U.S. patent application number 10/743952 was filed with the patent office on 2007-06-28 for ketone compounds and compositions for cholesterol management and related uses.
Invention is credited to Jean-Louis Henri Dasseux, Daniela Carmen Oniciu.
Application Number | 20070149615 10/743952 |
Document ID | / |
Family ID | 26932388 |
Filed Date | 2007-06-28 |
United States Patent
Application |
20070149615 |
Kind Code |
A9 |
Dasseux; Jean-Louis Henri ;
et al. |
June 28, 2007 |
KETONE COMPOUNDS AND COMPOSITIONS FOR CHOLESTEROL MANAGEMENT AND
RELATED USES
Abstract
The present invention relates to novel ketone compounds,
compositions comprising ketone compounds, and methods useful for
treating and preventing cardiovascular diseases, dyslipidemias,
dysproteinemias, and glucose metabolism disorders comprising
administering a composition comprising a ketone compound. The
compounds, compositions, and methods of the invention are also
useful for treating and preventing Alzheimer's Disease, Syndrome X,
peroxisome proliferator activated receptor-related disorders,
septicemia, thrombotic disorders, obesity, pancreatitis,
hypertension, renal disease, cancer, inflammation, and impotence.
In certain embodiments, the compounds, compositions, and methods of
the invention are useful in combination therapy with other
therapeutics, such as hypocholesterolemic and hypoglycemic
agents.
Inventors: |
Dasseux; Jean-Louis Henri;
(Brighton, MI) ; Oniciu; Daniela Carmen; (Ann
Arbor, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
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Prior
Publication: |
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Document Identifier |
Publication Date |
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US 20040198814 A1 |
October 7, 2004 |
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Family ID: |
26932388 |
Appl. No.: |
10/743952 |
Filed: |
December 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09976938 |
Oct 11, 2001 |
6699910 |
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10743952 |
Dec 24, 2003 |
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60239232 |
Oct 11, 2000 |
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Current U.S.
Class: |
514/526 ;
514/558; 554/113; 554/115 |
Current CPC
Class: |
C07D 305/12 20130101;
C07C 49/17 20130101; C07D 261/12 20130101; C07C 49/245 20130101;
C07C 309/07 20130101; C07F 9/4423 20130101; C07C 49/723 20130101;
C07C 49/743 20130101; C07C 49/215 20130101; C07C 49/507 20130101;
C07C 49/82 20130101; C07C 69/738 20130101; C07C 49/86 20130101;
C07D 495/04 20130101; C07D 233/72 20130101; C07D 233/86 20130101;
C07C 49/782 20130101; C07C 49/258 20130101; C07D 257/04 20130101;
C07C 49/185 20130101; C07D 307/33 20130101; C07D 309/12 20130101;
C07C 69/716 20130101; C07D 309/30 20130101; C07C 59/347 20130101;
C07F 9/093 20130101; C07C 50/30 20130101; C07C 59/353 20130101;
C07C 59/84 20130101; C07C 261/04 20130101; C07D 233/84 20130101;
C07C 49/747 20130101; C07D 309/40 20130101; C07F 9/2425 20130101;
C07C 309/24 20130101 |
Class at
Publication: |
514/526 ;
514/558; 554/113; 554/115 |
International
Class: |
A61K 31/275 20060101
A61K031/275; A61K 31/20 20060101 A61K031/20; C07C 59/147 20060101
C07C059/147; C07C 59/185 20060101 C07C059/185 |
Claims
1. A compound of a formula I: ##STR574## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) each occurrence of Z is independently CH.sub.2, CH.dbd.CH, or
phenyl, wherein each occurrence of m is independently an integer
ranging from 1 to 9, but when Z is phenyl then its associated m is
1; (b) G is (CH.sub.2).sub.x, CH.sub.2CH.dbd.CHCH.sub.2, CH.dbd.CH,
CH.sub.2-phenyl-CH.sub.2, or phenyl, wherein x is 2, 3, or 4; (c)
W.sup.1 and W.sup.2 are independently L, V,
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-C(R.sup.3)(R.sup.4)--(CH.sub.2).sub-
.n-Y, or C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V, wherein c is 1 or
2 and n is an independent integer ranging from 0 to 4; (d) R.sup.1
and R.sup.2 are independently CO.sub.2H,
CO.sub.2(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl or when W.sup.1 or W.sup.2 is
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-C(R.sup.3)(R.sup.4)--Y, then
R.sup.1 and R.sup.2 can both be H, or R.sup.1 and R.sup.2 and the
carbon to which they are both attached are taken together to form a
(C.sub.3-C.sub.7)cycloakyl group; (e) R.sup.3 and R.sup.4 are
independently H, OH, CO.sub.2H, CO.sub.2(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, phenyl, benzyl,
Cl, Br, CN, NO.sub.2, or CF.sub.3, with the proviso that when
