A.
Acc. Chem. Res. (1996) 29:132. (d) Gordon, E. M.; Gallop, M. A.;
Patel, D. V. A.cc. Chem. Res. (1996) 29:144. (e) Lowe, G. Chem.
Soc. Rev. (1995) 309), for producing an array of highly
functionalized molecular scaffolds, e.g., as described infra,
preferably in a diastereospecific manner. For example, it has now
been found that ROM reactions performed on a solid support can have
a product distribution different from the corresponding ROM
reaction performed in the solution phase. As described below, ROM
on solid support can have significantly improved regioselectivity
and/or stereoselectivity compared to solution-phase ROM. As
described in more detail below, solid-phase ROM provides access to
highly substituted and functionalized molecular scaffolds, e.g.,
cyclopentyl, fused cyclopentyl and tetrahydrofuranyl and fused
tetrahydrofuranyl molecular platforms in a regioselective and
stereoselective fashion.
[0058] Definitions
[0059] The term "electron-releasing substituent" is known in the
art (see, e.g., J. March, "Advanced Organic Chemistry", 3rd
Edition, Wiley-InterScience (1991)), and, as used herein, refers to
a substituent of an aryl group which has a greater tendency to
release electron density to the aryl group than does a hydrogen
atom. Exemplary electron releasing substituents include alkoxy
(e.g., methoxy), substituted or unsubstituted amino (e.g.,
dimethylamino), alkylthio (e.g., methylthio), and the like.
[0060] The term "alkyl" refers to the radical of saturated
aliphatic groups, including straight-chain alkyl groups,
branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl
substituted cycloalkyl groups, and cycloalkyl substituted alkyl
groups. In preferred embodiments, a straight chain or branched
chain alkyl has 30 or fewer carbon atoms in its backbone (e.g.,
C.sub.1-C.sub.30 for straight chain, C.sub.3-C.sub.30 for branched
chain), and more preferably 20 or fewer. Likewise, preferred
cycloalkyls have from 4-10 carbon atoms in their ring structure,
and more preferably have 5, 6 or 7 carbons in the ring
structure.
[0061] Moreover, the term alkyl as used throughout the
specification and claims is intended to include both "unsubstituted
alkyls" and "substituted alkyls", the latter of which refers to
alkyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino,
diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an
aromatic or heteroaromatic moiety. It will be understood by those
skilled in the art that the moieties substituted on the hydrocarbon
chain can themselves be substituted, if appropriate. Cycloalkyls
can be further substituted, e.g., with the substituents described
above. An "aralkyl" moiety is an alkyl substituted with an aryl
(e.g., phenylmethyl (benzyl)).
[0062] The term "aryl" as used herein includes 5- and 6-membered
single-ring aromatic groups that may include from zero to four
heteroatoms, for example, benzene, pyrrole, furan- thiophene,
imidazole, oxazole, thiazole, triazole, pyrazole, pyridine,
pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also
include polycyclic fused aromatic groups such as naphthyl,
quinolyl, indolyl, and the like. Those aryl groups having
heteroatoms in the ring structure may also be referred to as "aryl
heterocycles", "heteroaryls" or "heteroaromatics". The aromatic
ring can be substituted at one or more ring positions with such
substituents as described above, as for example, halogen, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,
phosphinato, cyano, amino (including alkyl amino, dialkylamino,
arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an
aromatic or heteroaromatic moiety. Aryl groups can also be fused or
bridged with alicyclic or heterocyclic rings which are not aromatic
so as to form a polycycle (e.g., tetralin).
[0063] The terms "alkenyl" and "alkynyl" refer to unsaturated
aliphatic groups analogous in length and possible substitution to
the alkyls described above, but that contain at least one double or
triple bond respectively.
[0064] Unless the number of carbons is otherwise specified, "lower
alkyl" as used herein means an alkyl group, as defined above, but
having from one to ten carbons, more preferably from one to six
carbon atoms in its backbone structure. Likewise, "lower alkenyl"
and "lower alkynyl" have similar chain lengths. Preferred alkyl
groups are lower alkyls.
[0065] The terms "heterocyclyl" or "heterocyclic group" refer to 3-
to 10-membered ring structures, more preferably 4- to 7-membered
rings, which ring structures include one to four heteroatoms.
Heterocyclyl groups include pyrrolidine, oxolane, thiolane,
oxazole, piperidine, piperazine, morpholine, lactones, lactams such
as azetidinones and pyrrolidinones, lactones, cyclic anhydrides,
sultams, sultones, and the like. The heterocyclic ring can be
substituted at one or more positions with such substituents as
described above, as for example, halogen, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,
phosphinato, cyano, amino (including alkyl amino, dialkylamino,
arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an
aromatic or heteroaromatic moiety.
[0066] The terms "polycyclyl" or "polycyclic group" refer to two or
more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls,
aryls and/or heterocyclyls) in which two or more carbons are common
to two adjoining rings, e.g., the rings are "fused rings". Rings
that are joined through non-adjacent atoms are termed "bridged"
rings. Each of the rings of the polycycle can be substituted with
such substituents as described above, as for example, halogen,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,
phosphinato, cyano, amino (including alkyl amino, dialkylamino,
arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkyl, aralkyl, or an
aromatic or heteroaromatic moiety.
[0067] The term "stannyl," as used herein, refers to a group
represented by the formula: 6
[0068] in which R.sub.11 and R.sub.12 and R.sub.13 are each
independently alkyl or aryl The term "silyl," as used herein,
refers to a group represented by the formula: 7
[0069] in which R.sub.11, R.sub.12 and R.sub.13 are each
independently alkyl or aryl.
[0070] The term "boronato," as used herein, refers to a group
represented the formula: 8
[0071] in which R.sub.14 and R.sub.15 are each independently alkyl,
aryl, or a salt-forming cation.
[0072] The term "heteroatom" as used herein means an atom of any
element other than carbon or hydrogen. Preferred heteroatoms are
nitrogen, oxygen, sulfur and phosphorus.
[0073] The term "linker group," as used herein, refers to a linking
or spacing moiety which can be used to covalently or non-covalently
link a compound to a solid support. Linker groups suitable for use
in the invention are known in the art for use in solid-phase
synthesis.
[0074] The term "substantially pure," as used herein, refers to a
compound which is substantially free of impurities, including (but
not limited to) starting materials, side products, and the like. A
compound is "substantially pure" if it comprises at least about
80%, more preferably 90%, still more preferably at least about 95%
of the composition. If a single isomer of a compound is desired
(e.g., a single diastereomer, enantiomer, or regioisomer), the
compound is preferably substantially free of any undesired isomers
(e.g., the unwanted enantiomer, diastereomers, or regioisomers),
i.e., the desired isomer comprises at least about 80%, more
preferably 90%, still more preferably at least about 95% of the
weight of the isomers present in the composition.
[0075] The term "subject," as used herein, refers to an animal,
more preferably a warm-blooded animal, most preferably a mammal,
including cattle, sheep, pigs, horses, dogs, cats, rats, mice, and
humans.
[0076] The term "treating a bacterial infection," as used herein,
refers to preventing an infection, preventing spread of an
infection, or decreasing the extent or severity of a bacterial
infection. In a preferred embodiment, the bacterial infection is
cured, i.e., substantially eliminated.
[0077] It will be noted that the structure of some of the compounds
of this invention includes asymmetric carbon atoms. It is to be
understood accordingly that the isomers arising from such asymmetry
(e.g., all enantiomers and diastereomers) are included within the
scope of this invention, unless indicated otherwise. Such isomers
can be obtained in substantially pure form by classical separation
techniques and by stereochemically controlled synthesis.
Furthermore, alkenes can include either the E- or Z- geometry,
where appropriate.
[0078] I. Compounds
[0079] In one aspect, the invention provides compounds which can be
represented by the formula (Formula I): 9
[0080] in which
[0081] X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q;
[0082] Y is a moiety selected from the group consisting of O, S,
NR.sub.5, and CR.sub.1R.sub.2Q;
[0083] Q is independently for each occurrence a direct bond or a
moiety selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2;
[0084] R.sub.1 and R.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0085] R'.sub.1 and R'.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0086] R.sub.3 and R.sub.4 are each independently hydrogen,
halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
or aminocarbonyloxy, with the proviso that R.sub.3 and R.sub.4 are
not both hydrogen;
[0087] R.sub.5 is independently for each occurrence hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl;
[0088] or a first occurrence of R.sub.1 or R.sub.2, taken together
with a second occurrence of R.sub.1 or R.sub.2, and the carbon
atoms to which they are attached, form a carbocyclic or
heterocyclic ring;
[0089] or at least one of R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, or
R.sub.5 is a linker group to a solid support;
[0090] or a salt thereof.
[0091] In certain preferred embodiments, at least one of R.sub.1,
R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5 is a linker group to a
solid support. In preferred embodiments, R.sub.3 and R.sub.4 are
not the same, i.e., are different moieties. In preferred
embodiments, at least one of R.sub.3 and R.sub.4 is aryl. In
particularly preferred embodiments, R.sub.3 and R.sub.4 are not
both hydrogen. In preferred embodiments, X is not a direct bond. In
certain embodiments, X is O, while in other embodiments, X is
CH.sub.2. In certain preferred embodiments, Q is a direct bond. In
preferred embodiments, R.sub.5 is --CH.sub.2C(O)R.sub.8, in which
R.sub.8 is hydroxy, alkoxy, aryloxy, or amino.