R.sup.1 and R.sup.2 are both H, then one of R.sup.3 or R.sup.4 is
not H or R.sup.3 and R.sup.4 and the carbon to which they are both
attached are taken together to form a (C.sub.3-C.sub.7)cycloakyl
group; (f) L is C(R.sup.1)(R.sup.2)CH.sub.2).sub.n-Y; (g) V is
##STR575## (h) Y is (C.sub.1-C.sub.6)alkyl, OH, COOH, CHO,
COOR.sup.5, SO.sub.3H, ##STR576## where (I) R.sup.5 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, (ii) each occurrence of R.sup.6 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted with
one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups; and
(iii) each occurrence of R.sup.7 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl; and provided that: (i) if G is
(CH.sub.2).sub.x, x is 4, each occurrence of Z is CH.sub.2, each
occurrence of m is 4, and W.sup.1 is --CH(CH.sub.3)CO.sub.2H, then
W.sup.2 is not the same as W.sup.1; (ii) if G is
CH.sub.2-phenyl-CH.sub.2, each occurrence of Z is CH.sub.2, each
occurrence of m is 2, and W.sup.1 is
--C(CH.sub.3).sub.2CH(CO.sub.2CH.sub.2CH.sub.3).sub.2, then W.sup.2
is not the same as W.sup.1; (iii) if G is CH.sub.2-phenyl-CH.sub.2,
each occurrence of Z is CH.sub.2, each occurrence of m is 2, and
W.sup.1 is --C(CH.sub.3).sub.2CH.sub.2(CO.sub.2CH.sub.2CH.sub.3),
then W.sup.2 is not the same as W.sup.1; (iv) if G is
CH.sub.2-phenyl-CH.sub.2, each occurrence of Z is CH.sub.2, each
occurrence of m is 1, and W.sup.1 is
--COCH.sub.2C(CH.sub.3).sub.2CH.sub.2CO.sub.2H, then W.sup.2 is not
the same as W.sup.1; (v) if G is (CH.sub.2).sub.x, x is 4, each
occurrence of Z is CH.sub.2, each occurrence of m is 2, and W.sup.1
is --C(phenyl).sub.2CH.sub.2CO.sub.2H, then W.sup.2 is not the same
as W.sup.1; (vi) if G is CH.dbd.CH, each occurrence of Z is
CH.sub.2, each occurrence of m is 1, and W.sup.1 is
--C(CH.sub.3).sub.2CH.sub.2(CO.sub.2H), then W.sup.2 is not the
same as W.sup.1; and (vii) if G is phenyl, each occurrence of Z is
CH.sub.2, each occurrence of m is 1, and W.sup.1 is
--C(phenyl).sub.2CO.sub.2H, then W.sup.2 is not the same as
W.sup.1.
2. The compound of claim 1, wherein: (a) W.sup.1 and W.sup.2 are
independently L, V, or C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V
where c is 1 or 2; and (b) R.sup.1 or R.sup.2 are independently
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl.
3. The compound of claim 1, wherein W.sup.1 is L.
4. The compound of claim 1, wherein W.sup.1 is V.
5. The compound of claim 1, wherein W.sup.1 is
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-C(R.sup.3)(R.sup.4)--(CH.sub.2).sub-
.n---Y.
6. The compound of claim 1, wherein W.sup.1 is
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V.
7. The compound of claim 1, wherein W.sup.1 and W.sup.2 are
independent L groups.
8. The compound of claim 7, wherein each occurrence of Y is
independently (CH.sub.2).sub.nOH, (CH.sub.2).sub.nCOOR.sup.5, or
(CH.sub.2).sub.nCOOH.
9. A compound of the formula Ia: ##STR577## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) each occurrence of Z is independently CH.sub.2 or CH.dbd.CH,
wherein each occurrence of m is independently an integer ranging
from 1 to 9; (b) G is (CH.sub.2).sub.x, CH.sub.2CH.dbd.CHCH.sub.2,
or CH.dbd.CH, where x is 2, 3, or 4; (c) W.sup.1 and W.sup.2 are
independently L, V, or C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V,
where c is 1 or 2; (d) each occurrence of R.sup.1 and R.sup.2 is
independently CO.sub.2H, CO.sub.2(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, benzyl, or R.sup.1 and R.sup.2
and the carbon to which they are both attached are taken together
to form a (C.sub.3-C.sub.7)cycloakyl group; (e) L is
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.n-Y, where n is an independent
integer ranging from 0 to 4; (f) V is ##STR578## (g) each
occurrence of Y is independently (C.sub.1-C.sub.6)alkyl, OH, COOH,
CHO, (CH.sub.2).sub.nCOOR.sup.3, SO.sub.3H, ##STR579## where (I)
R.sup.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, (ii) each occurrence of R.sup.4 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted with
one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups; and
(iii) each occurrence of R.sup.5 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl; and provided that: (i) if x is 4, each
occurrence of Z is CH.sub.2, each occurrence of m is 4, and W.sup.1
is --CH(CH.sub.3)CO.sub.2H, then W.sup.2 is not the same as
W.sup.1; (ii) if x is 4, each occurrence of Z is CH.sub.2, each
occurrence of m is 2, and W.sup.1 is
--C(phenyl).sub.2CH.sub.2CO.sub.2H, then W.sup.2 is not the same as
W.sup.1.
10. The compound of claim 9, wherein W.sup.1 is L.
11. The compound of claim 9, wherein W.sup.1 is V.
12. The compound of claim 9, wherein W.sup.1 is
C(R.sup.1)(R.sup.2)--CH.sub.2).sub.c-V.
13. The compound of claim 9, wherein W.sup.1 and W.sup.2 are
independent L groups.
14. The compound of claim 13, wherein each occurrence of Y is
independently OH, COOR.sup.3, or COOH.
15. A compound of the formula Ib ##STR580## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein:
(a) each occurrence of m is independently an integer ranging from 1
to 9; (b) x is 2, 3, or 4; (c) n is an independent integer ranging
from 0 to 4; (d) each occurrence of R.sup.1 and R.sup.2 is
independently CO.sub.2H, CO.sub.2(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, benzyl, or R.sup.1 and R.sup.2
and the carbon to which they are both attached are taken together
to form a (C.sub.3-C.sub.7)cycloakyl group; (e) each occurrence of
R.sup.11 and R.sup.12 is independently H, CO.sub.2H,
CO.sub.2(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, benzyl,
or R.sup.11 and R.sup.12 and the carbon to which they are both
attached are taken together to form a (C.sub.3-C.sub.7)cycloakyl
group; (f) each occurrence of Y is independently
(C.sub.1-C.sub.6)alkyl, OH, COOH, CHO, COOR.sup.3, SO.sub.3H,
##STR581## where (I) R.sup.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl and is unsubstituted or substituted with one or more halo,
OH, (C.sub.1-C.sub.6)alkoxy, or phenyl groups, (ii) each occurrence
of R.sup.4 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl and is
unsubstituted or substituted with one or two halo, OH,
C.sub.1-C.sub.6 alkoxy, or phenyl groups; and (iii) each occurrence
of R.sup.5 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl; provided
that: (i) if x is 4 each occurrence of m is 4, and W.sup.1 is
--CH(CH.sub.3)CO.sub.2H, then W.sup.2 is not the same as W.sup.1;
(ii) if x is 4 occurrence of m is 2, and W.sup.1 is
--C(phenyl).sub.2CH.sub.2CO.sub.2H, then W.sup.2 is not the same as
W.sup.1.
16. The compound of claim 15, wherein each occurrence of Y is
independently OH, COOR.sup.3, or COOH.
17. The compound of claim 16, wherein each R.sup.1 or R.sup.2 is
the same or different (C.sub.1-C.sub.6)alkyl group.
18. A compound of the formula Ic ##STR582## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein:
(a) each occurrence of m is an independent integer ranging from 1
to 9; (b) x is 2, 3, or 4; (c) V is ##STR583## provided that: (i)
if x is 4 each occurrence of m is 4, and W.sup.1 is
--CH(CH.sub.3)CO.sub.2H, then W.sup.2 is not the same as W.sup.1;
and (ii) if x is 4 each occurrence of m is 2, and W.sup.1 is
--C(phenyl).sub.2CH.sub.2CO.sub.2H, then W.sup.2 is not the same as
W.sup.1.
19. A compound according to claim 1, having the formula
5-[2-(5-hydroxy-4,4-dimethyl-pentyloxy)-ethoxy]-2,2-dimethyl-pentan-1-ol
or 4-[3-(3,3-Dimethyl-4-oxo-butoxy)-propoxy]-2,2-dimethyl-butyric
acid.
20. A compound of the formula II: ##STR584## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) R.sup.1 and R.sup.2 are independently CO.sub.2H,
CO.sub.2(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl; or R.sup.1, R.sup.2, and the carbon to which they are both
attached are taken together to form a (C.sub.3-C.sub.7)cycloalkyl
group; (b) R.sup.11 and R.sup.12 are independently CO.sub.2H,
CO.sub.2(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl; or R.sup.11, R.sup.12, and the carbon to which they are
both attached are taken together to form a
(C.sub.3-C.sub.7)cycloalkyl group; (c) n is an integer ranging from
1 to 6; (d) each occurrence of m is independently an integer
ranging from 0 to 4; (e) W.sup.1 and W.sup.2 are independently
(C.sub.1-C.sub.6)alkyl, CH.sub.2OH, C(O)OH, CHO, OC(O)R.sup.3,
C(O)OR.sup.3, SO.sub.3H, ##STR585## where (I) R.sup.3 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, (ii) each occurrence of R.sup.4 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted with
one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups;
(iii) each occurrence of R.sup.5 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl.
21. A compound of formula IIa: ##STR586## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) R.sup.1 and R.sup.2 are OH, COOH, CHO, COOR.sup.7, SO.sub.3H,
##STR587## where (I) R.sup.7 is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl and is unsubstituted or substituted with one or more halo,
OH, (C.sub.1-C.sub.6)alkoxy, or phenyl groups, (ii) each occurrence
of R.sup.8 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl and is
unsubstituted or substituted with one or two halo, OH,
C.sub.1-C.sub.6 alkoxy, or phenyl groups, (iii) each occurrence of
R.sup.9 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl; (b) R.sup.3
and R.sup.4 are CO.sub.2H, CO.sub.2(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl; (c) R.sup.5 and
R.sup.6 are hydrogen, halogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C6)aryloxy, CN, or NO.sub.2,
N(R.sup.5).sub.2 where R.sup.5 is H, (C.sub.1-C.sub.4)alkyl,
phenyl, or benzyl; (d) each occurrence of m is independently an
integer ranging from 1 to 5; (e) each occurrence of n is
independently an integer ranging from 0 to 4; and (f) *.sup.1 and
*.sup.2 represent independent chiral-carbon centers, wherein each
center may independently be R or S.