[0092] In certain preferred embodiments, if X is CH.sub.2 or O, and
Y is methylene (i.e., Y is CR.sub.1R.sub.2Q and Q is a direct
bond), then R.sub.3 and R.sub.4 are different. In certain preferred
embodiments, if X is CH.sub.2 or O, and Y is methylene (i.e., Q is
a direct bond), then R.sub.1 and R.sub.2 are different. In certain
preferred embodiments, if X is a direct bond, and Y is
CR.sub.1R.sub.2Q, then Q is not CR.sub.1R.sub.2. In preferred
embodiments, if X is CH.sub.2 or O, and Y is NR.sub.5 or
CR.sub.1R.sub.2Q, and Q is a direct bond, then at least one of
R.sub.3 and R.sub.4 is aryl. In preferred embodiments, if X is O,
and one of R.sub.3 and R.sub.4 is aryl, the other of R.sub.3 and
R.sub.4 is not alkyl.
[0093] In particularly preferred embodiments, the compounds of the
invention can be represented by the formula (Formula Ia): 10
[0094] in which
[0095] W is CH.sub.2 or O;
[0096] Z is CHC(O)R.sub.8 or NR.sub.5;
[0097] R.sub.5 is hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
[0098] R.sub.6 and R.sub.7 taken together are O, or R.sub.6 is
CHC(O)R'.sub.8 and R.sub.7 is hydrogen; and
[0099] R.sub.8 and R'.sub.8 are each independently hydroxy, alkoxy,
aryloxy, or amino;
[0100] or a salt thereof.
[0101] In preferred embodiments of the compounds of Formula Ia, if
Z is NR.sub.5, then R.sub.6 and R.sub.7 taken together are O. In
certain preferred embodiments, Z is CHC(O)R.sub.8, R.sub.6 is
CHC(O)R'.sub.8 and R.sub.7 is hydrogen. In preferred embodiments,
at least one of R.sub.5, R.sub.8 and R'.sub.8 is a linker to a
solid support. In certain preferred embodiments, one of R.sub.9 and
RIO is an aryl group which is substituted with one or more
electron-releasing substituents; more preferably, one of R.sub.9
and R.sub.10 is a 4-methoxyphenyl group. In preferred embodiments,
W is CH.sub.2. In certain preferred embodiments, Z is
CHC(O)R.sub.8, R.sub.6 is CHC(O)R'.sub.8 and R.sub.7 is
hydrogen.
[0102] Thus, the invention provides a wide variety of highly
substituted and functionalized compounds, e.g., substituted
cyclobutanes, oxetanes, .beta.-lactams, cyclopentanes,
cyclohexanes, tetrahydrofurans, tetrahydropyrans, pyrrolidines,
piperidines, 2-oxapiperidines, 1,3-dioxanes, tetrahydrothiophenes,
and the like. For example, when X and Y in the compound of Formula
I are both carbon (and Q is a direct bond), the compound is a
cyclopentane derivative. In another example, when X is a direct
bond in the compound of Formula I, Y is carbon (and Q is a direct
bond), the compound of Formula I is a cyclobutane derivative. In
yet another example, when X is NR.sub.5, and Y is carbon (and Q is
a direct bond) the compound is a substituted pyrrolidine.
[0103] Compounds such as substituted cyclopentanes,
tetrahydrofurans, and pyrrolidines are common in nature, and are
also present in a variety of synthetic compounds including
pharmaceuticals and agrochemicals. For example, prostaglandins and
other prostanoids are substituted cyclopentane or cyclopentene
derivatives. Muscarine, a naturally-occurring alkaloid, is a
cholinomimetic which includes the tetrahydrofuran structure.
Nicotine is a substituted pyrrolidine which has been used as an
agricultural insecticide. The invention thus provides analogs or
derivatives of these and other compounds, and methods of preparing
such compounds, as described herein.
[0104] Moreover, the compounds of the invention can have a variety
of closely spaced functionalities and may serve as interesting
molecular scaffolds. Such molecular scaffolds can be used to
present pharmacophores to certain receptors. For example, the
compounds of the invention, having suitable functional groups, may
have biological activity such as CNS activity, activity at steroid
receptors, antiinflammatory activity, protein kinase C inhibitory
activity, antifungal or antibacterial activity, opiate receptor
activity, and the like. For example, as described in Example 6,
infra, certain of the compounds of the invention exhibit moderate
antibacterial activity in in vitro screening assays.
[0105] In another embodiment, the invention provides compounds of
Formula II: 11
[0106] in which
[0107] X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q;
[0108] Q is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2;
[0109] R.sub.1 and R.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0110] R'.sub.1 and R'.sub.2 are each independently hydrogen,
halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy,
carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S;
[0111] R.sub.3 and R.sub.4 are each independently hydrogen,
halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
or aminocarbonyloxy;
[0112] R.sub.5 is independently for each occurrence hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl;
[0113] R.sub.a and R.sub.b are each hydrogen, or R.sub.a and
R.sub.b taken together are O;
[0114] or a salt thereof.
[0115] In preferred embodiments of the compound of Formula II, X is
O or CH.sub.2. In certain preferred embodiments of the compound of
Formula II, R.sub.3 is hydrogen. In certain preferred embodiments
of the compound of Formula II, R.sub.4 is aryl, and more
preferably, aryl having at least one electron-releasing
substituent. In certain preferred embodiments, R.sub.a and R.sub.b
taken together are O. It will be appreciated by the skilled artisan
that compounds in which R.sub.a and R.sub.b taken together are O
can be converted to the corresponding compound in which R.sub.a and
R.sub.b are each H by reduction, e.g., by treatment with diborane,
as is known in the art.
[0116] In preferred embodiments, the compound of Formula I, Ia or
II is substantially pure, i.e., the compound is at least 80%, 90%
or 95% pure. Compounds which are not substantially pure can be
purified by conventional methods, including the methods described
infra.
[0117] It has now been found that the compounds of the invention
have anti-bacterial activity. For example, as described in Example
6, infra, certain compounds of the invention have activity against
gram-positive bacteria. Accordingly, in a preferred embodiment, a
compound of the invention has anti-bacterial activity. Preferred
compounds include compounds of Formula I in which X is CH.sub.2. In
certain preferred embodiments, R.sub.1 is H. In some preferred
embodiments, R.sub.3 is H. In certain preferred embodiments, Y is
carbon, e.g., --CH(C(O)NR.sub.9R.sub.10)--, in which R.sub.9 and
R.sub.10 are each independently hydrogen or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or
heterocyclyl; or R.sub.9 and R.sub.10, taken together with the
nitrogen to which they are attached, form a heterocyclic ring.
[0118] II. Methods
[0119] In another aspect, the invention provides methods for
performing ring opening cross-metathesis reactions. In one
embodiment, the method includes the steps of reacting an
immobilized bicyclic alkene with a terminal olefin under ring
opening cross-metathesis conditions, such that ring opening
cross-metathesis occurs on a solid support. In a preferred
embodiment, the terminal olefin is a terminal aryl olefin.
[0120] In another embodiment, the invention provides a method for
performing ring opening cross-metathesis reactions of a bicyclic
alkene with a terminal aryl olefin. The method includes the step of
reacting a bicyclic alkene with a terminal aryl olefin under ring
opening cross-metathesis conditions, such that ring opening
cross-metathesis occurs.
[0121] The invention also provides a method for preparing a
compound of Formula I. In one embodiment, the method includes the
steps of reacting a compound represented by the formula (Formula
III): 12
[0122] in which
[0123] X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R' .sub.2Q;
[0124] Y is a moiety selected from the group consisting of O, S,
NR.sub.5, and CR.sub.1R.sub.2Q;
[0125] Q is independently for each occurrence a direct bond or a
moiety selected from the group consisting of O, S, NR.sub.5, and
CR.sub.1R.sub.2;
[0126] R.sub.1 and R.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0127] R'.sub.1 and R'.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0128] R.sub.5 is independently for each occurrence hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl;
[0129] or a first occurrence of R.sub.1 or R.sub.2, taken together
with a second occurrence of R.sub.1 or R.sub.2, and the carbon
atoms to which they are attached, form a carbocyclic or
heterocyclic ring;
[0130] or at least one of R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, or
R.sub.5 is a linker group to a solid support;
[0131] or a salt thereof;
[0132] with a compound of the formula (Formula IV): 13
[0133] in which
[0134] R.sub.3 and R.sub.4 are each independently hydrogen,
halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
or aminocarbonyloxy;
[0135] under ring opening cross-metathesis conditions, such that a
compound of Formula I is prepared.
[0136] In preferred embodiments of the compound of Formula III, at
least one of R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, or R.sub.5 is a
linker group for covalently linking the compound of Formula I
and/or Formula II to a solid support. Exemplary linker groups are
described infra. In certain preferred embodiments, X is O or
CR'.sub.1R'.sub.2. In certain preferred embodiments, if Y is
NR.sub.5, then R.sub.1 and R.sub.2 taken together are O.
[0137] In certain preferred embodiments of Formula III, in at least
one occurrence R.sub.5 is --C(O)NR.sub.14R.sub.15, in which
R.sub.14 and R.sub.15 are each independently hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, or heterocyclyl; or R.sub.14 and R.sub.15, taken
together with the nitrogen to which they are attached, form a
heterocyclic ring. In preferred embodiments, one of R.sub.14 and
R.sub.15 is hydrogen, i.e., R.sub.1 is a monosubstituted
carboxamide. In this embodiment, R.sub.1 can comprise a linking
moiety. In other embodiments, R.sub.14 and R.sub.15, taken together
with the nitrogen to which they are attached, form a
1,4-piperazinyl moiety, which, in certain embodiments, can be
substituted, e.g., with a linker moiety.