22. A compound as in claim 21 wherein *.sup.1 is a chiral-carbon
center of the stereochemical configuration R or substantially
R.
23. A compound as in claim 21 wherein *.sup.1 is a chiral-center of
the stereochemical configuration S or substantially S.
24. A compound as in claim 21 wherein *.sup.2 is a chiral-carbon
center of the stereochemical configuration R or substantially
R.
25. A compound as in claim 21 wherein *.sup.2 is a chiral-center of
the stereochemical configuration S or substantially S.
26. A compound of the formula III: ##STR588## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) each occurrence of Z is independently CH.sub.2, CH.dbd.CH, or
phenyl, where each occurrence of m is independently an integer
ranging from 1 to 5, but when Z is phenyl then its associated m is
1; (b) G is (CH.sub.2).sub.x, CH.sub.2CH.dbd.CHCH.sub.2, CH.dbd.CH,
CH.sub.2-phenyl-CH.sub.2, or phenyl, where x is an integer ranging
from 1 to 4; (c) W.sup.1 and W.sup.2 are independently
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.n-Y where n is an integer
ranging from 0 to 4; (d) R.sup.1 and R.sup.2 are independently
CO.sub.2H, CO.sub.2(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl or R.sup.1 and R.sup.2 are both H, or R.sup.1, R, and the
carbon to which they are both attached are taken together to form a
(C.sub.3-C.sub.7)cycloalkyl group; (e) Y is (C.sub.1-C.sub.6)alkyl,
(CH.sub.2).sub.nOH, (CH.sub.2).sub.nCOOH, (CH.sub.2).sub.nCHO,
(CH.sub.2).sub.nCOOR.sup.3, SO.sub.3H, ##STR589## ##STR590## where
(I) R.sup.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, (ii) each occurrence of R.sup.4 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted with
one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups,
(iii) each occurrence of R.sup.5 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl; and (f) each occurrence of p is
independently 2 or 3 where the broken line represents an optional
presence of one or more additional carbon-carbon bonds that when
present complete one or more carbon-carbon double bonds.
27. The compound of claim 26, wherein W.sup.1 and W.sup.2 are
independent C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.n--Y groups, where
n is an independent integer ranging from 0 to 4, and each
occurrence of Y is independently OH, COOR.sup.4, or COOH.
28. The compound of claim 26, wherein p is 0.
29. The compound of claim 26, wherein p is 1.
30. A compound of the formula IIIa: ##STR591## or a
pharmaceutically acceptable salt, hydrate, solvate, clathrate
thereof, wherein (a) each occurrence of m is independently an
integer ranging from 1 to 5; (b) x is an integer ranging from 1 to
4; (c) W.sup.1 and W.sup.2 are independently
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.n-Y; ##STR592## (d) each
occurrence of R.sup.1 or R.sup.2 is independently
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, benzyl, or R.sup.1, R.sup.1, and
the carbon to which they are both attached are taken together to
form a (C.sub.3-C.sub.7)cycloalkyl group; (e) Y is
(C.sub.1-C.sub.6)alkyl, OH, COOH, CHO, COOR.sup.3, SO.sub.3H,
##STR593## where (I) R.sup.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl and is unsubstituted or substituted with one or more halo,
OH, (C.sub.1-C.sub.6)alkoxy, or phenyl groups, (ii) each occurrence
of R.sup.4 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl and is
unsubstituted or substituted with one or two halo, OH,
C.sub.1-C.sub.6 alkoxy, or phenyl groups, (iii) each occurrence of
R.sup.5 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl; and (f) each
occurrence of p is independently 0 or 1.
31. The compound of claim 30, wherein W.sup.1 and W.sup.2 are
independent C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.n-Y groups, where n
is an integer from 0 to 4, and each occurrence of Y is
independently OH, COOR.sup.3, or COOH.
32. The compound of claim 30, wherein p is 0.
33. The compound of claim 30, wherein p is 1.
34. A pharmaceutical composition comprising a compound of claim 1,
9, 15, 18, 20, 21, 26, or 30 and a pharmaceutically acceptable
vehicle, excipient, or diluent.
35. A pharmaceutical composition comprising the following compound:
6-(5,5-Dimethyl-6-hydroxy-hexane-1-sulfinyl)-2,2-dimethyl-hexan-1-ol
or pharmaceutically acceptable salts, hydrates, solvates,
clathrates, enantiomers, diasteriomers, racemates, or mixtures of
steroisomers thereof and a pharmaceutically acceptable vehicle,
excipient, or diluent.