[0138] In preferred embodiments of the compound of Formula IV
(hereinafter referred to as an "olefin"), if R.sub.4 is aryl, then
R.sub.3 is hydrogen. In particularly preferred embodiments, R.sub.4
is substituted aryl, in which the aryl group has at least one
electron-releasing group.
[0139] In certain embodiments, the methods of the invention include
the further step of purifying the compound of Formula I and/or
Formula II (e.g., by washing the solid support upon which the
compound is immobilized). In certain embodiments, the method
includes the further step of cleaving the compound of Formula I
and/or Formula II from the solid support. In certain embodiments,
the method includes the step of purifying the compound (or
compounds) produced in the ring opening cross-metathesis reactions.
In certain embodiments, the compound or compounds of Formula I
and/or Formula II can be further reacted, e.g., to produce
derivatives and analogs of compounds of Formula I and/or Formula
II.
[0140] The invention also provides methods for preparing a compound
of Formula II. The method includes the steps of reacting a compound
represented by the formula (Formula V): 14
[0141] in which
[0142] X is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR'.sub.1R'.sub.2Q;
[0143] Q is a direct bond or a moiety selected from the group
consisting of O, S, NR.sub.5, and CR.sub.1R.sub.2;
[0144] P is hydrogen or a protecting group;
[0145] R.sub.1 and R.sub.2 are each independently for each
occurrence hydrogen, halogen, or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino,
hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy,
arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R.sub.1 and
R.sub.2 taken together are O or S;
[0146] R'.sub.1 and R'.sub.2 are each independently hydrogen,
halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl,
aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy,
carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
aminocarbonyloxy, or alkylthio; or R.sub.1 and R.sub.2 taken
together are O or S;
[0147] R.sub.5 is independently for each occurrence hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,
aminocarbonyl or heterocyclyl;
[0148] R.sub.a and R.sub.b are each hydrogen, or R.sub.a and
R.sub.b taken together are O;
[0149] or a salt thereof;
[0150] with a compound represented by the formula (Formula IV):
15
[0151] in which
[0152] R.sub.3 and R.sub.4 are each independently hydrogen,
halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
or aminocarbonyloxy;
[0153] under ring opening cross-metathesis conditions, such that a
cross-metathesis product is prepared; and cyclizing the
cross-metathesis product, such that a compound of Formula II is
prepared.
[0154] In preferred embodiments, the step of cyclizing the
cross-metathesis product includes exposing the cross-metathesis
product to acidic conditions, such that ring closure occurs. In
preferred embodiments, the step of cyclizing the cross-metathesis
product is performed without purification of the cross-metathesis
product. In preferred embodiments, P is hydrogen or a protecting
group which can be removed under the conditions of the step of
cyclizing the cross-metathesis product, e.g., P can be removed
under acidic conditions. Amine protecting groups which can be
removed under acidic conditions are well known (e.g., the
t-butyloxycarbonyl (BOC) group). For a discussion of suitable
protecting groups, see, e.g., Greene and Wuts, "Protective Groups
in Organic Synthesis," 2nd ed., Wiley, 1991). In the compounds of
Formula V, the protecting group P can also be a solid support or a
linker to a solid support (see, e.g., Examples 5 and 6, infra, in
which cleavage from the solid support occurs under acidic
conditions, with concomitant cyclization to compounds of Formula
II).
[0155] The invention also provides methods for preparing compounds
of Formula Ia. In one embodiment, the method includes the steps of
reacting a compound represented by the formula (Formula VI): 16
[0156] in which
[0157] W is CH.sub.2 or O;
[0158] Z is CHC(O)R.sub.8 or NR.sub.5;
[0159] R.sub.5 is hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
[0160] R.sub.6 and R.sub.7 taken together are O, or R.sub.6 is
CHC(O)R'.sub.8 and R.sub.7 is hydrogen;
[0161] R.sub.8 and R'.sub.8 are each independently hydroxy, alkoxy,
aryloxy, or amino; and
[0162] one of R.sub.9 and R.sub.10 is hydrogen and the other of
R.sub.9 and R.sub.10 is alkyl or aryl;
[0163] or a salt thereof;
[0164] with a compound represented by the formula (Formula VII)
17
[0165] under ring opening cross-metathesis conditions, such that a
compound of Formula Ia is prepared. In preferred embodiments, the
bicyclic alkene is immobilized on a solid support. In particularly
preferred embodiments, the ring opening cross-metathesis reaction
is a regioselective reaction.
[0166] In preferred embodiments of the methods of the invention,
the ring opening cross-metathesis conditions include a catalyst,
preferably a molybdenum or ruthenium catalyst, such as are
described herein.
[0167] The methods of the invention provide several advantages over
ring opening cross-metathesis reactions previously reported. For
example, when the bicyclic alkene of Formula III is immobilized on
a solid support, the undesired polymerization of the bicyclic
alkene, which may be a significant side reaction when ROM reactions
are performed in the solution phase, can be minimized. Furthermore,
the ROM reactions of the invention proceed cleanly, in good yield,
and are the products can be easily and quickly isolated and
purified, often by simply filtering the solid support, washing to
remove impurities, and cleaving the product from the solid
support.
[0168] The present method can also provide stereo- and
regioselective ROM reactions. For example, as described in Example
3, infra, the ROM reactions of the invention can be more
regioselective than the corresponding ROM performed in the
solution-phase. Thus, higher yields of a desired product can be
obtained, with less wasted side product (e.g., undesired stereo- or
regioisomers), thereby providing a more economical synthesis.
Moreover, by appropriate choice of the substitutents of the
bicyclic alkene and the olefin, the product ratio of the ROM
reaction can be influenced to produce either one of two products in
preference to the other. Thus, in a preferred embodiment, the ROM
reactions of the invention are regioselective, i.e., produce one
product in preference to a regioisomer of that product. In
preferred embodiments, the mole ratio of regioisomers is at least
about 1.5:1, more preferably at least about 2:1, and still more
preferably at least about 3:1.
[0169] Similarly, judicious selection of substituents can provide
compounds having pre-selected stereochemistry. For example, the
rigid bicyclic framework of a bicyclic alkene can be chosen such
that the ring-opened product bears an array of functional groups in
predictable stereochemical relation. For example, when a compound
of Formula III is employed in the methods of the invention, the
resulting cyclic compound of Formula I will have an R.sub.2
substituent (if any) on the ring which is cis relative to the vinyl
groups bearing R.sub.3 and R.sub.4. Moreover, the use of chiral
reactants or chiral solid supports can promote the predominant
formation of one enantiomer of two possible enantiomeric
products.
[0170] Reactants
[0171] In general, the solid-phase ROM reactions of the invention
involve reaction of a bicyclic alkene with an olefin. In certain
embodiments, bicyclic alkenes which can be used in the methods of
the invention can be represented by Formula III, Formula V, or
Formula VI. A variety of bicyclic alkenes having the general
structure of Formula III, Formula V, or Formula VI are known in the
art, and many bicyclic alkenes can be purchased commercially.
[0172] Bicyclic alkenes suitable for use in the methods of the
invention will be sufficiently reactive to undergo a ROM reaction
with an alkene (usually in the presence of a catalyst). Without
wishing to be bound by theory, it is believed that ring strain
increases the rate of ROM reaction of a bicyclic alkene, i.e.,
relief of ring strain provides a driving force for ROM.
Accordingly, highly strained bicyclic alkenes are preferred.
Bicyclic alkenes contemplated for use in the methods of the
invention include compounds having a [2.2.1], [2.2.2] or [3.2.0]
ring system. Bicyclic alkenes having a [2.2.1] ring system are
preferred. Illustrative examples of bicyclic alkenes include
substituted or unsubstituted compounds norbornene, norbornadiene,
7-oxanorbornene, 7-oxanorbornadiene, and the like.
[0173] In preferred embodiments, the bicyclic alkene of Formula
III, Formula V, or Formula VI is immobilized on a solid support.
Such immobilization can be covalent, or can be due to ionic,
hydrophobic, hydrophilic, or other interactions between the
compound and the support. Linkers can be used to provide for
convenient attachment to, and release from, the solid support (see
infra). Thus, the bicyclic alkene preferably includes at least one
functional group which can be used to immobilize the bicyclic
alkene on the solid support.
[0174] An olefin which reacts with a bicyclic alkene in a ROM
reaction preferably has the structure shown in Formula IV. In
preferred embodiments, if either of R.sub.3 and R.sub.4 is aryl,
the olefin is monosubstituted (i.e., the remaining substituents of
the olefinic bond are hydrogen). Thus, terminal aryl olfins are
preferred for reaction with a bicyclic alkene. If neither of
R.sub.3 and R.sub.4 is aryl, the olefin can be a 1,2-disubstituted
olefin (having either the E- or Z-configuration at the double
bond). In certain embodiments, at least one of R.sub.3 and R.sub.4
can comprise a functional group (e.g., a linker moiety) which can
be used to immobilize the olefin on a solid support.
[0175] It has been found that terminal aryl olefins having at least
one electron-releasing substitutent can react to provide products
with high regioselectivity (See, e.g., Example 3, infra).