36. A method for treating or preventing a cardiovascular disease in
a patient, comprising administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
37. A method for treating or preventing a dyslipidemia in a
patient, comprising administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
38. A method for treating or preventing a dyslipoproteinemia in a
patient, comprising administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
39. A method for treating or preventing a disorder of glucose
metabolism in a patient, comprising administering to a patient in
need of such treatment or prevention a therapeutically effective
amount of a compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
40. A method for treating or preventing Alzheimer's Disease in a
patient, comprising administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
41. A method for treating or preventing Syndrome X or Metabolic
Syndrome in a patient, comprising administering to a patient in
need of such treatment or prevention a therapeutically effective
amount of a compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
42. A method for treating or preventing septicemia in a patient,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of
claim 1, 9, 15, 18, 20, 21, 26, or 30.
43. A method for treating or preventing a thrombotic disorder in a
patient, comprising administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
44. A method for treating or preventing a peroxisome proliferator
activated receptor associated disorder in a patient, comprising
administering to a patient in need of such treatment or prevention
a therapeutically effective amount of a compound of claim 1, 9, 15,
18,20, 21, 26, or 30.
45. A method for treating or preventing obesity in a patient,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of
claim 1, 9, 15, 18, 20, 21, 26, or 30.
46. A method for treating or preventing pancreatitis in a patient,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of
claim 1, 9, 15, 18, 20, 21, 26, or 30.
47. A method for treating or preventing hypertension in a patient,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of
claim 1, 9, 15, 18, 20, 21, 26, or 30.
48. A method for treating or preventing renal disease in a patient,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of
claim 1, 9, 15, 18, 20, 21, 26, or 30.
49. A method for treating or preventing cancer in a patient,
comprising administering to a patient in claim 1, 9, 15, 18, 20,
21, 26, or 30.
50. A method for treating or preventing inflammation in a patient,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of
claim 1, 9, 15, 18, 20, 21, 26, or 30.
51. A method for treating or preventing impotence in a patient,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of
claim 1, 9, 15, 18, 20, 21, 26, or 30.
52. A method for treating or preventing a neurodegenerative disease
or disorder in a patient, comprising administering to a patient in
need of such treatment or prevention a therapeutically or
prophylactically effective amount of a compound of claim 1, 9, 15,
18, 20, 21, 26, or 30.
53. A method of inhibiting hepatic fatty acid synthesis in a
patient, comprising administering to a patient in need thereof a
therapeutically or prophylactically effective amount of a compound
of claim 1, 9, 15, 18, 20, 21, 26, or 30.
54. A method of inhibiting sterol synthesis in a patient,
comprising administering to a patient in need thereof a
therapeutically or prophylactically effective amount of a compound
of claim 1, 9, 15, 18, 20,21, 26, or 30.
55. A method of treating or preventing metabolic syndrome disorders
in a patient, comprising administering to a patient in need of such
treatment or prevention a therapeutically or prophylactically
effective amount of a compound of claim 1, 9, 15, 18, 20, 21, 26,
or 30.
56. A method of treating or preventing a disease or disorder that
is capable of being treated or prevented by increasing HDL levels,
which comprises administering to a patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
57. A method of treating or preventing a disease or disorder that
is capable of being treated or prevented by lowering LDL levels,
which comprises administering to such patient in need of such
treatment or prevention a therapeutically effective amount of a
compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.
Description
1. FIELD OF THE INVENTION
[0001] The invention encompasses ketone compounds and
pharmaceutically acceptable salts, hydrates, solvates, and mixtures
thereof; compositions comprising urea and thiourea compounds and
pharmaceutically acceptable salts, hydrates, solvates, and mixtures
thereof; and methods for treating or preventing a disease or
disorder such as, but not limited to, aging, Alzheimer's Disease,
cancer, cardiovascular disease, diabetic nephropathy, diabetic
retinopathy, a disorder of glucose metabolism, dyslipidemia,
dyslipoproteinemia, hypertension, impotence, inflammation, insulin
resistance, lipid elimination in bile, modulating C reactive
protein, obesity, oxysterol elimination in bile, pancreatitis,
Parkinson's disease, a peroxisome proliferator activated
receptor-associated disorder, phospholipid elimination in bile,
renal disease, septicemia, metabolic syndrome disorders (e.g.,
Syndrome X), a thrombotic disorder, or enhancing bile production,
or enhancing reverse lipid transport, which method comprise
administering a ketone compound or composition of the invention to
a patient in need thereof. The compounds of the invention can also
treat or prevent inflammatory processes and diseases like
gastrointestinal disease, irritable bowel syndrome (IBS),
inflammatory bowel disease (e.g., Crohn's Disease, ulcerative
colitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis),
autoimmune disease (e.g., systemic lupus erythematosus),
scleroderma, ankylosing spondylitis, gout and pseudogout, muscle
pain: polymyositis/polymyalgia rheumatica/fibrositis; infection and
arthritis, juvenile rheumatoid arthritis, tendonitis, bursitis and
other soft tissue rheumatism.
2. BACKGROUND OF THE INVENTION
[0002] Obesity, hyperlipidemia, and diabetes have been shown to
play a causal role in atherosclerotic cardiovascular diseases,
which currently account for a considerable proportion of morbidity
in Western society. Further, one human disease, termed "Syndrome X"
or "Metabolic Syndrome", is manifested by defective glucose
metabolism (insulin resistance), elevated blood pressure
(hypertension), and a blood lipid imbalance (dyslipidemia). See
e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.