Accordingly, in certain embodiments, terminal aryl olefins having
at least one electron-releasing substituent are preferred. However,
in certain embodiments, the use of an aryl olefin having an
electron-releasing substituent can result in the undesired
regioisomeric product; accordingly, in certain embodiments, the
aryl group does not include an electron-releasing substituent. The
skilled artisan will be able to select appropriate substituents of
the olefin (e.g., substituted aryl groups) for a particular product
using no more than routine experimentation.
[0176] Catalysts
[0177] Catalysts useful in the methods of the invention include
catalysts known in the art to be useful for ring opening or
ring-closing cross-metathesis or polymerization reactions. Examples
of such catalysts include the catalysts described in U.S. Pat. Nos.
5,342,909 and 4,945,144, both to Grubbs et al. Other catalysts may
find use in the methods of the invention. In general, such catalyst
are alkylidene complexes of transition metals such as molybdenum or
ruthenium. For examples of catalysts useful in olefin metathesis
reactions, see, e.g., the references cited in notes 2 and 8, infra.
A catalyst will generally be selected to have suitable activity
with a selected bicyclic alkene and olefin. For example, certain
catalysts can be sensitive to particular functional groups of the
bicyclic alkene or olefin, which can deactivate a catalyst. In such
a case, another catalyst should be chosen. In light of the
teachings herein, the choice of an appropriate catalyst can be made
by the skilled artisan using no more than routine
experimentation.
[0178] In certain embodiments, the catalyst can be prepared in an
immobilized form (i.e., immobilized on an inert solid support) for
ease of handling and recycling (see, e.g, Nyugen et al, J. Orgmet.
Chem. 497:195-200 (1995)).
[0179] Linkers
[0180] Linkers useful for immobilizing compounds on a solid support
are well known in the art and include, e.g., diamino linkers,
phenylene moieties, and the like. A particularly preferred linker
is the linker described in Hauske, J. R.; Dorff, P. Tetrahedron
Lett. 1995, 36, 1589. This linker is easily synthesized, stable
under a variety of reaction conditions, and readily cleaved to
release the product from the solid support.
[0181] It will be understood that the linker can be selected to
have a length which permits facile reaction with a substrate
compound immobilized on a solid support. For example, the linker
should be long enough to avoid steric encumbrance of the
immobilized compound by the solid support. The linker can be
selected to be cleavable under a variety of conditions (e.g.,
hydrolytic, nucleophilic, electrolytic, oxidative, photolytic, and
the like), if desired, as is known in the art. The skilled artisan
will appreciate that the choice of linker, in combination with the
choice of solid support, can influence factors such as reaction
time, completeness of reaction, releasability of the reaction
products, and the like. Thus, the linker and solid support will in
general be selected to permit ready immobilization, reaction,
isolation, and purification of the compounds of the invention.
[0182] Solid Supports
[0183] Solid supports suitable for use in solid phase synthesis are
known in the art (for examples, see, e.g., M. Bodansky "Principles
of Peptide Synthesis", 2nd edition, Springer-Verlag, Berlin (1993);
Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589; and
references cited therein). Many such art-recognized solid supports
are useful in the methods of the invention. For example, solid
supports suitable for use in the present invention include suitably
modified forms of: silica (e.g., particles such as silica gel),
silicon (e.g., wafers or chips), glass (e.g., a glass plate or
controlled pore glass beads), polystyrene, polyacrylamide,
Tenta-Gel, Wang resin, Rapp resin, Merrifield resin, Rink resin,
and the like.
[0184] Reaction Conditions
[0185] The reactions of the present invention may be performed
under a wide range of conditions, though it will be understood that
the solvents and temperature ranges recited herein are not
limitative and only correspond to a preferred mode of the process
of the invention.
[0186] In general, it is desirable that reactions are run using
mild conditions that will not adversely affect the bicyclic alkene,
the olefin, the catalyst, the intermediates, the resin, the linker
or the products. For example, the reaction temperature influences
the speed of the reaction, as well as the stability of the
reactants, resin, and catalyst. The reactions will usually be run
at temperatures in the range of -78.degree. C. to 100.degree. C.,
more preferably in the range -20.degree. C. to 50.degree. C. and
still more preferably in the range -20.degree. C. to 25.degree.
C.
[0187] In general, the reactions according to the invention will be
performed in a liquid medium, e.g., in a suspension of a solid
support in a liquid medium. The reactions may be run in an inert
solvent, preferably one in which the reaction ingredients,
optionally including the polymeric support, are substantially
soluble. Suitable solvents include ethers such as diethyl ether,
1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran
and the like; halogenated solvents such as chloroform,
dichloromethane, dichloroethane, chlorobenzene, and the like;
aliphatic or aromatic hydrocarbon solvents such as benzene,
toluene, hexane, pentane and the like; esters and ketones such as
ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such
as acetonitrile, dimethylsulfoxide, dimethylformamide and the like;
or combinations of two or more solvents. The reactions can be
conducted under anhydrous conditions and in certain embodiments it
is preferable to perform the reactions under an inert atmosphere of
a gas such as nitrogen or argon.
[0188] The progress of the metathesis reactions can be monitored by
techniques known to one of ordinary skill in the art. For example,
aliquots of the reaction mixture can be taken at intervals and the
aliquots tested, e.g., by cleavage of compounds from the solid
support followed by spectroscopic analysis of the crude reaction
mixture. Alternatively, the reaction can be monitored by
chromatographic techniques such as thin-layer chromatography (TLC)
or HPLC.
[0189] In certain embodiments, the methods for preparing compounds
include the further step of purifying the compounds. Purity of the
reaction products can be determined according to known techniques.
If the products are impure, they can be purified according to a
variety of methods known in the art. For example, compounds
immobilized on a solid support can be separated from some
impurities by simple filtration and washing of the solid support to
remove soluble impurities. Compounds which are not immobilized on
solid supports can be purified by methods including crystallization
(where the compound is crystalline), trituration, distillation, and
chromatographic techniques such as TLC and HPLC (analytical or
preparative scale), flash chromatography, and the like. The
selection of methods for purifying compounds will be routine for
the ordinarily skilled artisan.
[0190] In preferred embodiments, the purity of a compound produced
according to the methods of the invention is at least about 50%,
more preferably at least about 70%, still more preferably at least
about 90%, and most preferably at least about 95%.
[0191] In another aspect, the invention provides methods for
treating bacterial infection. In general, the method comprises
administering to a subject in need thereof an effective amount of a
compound of the invention, such that the bacterial infection is
treated. The compound of the invention can be, e.g., a compound of
Formula I or Formula II, and can optionally be administered in a
pharmaceutically acceptable vehicle. Bacterial infections which can
be treated according to the methods of the invention include (but
are not limited to) infections due to gram-positive bacteria such
as Staphylococcus aureus, methicillin-resistant S. aureus (MRSA),
or vancomycin-resistant Enterococcus faceium (VREF). It will be
understood that more than one compound of the invention can be
employed to treat a bacterial infection; such multi-drug therapy
can be useful to provide a broader spectrum of action against
bacteria or to prevent the development of drug-resistant bacterial
strains.
[0192] As is described in more detail below, a compound of the
invention can be administered to a subject topically, e.g., to
treat a localized bacterial infection, or systemically, e.g., to
treat a systemic bacterial infection. The compound of the invention
is preferably administered such that the bacterial infection is
cured.
[0193] In certain preferred embodiments, the compound is a compound
of Formula I in which X is CH.sub.2. In certain preferred
embodiments, R.sub.1 is H. In some preferred embodiments, R.sub.3
is H. In certain preferred embodiments, Y is carbon, e.g.,
--CH(C(O)NR'.sub.14R'.sub.15)--- , in which R'.sub.14 and R'.sup.15
are each independently hydrogen or substituted or unsubstituted
alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl; or
R'.sub.14 and R'.sub.15, taken together with the nitrogen to which
they are attached, form a heterocyclic ring.
[0194] III. Libraries
[0195] In another aspect, the invention provides libraries of
compounds of Formula I, Formula Ia or Formula II, and methods of
preparing such libraries.
[0196] The synthesis of combinatorial libraries is well known in
the art and has been reviewed (see, e.g., E. M. Gordon et al., J.
Med. Chem. 37:1385-1401 (1994)). Thus, the subject invention
contemplates methods for synthesis of combinatorial libraries of
compounds of Formula I or Formula II. Such libraries can be
synthesized according to a variety of methods. For example, a
"split-pool" strategy can be implemented in the following way:
beads of a functionalized polymeric support are placed in a
plurality of reaction vessels. To each aliquot of beads is added a
solution of a different bicyclic alkene, and the reactions proceed
to yield a plurality of immobilized bicyclic alkenes. The aliquots
of derivatized beads are then washed, "pooled" (i.e., recombined),
and the pool of beads is again divided, with each aliquot being
placed in a separate reaction vessel. To each reaction vessel is
added a solution of a different olefin in solution (e.g., a
terminal aryl olefin) and a catalyst, and reaction occurs to yield
a plurality of reaction vessels each containing a plurality of
compounds of Formula I immobilized on solid support. The library of
immobilized compounds can then be washed to remove impurities. In
certain embodiments, the compound of Formula I can further be
treated (e.g., by cleavage, if desired, and cyclization) to yield a
compound of Formula II.