[0003] The evidence linking elevated serum cholesterol to coronary
heart disease is overwhelming. Circulating cholesterol is carried
by plasma lipoproteins, which are particles of complex lipid and
protein composition that transport lipids in the blood. Low density
lipoprotein (LDL) and high density lipoprotein (HDL) are the major
cholesterol-carrier proteins. LDL is believed to be responsible for
the delivery of cholesterol from the liver, where it is synthesized
or obtained from dietary sources, to extrahepatic tissues in the
body. The term "reverse cholesterol transport" describes the
transport of cholesterol from extrahepatic tissues to the liver,
where it is catabolized and eliminated. It is believed that plasma
HDL particles play a major role in the reverse transport process,
acting as scavengers of tissue cholesterol. HDL is also responsible
for the removal of non-cholesterol lipid, oxidized cholesterol and
other oxidized products from the bloodstream.
[0004] Atherosclerosis, for example, is a slowly progressive
disease characterized by the accumulation of cholesterol within the
arterial wall. Compelling evidence supports the belief that lipids
deposited in atherosclerotic lesions are derived primarily from
plasma apolipoprotein B (apo B)-containing lipoproteins, which
include chylomicrons, CLDL, intermediate-density lipoproteins
(IDL), and LDL. The apo B-containing lipoprotein, and in particular
LDL, has popularly become known as the "bad" cholesterol. In
contrast, HDL serum levels correlate inversely with coronary heart
disease. Indeed, high serum levels of HDL are regarded as a
negative risk factor. It is hypothesized that high levels of plasma
HDL are not only protective against coronary artery disease, but
may actually induce regression of atherosclerotic plaque (e.g., see
Badimon et al., 1992, Circulation 86:(Suppl. III)86-94; Dansky and
Fisher, 1999, Circulation 100:1762 3.). Thus, HDL has popularly
become known as the "good" cholesterol.
2.1. Cholesterol Transport
[0005] The fat-transport system can be divided into two pathways:
an exogenous one for cholesterol and triglycerides absorbed from
the intestine and an endogenous one for cholesterol and
triglycerides entering the bloodstream from the liver and other
non-hepatic tissue.
[0006] In the exogenous pathway, dietary fats are packaged into
lipoprotein particles called chylomicrons, which enter the
bloodstream and deliver their triglycerides to adipose tissue for
storage and to muscle for oxidation to supply energy. The remnant
of the chylomicron, which contains cholesteryl esters, is removed
from the circulation by a specific receptor found only on liver
cells. This cholesterol then becomes available again for cellular
metabolism or for recycling to extrahepatic tissues as plasma
lipoproteins.
[0007] In the endogenous pathway, the liver secretes a large,
very-low-density lipoprotein particle (VLDL) into the bloodstream.
The core of VLDL consists mostly of triglycerides synthesized in
the liver, with a smaller amount of cholesteryl esters either
synthesized in the liver or recycled from chylomicrons. Two
predominant proteins are displayed on the surface of VLDL,
apolipoprotein B-100 (apo B-100) and apolipoprotein E (apo E),
although other apolipoproteins are present, such as apolipoprotein
CIII (apo CIII) and apolipoprotein CII (apo CII). When VLDL reaches
the capillaries of adipose tissue or of muscle, its triglyceride is
extracted. This results in the formation of a new kind of particle
called intermediate-density lipoprotein (IDL) or VLDL remnant,
decreased in size and enriched in cholesteryl esters relative to a
VLDL, but retaining its two apoproteins.
[0008] In human beings, about half of the IDL particles are removed
from the circulation quickly, generally within two to six hours of
their formation. This is because IDL particles bind tightly to
liver cells, which extract IDL cholesterol to make new VLDL and
bile acids. The IDL not taken up by the liver is catabolized by the
hepatic lipase, an enzyme bound to the proteoglycan on liver cells.
Apo E dissociates from IDL as it is transformed to LDL. Apo B-100
is the sole protein of LDL.
[0009] Primarily, the liver takes up and degrades circulating
cholesterol to bile acids, which are the end products of
cholesterol metabolism. The uptake of cholesterol-containing
particles is mediated by LDL receptors, which are present in high
concentrations on hepatocytes. The LDL receptor binds both apo E
and apo B-100 and is responsible for binding and removing both IDL
and LDL from the circulation. In addition, remnant receptors are
responsible for clearing chylomicrons and VLDL remnants (i.e.,
IDL). However, the affinity of apo E for the LDL receptor is
greater than that of apo B-100. As a result, the LDL particles have
a much longer circulating life span than IDL particles; LDL
circulates for an average of two and a half days before binding to
the LDL receptors in the liver and other tissues. High serum levels
of LDL, the "bad" cholesterol, are positively associated with
coronary heart disease. For example, in atherosclerosis,
cholesterol derived from circulating LDL accumulates in the walls
of arteries. This accumulation forms bulky plaques that inhibit the
flow of blood until a clot eventually forms, obstructing an artery
and causing a heart attack or stroke.