[0197] In another illustrative method of combinatorial synthesis, a
"diversomer library" is created by the method of Hobbs, DeWitt et
al. (Proc. Natl. Acad. Sci. U.S.A. 90:6909 (1993)). Aliquots of
functionalized polymeric support beads are placed in an array of
reaction vessels, and one of a plurality of bicyclic alkenes is
introduced into each vessel. After reaction, the beads are washed
to yield an array of immobilized bicyclic alkenes. Each vessel in
the array is then reacted with one of a plurality of olefins, in
the presence of a catalyst. After reaction, purification and workup
yields a soluble library of substituted compounds of Formula I
and/or Formula II.
[0198] Other synthesis methods, including the "tea-bag" technique
of Houghten (see, e.g., Houghten et al., Nature 354:84-86 (1991))
can also be used to synthesize libraries of compounds according to
the subject invention.
[0199] Combinatorial libraries can be screened to determine whether
any members of the library have a desired activity, and, if so, to
identify the active species. Methods of screening combinatorial
libraries have been described (see, e.g., Gordon et al., J Med.
Chem., op. cit.). Soluble compound libraries can be screened by
affinity chromatography with an appropriate receptor to isolate
ligands for the receptor, followed by identification of the
isolated ligands by conventional techniques (e.g., mass
spectrometry, NMR, and the like). Immobilized compounds can be
screened by contacting the compounds with a soluble receptor;
preferably, the soluble receptor is conjugated to a label (e.g.,
fluorophores, colorimetric enzymes, radioisotopes, luminescent
compounds, and the like) that can be detected to indicate ligand
binding. Alternatively, immobilized compounds can be selectively
released and allowed to diffuse through a membrane to interact with
a receptor. Exemplary assays useful for screening the libraries of
the invention are known in the art (see, e.g., E. M. Gordon et al.,
J. Med. Chem. 37:1385-1401 (1994)).
[0200] Combinatorial libraries of compounds can also be synthesized
with "tags" to encode the identity of each member of the library
(see, e.g., W. C. Still et al., U.S. Pat. No. 5,565,324 and PCT
Publication No. WO 94/08051). In general, this method features the
use of inert, but readily detectable, tags, that are attached to
the solid support or to the compounds. When an active compound is
detected (e.g., by one of the techniques described above), the
identity of the compound is determined by identification of the
unique accompanying tag. This tagging method permits the synthesis
of large libraries of compounds which can be identified at very low
levels.
[0201] In preferred embodiments, the libraries of compounds of the
invention contain at least 30 compounds, more preferably at least
100 compounds, and still more preferably at least 500 compounds. In
preferred embodiments, the libraries of compounds of the invention
contain fewer than 10.sup.9 compounds, more preferably fewer than
10.sup.8 compounds, and still more preferably fewer than 10.sup.7
compounds.
[0202] A library of compounds is preferably substantially pure,
i.e., substantially free of compounds other than the intended
products, e.g., members of the library. In preferred embodiments,
the purity of a library produced according to the methods of the
invention is at least about 50%, more preferably at least about
70%, still more preferably at least about 90%, and most preferably
at least about 95%.
[0203] The libraries of the invention can be prepared according to
the methods of the invention, wherein at least one of the bicyclic
alkene and the olefin is provided as a variegated population. In a
preferred embodiment, the methods for preparing libraries are
performed on a solid support (i.e., at least one of the bicyclic
alkene or the olefin is immobilized on a solid support). The term
"variegated population", as used herein, refers to a population
including at least two different chemical entities, e.g., of
different chemical structure. For example, a "variegated
population" of bicyclic alkenes would comprise at least two
different bicyclic alkenes. Similarly, a variegated population of
olefins comprises at least two different olefins. Use of a
variegated population of linkers can produce a variety of compounds
upon cleavage of the linkers (see, e.g., Example 6, infra). Thus,
the methods of the invention also can include the further step of
providing a variegated population of linkers.
[0204] Libraries of the invention are useful, e.g., for drug
discovery. For example, a library of the invention can be screened
(e.g., according to the methods described herein) to determine
whether the library includes compounds having a pre-selected
activity. Thus, for example, a library can be screened to determine
whether compounds of the library have anti-bacterial activity or
any other activity which can be detected in vitro or in vivo, e.g.,
anti-inflammatory activity, enzyme inhibitory activity, and the
like.
[0205] IV Pharmaceutical Compositions
[0206] In another aspect, the present invention provides
pharmaceutically acceptable compositions which comprise a
therapeutically-effective amount of one or more of the compounds
described above, formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
As described in detail below, the pharmaceutical compositions of
the present invention may be specially formulated for
administration in solid or liquid form, including those adapted for
the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets,
boluses, powders, granules, pastes for application to the tongue;
(2) parenteral administration, for example, by subcutaneous,
intramuscular or intravenous injection as, for example, a sterile
solution or suspension; (3) topical application, for example, as a
cream, ointment or spray applied to the skin; or (4) intravaginally
or intrarectally, for example, as a pessary, cream or foam.
[0207] The phrase "therapeutically-effective amount" as used herein
means that amount of a compound, material, or composition
comprising a compound of the present invention which is effective
for producing some desired therapeutic effect by treating (i.e.,
preventing or ameliorating) a bacterial infection in a subject, at
a reasonable benefit/risk ratio applicable to any medical
treatment.
[0208] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0209] The phrase "pharmaceutically-acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material, involved in carrying or
transporting the subject peptidomimetic agent from one organ, or
portion of the body, to another organ, or portion of the body. Each
carrier must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation and not injurious to the
patient. Some examples of materials which can serve as
pharmaceutically-acceptable carriers include: (1) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and
potato starch; (3) cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations.
[0210] As set out above, certain embodiments of the present
compounds can contain a basic functional group, such as amino or
alkylamino, and are, thus, capable of forming
pharmaceutically-acceptable salts with pharmaceutically-acceptable
acids. The term "pharmaceutically-acceptable salts" in this
respect, refers to the relatively non-toxic, inorganic and organic
acid addition salts of compounds of the present invention. These
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or by separately
reacting a purified compound of the invention in its free base form
with a suitable organic or inorganic acid, and isolating the salt
thus formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,
valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,
phosphate, tosylate, citrate, maleate, fumarate, succinate,
tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts and the like. (See, e.g., Berge et al.
(1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
[0211] In other cases, the compounds of the present invention may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically-acceptable salts with
pharmaceutically-acceptable bases. The term
"pharmaceutically-acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ during the final isolation and purification of the
compounds, or by separately reacting the purified compound in its
free acid form with a suitable base, such as the hydroxide,
carbonate or bicarbonate of a pharmaceutically-acceptable metal
cation, with ammonia, or with a pharmaceutically-acceptable organic
primary, secondary or tertiary amine. Representative alkali or
alkaline earth salts include the lithium, sodium, potassium,
calcium, magnesium, and aluminum salts and the like. Representative
organic amines useful for the formation of base addition salts
include ethylamine, diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like. (See, for example, Berge
et al., supra).
[0212] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0213] Examples of pharmaceutically-acceptable antioxidants
include: (1) water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0214] Formulations of the present invention include those suitable
for oral, nasal, topical (including buccal and sublingual), rectal,
vaginal and/or parenteral administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will vary depending upon the host
being treated, the particular mode of administration. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will generally be that amount of the
compound which produces a therapeutic effect. Generally, out of one
hundred percent, this amount will range from about 1 percent to
about ninety-nine percent of active ingredient, preferably from
about 5 percent to about 70 percent, most preferably from about 10
percent to about 30 percent.
[0215] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0216] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouth washes and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste.
[0217] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingredient is mixed with one or
more pharmaceutically-acceptable carriers, such as sodium citrate
or dicalcium phosphate, aid/or any of the following: (1) fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption accelerators, such as quaternary ammonium compounds; (7)
wetting agents, such as, for example, cetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay;
(9) lubricants, such a talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and (10) coloring agents. In the case of capsules, tablets
and pills, the pharmaceutical compositions may also comprise
buffering agents. Solid compositions of a similar type may also be
employed as fillers in soft and hard-filled gelatin capsules using
such excipients as lactose or milk sugars, as well as high
molecular weight polyethylene glycols and the like.
[0218] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0219] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0220] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups, and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0221] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0222] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0223] Formulations of the pharmaceutical compositions of the
invention for rectal or vaginal administration may be presented as
a suppository, which may be prepared by mixing one or more
compounds of the invention with one or more suitable nonirritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the rectum or vaginal cavity and release
the active compound.
[0224] Formulations of the present invention which are suitable for
vaginal administration also include pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing such carriers
as are known in the art to be appropriate.
[0225] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically-acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0226] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0227] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0228] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
peptidomimetic in the proper medium. Absorption enhancers can also
be used to increase the flux of the peptidomimetic across the skin.
The rate of such flux can be controlled by either providing a rate
controlling membrane or dispersing the peptidomimetic in a polymer
matrix or gel.
[0229] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0230] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
antioxidants, buffers, bacteriostats, solutes which render the
formulation isotonic with the blood of the intended recipient or
suspending or thickening agents.
[0231] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0232] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents which delay
absorption such as aluminum monostearate and gelatin.
[0233] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0234] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue.
[0235] When the compounds of the present invention are administered
as pharmaceuticals, to humans and animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99.5% (more preferably, 0.5 to 90%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0236] The preparations of the present invention may be given
orally, parenterally, topically, or rectally. They are of course
given by forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, etc. administration
by injection, infusion or inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral or topical
administration is preferred.
[0237] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticulare, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0238] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0239] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0240] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically-acceptable
dosage forms by conventional methods known to those of skill in the
art.
[0241] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0242] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the derivative (e.g., ester, salt or
amide) thereof, the route of administration, the time of
administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compound employed, the age, sex, weight, condition, general health
and prior medical history of the patient being treated, and like
factors well known in the medical arts.
[0243] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0244] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, doses of the compounds of this invention for a patient,
when used for the indicated effects, will range from about 0.0001
to about 100 mg per kilogram of body weight per day, more
preferably from about 0.01 to about 50 mg per kg per day, and still
more preferably from about 0.1 to about 40 mg per kg per day.
[0245] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms.
[0246] While it is possible for a compound of the present invention
to be administered alone, it is preferable to administer the
compound as a pharmaceutical composition.
[0247] Exemplification
General Experimental
[0248] Nuclear magnetic resonance (NMR) spectra were recorded using
a 300 MHz Varian Unity Fourier transform NMR spectrometer. Low
resolution mass spectra (LRMS) were obtained by direct injection of
samples in methanol into a single quadrapole mass spectrometer
(Finnigan SSQ 7000) equipped with an atmospheric pressure
ionization module (APCI-MS). High resolution mass spectroscopy
(HRMS) was performed by M-Scan, West Chester, Pa. Elemental
analyses were performed by Atlantic Microlabs, Inc., Norcross, Ga.
High pressure liquid chromatography (HPLC) was performed on a
Hewlett-Packard 1090 instrument with a C.sub.18 column (4.6
mm.times.25 cm) and a diode array detector (peakwidth: 0.53 min,
sampling interval: 0.32 min, spectrum from 200-350 nm). A flow rate
of 1 mL/min, oven temperature of 40.degree. C. and an injector
volume of 4 .mu.L were used. The eluent was a mixture of water and
acetonitrile both containing 0.05% trifluoroacetic acid (TFA). HPLC
samples were prepared in water/acetonitrile (1:1). A small amount
of methanol was sometimes added to increase solubility. The
following two methods were used:
1 Gradient time table: Time (min) % Water % Acetonitile Method A:
Run time: 15 min 0 95 5 4 60 40 8 0 100 11 0 100 12 95 5 15 95 5
Method B: Run time: 18 min 0 50 50 5 35 65 9 15 85 11 10 90 12 5 95
14 5 95 15 50 50 18 50 50
[0249] All metathesis reactions were conducted under an argon
atmosphere in dichloromethane (Aldrich Chem. Co.) stored under
nitrogen in SurelSeal.TM. bottles. All reagents obtained from
commercial sources were used without further purification, unless
otherwise indicated. Bis(tricyclohexylphosphine)benzylidine
ruthenium dichloride, 1, was purchased from Strem Chemicals, Inc.
Wang Resin (1% divinylbenzene cross-linked; 0.85-1.01 mmol/g;
100-200 mesh) was purchased from Advanced ChemTech, Louisville, Ky.
The resin was saturated with reaction solvent prior to use. For
metathesis reactions the resin was saturated with dichloromethane
in an inert atmosphere prior to the addition of the other reaction
materials.
Example 1
[0250] In order to assess the potential structure diversity that
could result from ROM, we chose to evaluate aryl olefin substrates
first in solution-phase reactions. For the metathesis reactions
described in this example, the commercially available
(Cy.sub.3P).sub.2Cl.sub.2Ru.dbd.CHPh, 1, was used. In the presence
of a terminal aryl olefin substrate cross-metathesis can occur
generating a different ruthenium phenylalkylidene catalyst.
However, Grubbs recently communicated that the electronic effect of
the phenylalkylidene moiety of 1 on metathesis activity was
relatively small (see (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W.
J Am. Chem. Soc. (1996) 118:100. (b) Schab, P.; France M. B.;
Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. Engl. (1995) 34,
2039).
[0251] When bicyclic olefin 2 (0.12M in dichloromethane) was
allowed to react at room temperature with 4-vinylanisole (5 eq.) in
the presence of 1 (5 mol %) tetrasubstituted cyclopentane 3 was
produced in 61% isolated yield (Scheme 1). 18
[0252] Unlike alkyl substituted olefins (see Schneider, M. F. and
Blechert, S. (1996), cited above; Randall, M. L. et al. (1995),
cited above), 4-vinylanisole lead to only the trans-substituted
isomer (J.sub.trans=16.5 Hz). Styrene and other styrene derivatives
(e.g. 4-acetoxy and 3-chloro) similarly participated in ROM with 2.
However, non-terminal aryl olefins (e.g. cis and trans-stilbene,
and 1-phenyl-1-propene) were unreactive under the same experimental
conditions.
[0253] 3: A flask, under an atmosphere of argon, was charged with
cis-5-norbornene-endo-2,3-dicarboxylic anhydride, 2 (90 mg, 0.548
mmol), dichloromethane (4.5 mL), 4-vinylanisole (364 ,.mu.L, 2.74
mmol), and 1 (23 mg, 5 mol %). The reaction mixture was allowed to
stir at room temperature for 24 h. The mixture was concentrated.
The residue was dissolved in ethyl acetate/hexane (50:50) and
passed through a small plug of silica gel. Decolorizing carbon was
added to the solution before it was filtered. The filtrate was
concentrated and the residue purified by column chromatogaphy on
silica gel using hexane/ethyl acetate (75:25) as the eluent to give
99 mg (61% yield) of 3 as a white crystalline solid. .sup.1H NMR
(300 MHz, CD.sub.2Cl.sub.2): .delta. 1.54 (q, 1H, J=12.9 Hz); 2.10
(m, 1H); 3.00-3.20 (m, 2H); 3.50-3.59 (m, 2H); 3.79 (s, 3H); 5.18
(pent, 1H, J=1.2 Hz); 5.20-5.32 (m, 1H); 5.97 (sept, 1H,
J.sub.1,=7.5 Hz, J.sub.2=3.0 Hz); 6.13 (dd, 1H, J.sub.1,-15.8 Hz,
J.sub.2=7.8 Hz); 6.47 (d, 1H, J=15.8 Hz); 6.86 (d, 2H, J=8.6 Hz);
7.32 (d, 2H, J=8.6 Hz); .sup.13C{.sup.1H} NMR (75 MHz,
CD.sub.2Cl.sub.2): .delta. 37.11,46.69,47.21, 50.06, 50.53, 55.78,
114.5, 117.29, 125.00, 128.01, 130.06, 131.80, 135.83, 159.91,
171.39, 171.46; Elemental Analysis: (cal.) C 72.47, H 6.08; (found)
C 72.40, H 6.12.
EXAMPLE 2
[0254] Several unsymmetrically substituted bicyclic olefins (4a-d)
were allowed to react with 4-vinylanisole utilizing solution-phase
ROM conditions. Slow addition of the bicyclic olefin (via a syringe
pump) minimized undesired polymerization (see Schneider, M. F. and
Blechert, S. (1996), cited above; Randall, M. L. et al. (1995),
cited above). However, in all cases two isomers were produced with
only slight regioselectivity (Scheme 2). 19
[0255] Preparation of 4a:
[0256] Resin 8 (900 mg, 0.675 mmol; prewashed with dichloromethane)
was treated with 10 mL 50% TFA in dichloromethane for 20 min. The
resin was washed with dichloromethane (4.times.10 mL). The eluents
were combined and then concentrated. The residue was redissolved in
dimethylformamide (DMF) (5 mL) and then triethylamine (1.0 mL) was
added followed by di-tert-butyldicarbonate (162 mg, 0.743 mnol).
The reaction mixture was stirred at room temperature overnight. The
mixture was diluted with water (50 mL) and extracted with ethyl
acetate (2.times.50 mL). The organic extracts were combined, washed
sequentially with water (50 mL) and brine (50 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated to give a
yellow oil. The oil was purified by column chromatography on silica
gel using hexane/ethyl acetate (1:1) as eluent to give 4a (190 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.20-1.48 (m, 1 1H);
3.10-3.70 (m, 12H); 6.16 (dd, 1H, J.sub.1=5.6 Hz, J.sub.2=3.0 Hz);
6.41 (dd,1H, J.sub.1=5.6 Hz, J.sub.2=3.0 Hz); .sup.13C{.sup.1H} NMR
(75 MHz, CDCl.sub.3): .delta. 28.56,41.83, 45.27,47.01, 47.08,
47.13, 48.62, 49.04, 51.79, 80.20, 80.38, 133.52, 136.55, 154.86,
171.15, 172.85.
[0257] Preparation of 4b:
[0258] A flask was charged with mono-methyl
cis-5-norbornene-endo-2,3-dica- rboxylate, 4e (500 mg, 2.55 mmol),
dichloromethane (35 mL), 4-methoxybenzylamine (302 .mu.L, 2.31
mmol), 1-hydroxybenzotriazole (HOBt) (338 mg, 2.50 mmol), and
dicyclohexylcarbodiimide (DCC) (516 mg, 2.50 mmol). The reaction
mixture was allowed to stir at room temperature for 24 h. The
mixture was filtered. The filtrate was diluted with dichloromethane
(20 mL) and then washed sequentially with saturated sodium
bicarbonate (20 mL) and brine (20 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated to give a white
solid. The solid was recrystallized from 50% aqueous ethanol to
give 4b as a white solid (473 mg). .sup.1H NMR (300 MHz,
CD.sub.2Cl.sub.2): .delta. 1.31 (d, 1H, J=8.3 Hz); 1.43 (d, 1H,
J=8.3 Hz); 3.07 (s, 2H); 3.20 (s, 2H); 3.46 (s, 3H); 3.77 (s, 3H);
4.24 (mn, 2H); 5.81 (bs, 1H); 6.07 (dd, 1H, J.sub.1=5.4 Hz,
J.sub.2=3.0 Hz); 6.39 (dd, 1H, J.sub.1,=5.4 Hz, J.sub.2=3.0 Hz);
6.85 (d, 2H, J=8.6 Hz); 7.18 (d, 2H, J=8.6 Hz).