[0010] Ultimately, the amount of intracellular cholesterol
liberated from the LDL controls cellular cholesterol metabolism.
The accumulation of cellular cholesterol derived from VLDL and LDL
controls three processes. First, it reduces the ability of the cell
to make its own cholesterol by turning off the synthesis of HMGCoA
reductase, a key enzyme in the cholesterol biosynthetic pathway.
Second, the incoming LDL-derived cholesterol promotes storage of
cholesterol by the action of cholesterol acyltransferase ("ACAT"),
the cellular enzyme that converts cholesterol into cholesteryl
esters that are deposited in storage droplets. Third, the
accumulation of cholesterol within the cell drives a feedback
mechanism that inhibits cellular synthesis of new LDL receptors.
Cells, therefore, adjust their complement of LDL receptors so that
enough cholesterol is brought in to meet their metabolic needs,
without overloading (for a review, see Brown & Goldstein, in
The Pharmacological Basis Of Therapeutics, 8th Ed., Goodman &
Gilman, Pergamon Press, New York, 1990, Ch. 36, pp. 874-896).
[0011] High levels of apo B-containing lipoproteins can be trapped
in the subendothelial space of an artery and undergo oxidation. The
oxidized lipoprotein is recognized by scavenger receptors on
macrophages. Binding of oxidized lipoprotein to the scavenger
receptors can enrich the macrophages with cholesterol and
cholesteryl esters independently of the LDL receptor. Macrophages
can also produce cholesteryl esters by the action of ACAT. LDL can
also be complexed to a high molecular weight glycoprotein called
apolipoprotein(a), also known as apo(a), through a disulfide
bridge. The LDL-apo(a) complex is known as Lipoprotein(a) or Lp(a).
Elevated levels of Lp(a) are detrimental, having been associated
with atherosclerosis, coronary heart disease, myocardial
infarction, stroke, cerebral infarction, and restenosis following
angioplasty.
2.2. Reverse Cholesterol Transport
[0012] Peripheral (non-hepatic) cells predominantly obtain their
cholesterol from a combination of local synthesis and uptake of
preformed sterol from VLDL and LDL. Cells expressing scavenger
receptors, such as macrophages and smooth muscle cells, can also
obtain cholesterol from oxidized apo B-containing lipoproteins. In
contrast, reverse cholesterol transport (RCT) is the pathway by
which peripheral cell cholesterol can be returned to the liver for
recycling to extrahepatic tissues, hepatic storage, or excretion
into the intestine in bile. The RCT pathway represents the only
means of eliminating cholesterol from most extrahepatic tissues and
is crucial to the maintenance of the structure and function of most
cells in the body.
[0013] The enzyme in blood involved in the RCT pathway,
lecithin:cholesterol acyltransferase (LCAT), converts cell-derived
cholesterol to cholesteryl esters, which are sequestered in HDL
destined for removal. LCAT is produced mainly in the liver and
circulates in plasma associated with the HDL fraction. Cholesterol
ester transfer protein (CETP) and another lipid transfer protein,
phospholipid transfer protein (PLTP), contribute to further
remodeling the circulating HDL population (see for example Bruce et
al., 1998, Annu. Rev. Nutr. 18:297 330). PLTP supplies lecithin to
HDL, and CETP can move cholesteryl esters made by LCAT to other
lipoproteins, particularly apoB-containing lipoproteins, such as
VLDL. HDL triglycerides can be catabolized by the extracellular
hepatic triglyceride lipase, and lipoprotein cholesterol is removed
by the liver via several mechanisms.
[0014] Each HDL particle contains at least one molecule, and
usually two to four molecules, of apolipoprotein A I (apo A I). Apo
A I is synthesized by the liver and small intestine as
preproapolipoprotein, which is secreted as a proprotein that is
rapidly cleaved to generate a mature polypeptide having 243 amino
acid residues. Apo A I consists mainly of a 22 amino acid repeating
segment, spaced with helix-breaking proline residues. Apo A I forms
three types of stable structures with lipids: small, lipid-poor
complexes referred to as pre-beta-1 HDL; flattened discoidal
particles, referred to as pre-beta-2 HDL, which contain only polar
lipids (e.g., phospholipid and cholesterol); and spherical
particles containing both polar and nonpolar lipids, referred to as
spherical or mature HDL (HDL3 and HDL2). Most HDL in the
circulating population contains both apo A I and apo A II, a second
major HDL protein. This apo A I- and apo A II-containing fraction
is referred to herein as the AI/AII-HDL fraction of HDL. But the
fraction of HDL containing only apo A I, referred to herein as the
Al HDL fraction, appears to be more effective in RCT. Certain
epidemiologic studies support the hypothesis that the AI-HDL
fraction is antiartherogenic (Parra et al., 1992, Arterioscler.
Thromb. 12:701-707; Decossin et al., 1997, Eur. J. Clin. Invest.
27:299-307).
[0015] Although the mechanism for cholesterol transfer from the
cell surface is unknown, it is believed that the lipid-poor
complex, pre-beta-1 HDL, is the preferred acceptor for cholesterol
transferred from peripheral tissue involved in RCT. Cholesterol
newly transferred to pre-beta-1 HDL from the cell surface rapidly
appears in the discoidal pre-beta-2 HDL. PLTP may increase the rate
of disc formation (Lagrost et al., 1996, J. Biol. Chem.