[0259] Preparation of 4c:
[0260] A flask was charged with mono-methyl
cis-5-norbornene-endo-2,3-dica- rboxylate, 4e (500 mg, 2.55 mmol),
dichloromethane (35 mL), n-butylamine (228 .mu.L, 2.31 mmol), HOBt
(338 mg, 2.50 mmol), and DCC (516 mg, 2.50 mmol). The reaction
mixture was allowed to stir at room temperature for 24 h. The
mitture was filtered. The filtrate was diluted with dichloromethane
(20 mL) and then washed sequentially with saturated sodium
bicarbonate (20 mL) and brine (20 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated to give a white
solid. The solid was purified by column chromatography on silica
gel using hexane/ethyl acetate (1:1) as eluent to give 4c as a
white solid. The sample was contaminated with 5% benzotriazole.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 0.91 (t, 3H, J=7.1 Hz);
1.30-1.50 (m, 6H); 3.10-3.24 (m, 6H); 3.60 (s, 3H); 5.45 (bs, 1H);
6.16 (dd, 1H, J.sub.1,=5.6 Hz, J.sub.2=3.0 Hz); 6.50 (dd, 1H,
J.sub.1,=5.6 Hz, J.sub.2=3.0 Hz).
[0261] Preparation of 4d:
[0262] Resin 7 (400 mg, 0.340 mmol; prewashed with dichloromethane)
was treated with 5 mL 50% TFA in dichloromethane for 30 min. The
resin was washed with dichloromethane (4.times.5 mL). The eluents
were combined and then concentrated. The residue was redissolved in
dichloromethane (5 mL) and then triethylamine (1.0 mL) was added
followed by di-tert-butyldicarbonate (164 mg, 0.75 mmol). The
reaction mixture was stirred at room temperature for 2 h. The
mixture was diluted with water (25 mL) and extracted with
dichloromethane (3.times.25 mL). The organic extracts were
combined, washed with brine (25 mL), dried over anhydrous magnesium
sulfate, filtered, and concentrated (bath temperature
<30.degree. C.) to give a white oily solid. The residue was
purified by column chromatography on silica gel using hexane/ethyl
acetate (20:80) as eluent to give 4d (69 mg). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.32-1.48 (m, 11H); 3.09-3.30 (m, 10); 3.58
(s, 3H); 5.13 (bs, 1H); 6.15 (dd, 1H, J.sub.1=5.5 Hz, J.sub.2=3.0
Hz); 6.46 (dd, 1H, J.sub.1,=5.5 Hz, J.sub.2=3.0 Hz).
[0263] ROM of 4a:
[0264] A flask, under an atmosphere of argon, was charged with 1 (7
mg, 6 mol %), dichloromethane. (3 mL), and 4-vinylanisole (92
.mu.L,5 eq). A solution of 4a (50 mg, 0.138 mmol) in
dichloromethane (6 mL) was added over a 6 h period by syringe pump.
The resulting reaction mixture was allowed to stir at room
temperature overnight. The mixture was concentrated. The residue
was purified by column chromatogaphy on silica gel using
hexane/ethyl acetate (60:40) as the eluent to a colorless oil (42
mg).
[0265] ROM of 4b:
[0266] A flask, under an atmosphere of argon, was charged with 1 (7
mg, 6 mol %), dichloromethane (4 mL), and 4-vinylanisole (92 .mu.L,
5 eq). A solution of 4b (34.8 mg, 0.110 mmol) in dichloromethane (5
mL) was added over a 12 h period by syringe pump. The resulting
reaction mixture was allowed to stir at room temperature for an
additional 8 h. The mixture was concentrated. The residue was
purified by column chromatogaphy on silica gel using a gradient of
hexane/ethyl acetate (75:25 to 60:40) as the eluent to a white
semi-solid (43 mg).
[0267] ROM of 4c:
[0268] A flask, under an atmosphere of argon, was charged with 1
(3.5 mg, 6 mol %), dichloromethane (2 mL), and 4-vinylanisole (46
.mu.L, 5 eq). A solution of 4c (17.3 mg, 0.069 mmol) in
dichloromethane (3 mL) was added over a 6 h period by syringe pump.
The resulting reaction mixture was allowed to stir at room
temperature for an additional 18 h. The mixture was concentrated.
The residue was purified by column chromatogaphy on silica gel
using hexane/ethyl acetate (75:25) as the eluent to an oil (23
mg).
[0269] ROM of 4d:
[0270] A flask, under an atmosphere of argon, was charged with 1
(3.5 mg, 8.7 mol %), dichloromethane (2 mL), and 4-vinylanisole (46
.mu.L, 8.2 eq). A solution of 4d (18.7 mg, 0.053 mmol) in
dichloromethane (3 mL) was added over a 6 h period by syringe pump.
The resulting reaction mixture was allowed to stir at room
temperature for an additional 9 h. The mixture was concentrated.
The residue was purified by column chromatogaphy on silica gel
using hexane/ethyl acetate (50:50) as the eluent to an oil (16 mg).
Regioisomer ratio determined by .sup.1H NMR.
EXAMPLE 3
[0271] In order to evaluate solid-phase ROM, a bicyclic olefin
substrate was attached to Wang resin, 5 (0.85-1.01 mmol/g). First,
5 was allowed to react with 1,1'-carbonyldiimidizole (CDI) followed
by treatment with 1,3-propanediamine to give 6 (Scheme 3) (see,
e.g., Hauske, J. R; Dorff, P. Tetrahedron Lett. (1995)36:1589). The
resin was acylated with bicyclic olefin 4e in the presence of PyBOP
(PyBOP: benztriazole-1-y1-oxy-tris-pyr- rolidinophosphonium
hexafluorophosphate. Coste, J.; Dufour, M. -N.; Pantaloni, A.;
Castro, B. Tetrahedron Lett. (1990) 31, 669) and N-methylmorpholine
(NMM) to give 7. Similarly, resin 8 was prepared utilizing the same
protocol, except piperazine was substituted for 1,3-propanediamine.
20
[0272] Resin 7 was allowed to react with 3-chlorostyrene (10 eq.)
in the presence of 1 (10 mol %) at room temperature for 8 h. After
sequential washing with DMF, methanol and dichloromethane, the
resin was treated with 50% trifluoroacetic acid (TFA) in
dichloromethane for 30 min yielding a mixture of regioisomer
products 9a and 9b in a ratio of 1:1 (regioisomer ratios were
determined either by .sup.1H NMR analysis of the crude reaction
material or by HPLC analysis of the corresponding t-butylcarbamate
derivatives, which gave better separation). Likewise, resin 8 was
allowed to react with 4-vinylanisole, followed by TFA treatment, to
give a mixture of 10a and 10b in a ratio of 2.7:1. The overall
isolated yield (based on resin loading) of the highly
functionalized cyclopentane products was 60-70%. The solid-phase
ROM reaction was compatible with an array of electronically
differentiated terminal aryl olefins including 4-acetoxystyrene,
4-trifluoromethylstyren- e, and 3-nitrostyrene.
[0273] Resin 5a:
[0274] Wang Resin 5 (4.5 g, 3.8 mmol; prewashed with THF) was
shaken with CDI (3.1 g) in THF (50 mL) at room temperature for
overnight. The resin was washed sequentially with THF (50 mL), DMF
(2.times.50 mL), MeOH (2.times.50 mL), and dichloromethane
(2.times.100 mL). The resin was dried under vacuum.
[0275] Resin 7:
[0276] Resin 5a (2.0 g, 1.7 mmol); prewashed with THF) was shaken
with 1,3-propanediamine (708 .mu.L) in THF (20 mL) at room
temperature for 3 h. The resin was washed sequentially with THF (20
mL), MeOH (2.times.20 mL), and dichloromethane (2.times.50 mL) to
give resin 6. Resin 6 was prewashed with DMF before being shaken
with mono-methyl cis-5-norbornene-endo-2,3-dicarboxylate, 4e (1.33
g), PyBOP (3.78 g), and NMM (1.6 mL) in DMF for 3 h. The resin was
washed sequentially with THF (2.times.20 mL), MeOH (2.times.20 mL),
and dichloromethane (2.times.20 mL). The resin was dried under
vacuum. A sample was cleaved from the resin with 50% TFA in
dichloromethane and analyzed by HPLC.
[0277] Resin 8:
[0278] Resin 5a (2.0 g, 1.7 mmol); prewashed with THF) was shaken
with piperazine (0.731 g) in THF (20 mL) at room temperature for 3
h. The resin was washed sequentially with THF (20 mL), MeOH
(2.times.20 mL), and dichloromethane (2.times.50 mL). The resin was
prewashed with DMF before being shaken with mono-methyl
cis-5-norbornene-endo-2,3-dicarboxylate, 4e (1.33 g), PyBOP (3.78
g), and NMM (1.6 mL) in DMF for 3 h. The resin was washed
sequentially with THF (2.times.20 mL), MeOH (2.times.20 mL), and
dichloromethane (2.times.20 mL). The resin was dried under vacuum.
A sample was cleaved from the resin with 50% TFA in dichloromethane
and analyzed by HPLC.
[0279] ROM of 7:
[0280] A reaction tube, under an atmosphere of argon, was charged
with resin 7 (100 mg, 0.085 mmol) (Scheme 4). The resin was washed
with dichloromethane. The tube was then charged with
dichloromethane (1.0 mL), 3-chlorostyrene (108 .mu.l, 0.85 mmol),
and 1 (7 mg, 10 mol %). The tube was sealed under an atmosphere of
argon and shaken at room temperature for 20 h. The resin was washed
sequentially with DMF (3 mL), MeOH (2.times.3 mL), and
dichloromethane (5.times.3 mL). The resin was treated with 50% TFA
in dichloromethane (1.5 mL) for 30 min. The resin was washed with
dichloromethane (5.times.3 mL). The washings were concentrated to
9a/9b as an oil.
[0281] The oil, 9a/9b, was dissolved in dichloromethane (2 mL) and
then treated with triethylamine (250 .mu.L) and
d-tert-butyldicarbonate (41 mg) for 4 h. A sample of BOC-
(N-butyloxycarbonyl) protected 9a/9b was analyzed by HPLC.
[0282] The oil, 10a/10b, was dissolved in dichloromethane (2 mL)
and then treated with triethylamine (250 .mu.L) and
di-tert-butyldicarbonate (41 mg) for 4 h. A sample of BOC-protected
10a/10b was analyzed by HPLC.
[0283] ROM of 8:
[0284] A reaction tube, under an atmosphere of argon, was charged
with resin 8 (100 mg, 0.085 mmol). The resin was washed with
dichloromethane. The tube was then charged with dichloromethane
(1.0 mL), 4-vinylanisole (113 .mu.l, 0.85 mmol), and 1 (7 mg, 10
mol %). The tube was sealed under an atmosphere of argon and shaken
at room temperature for 20 h. The resin was washed sequentially
with DMF (3 mL), MeOH (2.times.3 mL), and dichloromethane
(5.times.3 mL). The resin was treated with 50% TFA in
dichloromethane (1.5 mL) for 30 min. The resin was washed with
dichloromethane (5.times.3 mL). The washings were concentrated to
10a/10b as an oil. After lyophilization the overall yield was
68.3%. HRMS: (cal) 399.2283, (found) 399.2279. 21
EXAMPLE 4
[0285] The ability of bicyclic lactams to undergo ROM was examined
as follows (Scheme 5):
[0286] Resin 11:
[0287] Resin 5a (100 mg. 0.085 mmol; prewashed with THF) was shaken
with piperazine (37 mg) in THF (1 mL) at room temperature for 3 h.
The resin was washed sequentially with THF (3 mL), MeOH (2.times.3
mL), and dichloromethane (3.times.3 mL). The resin was prewashed
with DMF before being shaken with bromoacetic acid (118 mg) and DIC
(54 .mu.L). The amide coupling was repeated. Then the resin was
washed sequentially with DMF (3 mL), MeOH (2.times.3 mL), and
dichloromethane (3.times.3 mL). The resin was shaken with potassium
hydroxide (96 mg, finely powdered) and
2-azabicyclo[2.2.1]hept-5-en-3-one (46 mg) in dimethylsulfoxide (1
mL) at room temperature for 5 h. Then the resin was washed
sequentially with water (5.times.3 mL), MeOH (3.times.3 mL), and
dichloromethane (5.times.3 mL) and dried.
[0288] ROM of 11:
[0289] A reaction tube, under an atmosphere of argon, was charged
with resin 11 (50 mg, 0.042 mmol). The resin was washed with
dichloromethane. The tube was charged with dichloromethane (1.5
mL), 4-vinylanisole (57 .mu.L), and 1 (8 mg). The tube was sealed
under an atmosphere of argon and shaken at room temperature for 18
h. The resin was washed sequentially with DMF (3 mL), MeOH
(2.times.3 mL), and dichloromethane (3.times.3 mL). The resin was
treated with 50% TFA in dichloromethane (1 mL) for 30 min. The
resin was washed with dichloromethane (3.times.3 mL). The washings
were concentrated to give 12 as a mixture of regioisomers. 22
EXAMPLE 5
[0290] The ROM reactions of the invention also provide substituted
tetrahydrofurans. Resin 6 was shaken with
exo-3,6-epoxy-1,2,3,6-tetrahydr- ophthalic anhydride, followed by
amidation of the free carboxylate with butylamine with PyBOP and
NMM, to provide the resin 13 (Scheme 6). Reaction of resin 13 with
4-vinylanisole in the presence of 1 , followed by TFA cleavage from
the resin, provided the isomeric substituted tetrahydrofurans 14a
and 14b as a mixture of regioisoomers in 70% yield. 23
EXAMPLE 6
[0291] When resin 7 was allowed to react with 4-vinylanisole in the
presence of 1, followed by treatment with 50% TFA in CDCl.sub.3
only one major ROM product was produced in 77% overall yield
(Scheme 7). Structure elucidation of the product by NMR revealed
the fused bicyclic lactam 16. (For examples of similar cyclizations
see, e.g.,: (a) Ukhov, S. V.; Konshin, M. E. Khim. Geterosikl.
Soedin. 1992, 28, 92. (b) ) Ukhov, S. V.; Konshin, M. E. Khim.
Geterosikl. Soedin. 1989, 25, 196. (c) Sigova, V. I.; Konshin, M.
E. Khim. Geterosikl. Soedin. 1986, 22, 415. (d) Sigova, V. I.;
Konshin, M. E. Khim. Geterosikl. Soedin. 1984, 20, 635. (e) Sigova,
V. I.; Konshin, M. E. Khim. Geterosikl. Soedin. 1984, 22, 415. (f)
Sigova, V. I.; Konshin, M. E. Zh. Obshch. Khim. 1984, 54, 1859.)
Note that the solid-supported reaction provides greater
regioselectivity than the solution-phase reaction The initial
product of the cross-metathesis reaction evidently cyclizes under
the acidic conditions employed.
[0292] Preparation of 16:
[0293] A reaction tube, under an atmosphere of argon, was charged
with resin 7 (150 mg, 0.128 mmol). The resin was washed with
dichloromethane. The tube was then charged with dichloromethane
(1.5 mL), 4-vinylanisole (170 .mu.l, 1.28 mmol), and 1 (11 mg, 10
mol %). The tube was sealed under an atmosphere of argon and shaken
at room temperature for 20 h. The resin was washed sequentially
with DMF (3 mL), MeOH (2.times.3 ml,), and dichloromethane
(5.times.3 mL). The resin was treated with 50% TFA in CDCl.sub.3
(1.5 mL) for 45 min. NMR analyses were performed (vida infra).
After concentration and lyophilization the overall yield was 77%.
.sup.1H-NMR (300 MHz, CDCl.sub.3/TFA) .delta. 7.40 (d, J=8.7 Hz,
2H); 7.08 (d, J=9 Hz, 2H); 5.83 (m, 1H); 5.18 (m, 2H); 4.61(dd,
J=11.7, 3 Hz, IH); 3.98 (s, 3H); 3.77(s, 3H); .sup.13C NMR (300
MHz, CDCl.sub.3/TFA) .delta. 178.39, 176.95, 159.79, 135.56,
130.73, 130.29, 117.24, 115.57, 64.25, 56.14, 53.19, 52.92, 47.12,
46.75, 42.73, 38.52, 37.25, 36.97, 34.19, 26.33. 24
EXAMPLE 7
[0294] A combinatorial library of compounds is prepared as
follows:
[0295] Wang resin is treated with carbonyldiimidazole and then
reacted, in 12 different reaction vessels, with 12 diamine
compounds. The resulting amino-functionalized Wang resins are
combined in groups of three to provide 4 reaction vessels, each
containing 3 diamine-functionalized resins. To each reaction vessel
is added bicyclic alkene 4e in the presence of PyBOP and NMM to
provide bicyclic alkene immobilized to a solid support through a
variety of linkers, and the four resin aliquots are further divided
into eight reaction vessels each (for a total of 32 reaction
vessels). Each vessels is treated with one of eight styrene
derivatives in the presence of catalyst 1, and, after reaction is
complete, the methyl ester of the bicyclic alkene is hydrolyzed to
the carboxylic acid. The aliquots are divided into 24 vessels each
(a total of 768 aliquots). Each vessel is treated with one of
twenty-four different amines in the presence of PyBOP and NMM to
provide 768 groups of compounds, each group containing compounds
immobilized through one of three linkers. Where the ROM reaction is
less than completely regioselective, two products can result; thus,
a total of 4608 compounds (768.times.3.times.2) can be
produced.
EXAMPLE 8
[0296] Two compounds were assayed for antibacterial activity in an
in vitro assay system: 25
[0297] Compounds 17 and 18 were synthesized as described above,
cleaved from the solid support, and used as a mixture of
regioisomers. Each test compound was then applied to a small disc
of filter paper. The filter paper was placed in a petri dish in
which S. aureus, methicillin-resistant S. aureus (MRSA), or
vancomycin-resistant E. faceium (VREF) was inoculated. The
bacterial cultures were incubated and then surveyed to determine
the zone of inhibition (if any) of bacterial growth around each
filter paper disc.
[0298] In each assay, both compound 17 and compound 18 displayed
modest inhibitory activity against at least one organism.
[0299] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the following claims.
[0300] The contents of all publications cited herein are hereby
incorporated by reference.
[0301] Other embodiments are within the following claims.
* * * * *