271:19058-19065), but data indicating a role for PLTP in RCT is
lacking. LCAT reacts preferentially with discoidal and spherical
HDL, transferring the 2-acyl group of lecithin or
phosphatidylethanolamine to the free hydroxyl residue of fatty
alcohols, particularly cholesterol, to generate cholesteryl esters
(retained in the HDL) and lysolecithin. The LCAT reaction requires
an apolipoprotein such as apo A I or apo A-IV as an activator.
ApoA-I is one of the natural cofactors for LCAT. The conversion of
cholesterol to its HDL-sequestered ester prevents re-entry of
cholesterol into the cell, resulting in the ultimate removal of
cellular cholesterol. Cholesteryl esters in the mature HDL
particles of the AI-HDL fraction are removed by the liver and
processed into bile more effectively than those derived from the
AI/AII-HDL fraction. This may be due, in part, to the more
effective binding of AI-HDL to the hepatocyte membrane. Several HDL
receptors have been identified, the most well characterized of
which is the scavenger receptor class B, type I (SR BI) (Acton et
al., 1996, Science 271:518-520). The SR-BI is expressed most
abundantly in steroidogenic tissues (e.g., the adrenals), and in
the liver (Landshulz et al., 1996, J. Clin. Invest. 98:984-995;
Rigotti et al., 1996, J. Biol. Chem. 271:33545-33549). Other
proposed HDL receptors include HB1 and HB2 (Hidaka and Fidge, 1992,
Biochem J. 15:161 7; Kurata et al., 1998, J. Atherosclerosis and
Thrombosis 4:112 7).
[0016] While there is a consensus that CETP is involved in the
metabolism of VLDL- and LDL-derived lipids, its role in RCT remains
controversial. However, changes in CETP activity or its acceptors,
VLDL and LDL, play a role in "remodeling" the HDL population. For
example, in the absence of CETP, the HDL becomes enlarged particles
that are poorly removed from the circulation (for reviews on RCT
and HDL, See Fielding & Fielding, 1995, J. Lipid Res.
36:211-228; Barrans et al., 1996, Biochem. Biophys. Acta.
1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol.
17:1053-1059).
2.3. Reverse Transport of Other Lipids
[0017] HDL is not only involved in the reverse transport of
cholesterol, but also plays a role in the reverse transport of
other lipids, i.e., the transport of lipids from cells, organs, and
tissues to the liver for catabolism and excretion. Such lipids
include sphingomyelin, oxidized lipids, and lysophophatidylcholine.
For example, Robins and Fasulo (1997, J. Clin. Invest. 99:380 384)
have shown that HDL stimulates the transport of plant sterol by the
liver into bile secretions.
2.4. Peroxisome Proliferator Activated Receptor Pathway
[0018] Peroxisome proliferators are a structurally diverse group of
compounds that, when administered to rodents, elicit dramatic
increases in the size and number of hepatic and renal peroxisomes,
as well as concomitant increases in the capacity of peroxisomes to
metabolize fatty acids via increased expression of the enzymes
required for the .beta.-oxidation cycle (Lazarow and Fujiki, 1985,
Ann. Rev. Cell Biol. 1:489 530; Vamecq and Draye, 1989, Essays
Biochem. 24:1115 225; and Nelali et al., 1988, Cancer Res. 48:5316
5324). Chemicals included in this group are the fibrate class of
hypolipidemic drugs, herbicides, and phthalate plasticizers (Reddy
and Lalwani, 1983, Crit. Rev. Toxicol. 12:1 58). Peroxisome
proliferation can also be elicited by dietary or physiological
factors, such as a high fat diet and cold acclimatization.
[0019] Insight into the mechanism whereby peroxisome proliferators
exert their pleiotropic effects was provided by the identification
of a member of the nuclear hormone receptor superfamily activated
by these chemicals (Isseman and Green, 1990, Nature 347:645 650).
This receptor, termed peroxisome proliferator activated receptor
.alpha. (PPAR.alpha.), was subsequently shown to be activated by a
variety of medium and long chain fatty acids. PPAR.alpha. activates
transcription by binding to DNA sequence elements, termed
peroxisome proliferator response elements (PPRE), in the form of a
heterodimer with the retinoid X receptor (RXR). RXR is activated by
9-cis retinoic acid (see Kliewer et al., 1992, Nature 358:771 774;
Gearing et al., 1993, Proc. Natl. Acad. Sci. USA 90:1440 1444,
Keller et al., 1993, Proc. Natl. Acad. Sci. USA 90:2160 2164;
Heyman et al., 1992, Cell 68:397 406, and Levin et al., 1992,
Nature 355:359 361). Since the discovery of PPAR.alpha., additional
isoforms of PPAR have been identified, e.g., PPAR.beta.,
PPAR.gamma. and PPAR.delta., which have similar functions and are
similarly regulated.
[0020] PPARs have been identified in the enhancers of a number of
gene-encoding proteins that regulate lipid metabolism. These
proteins include the three enzymes required for peroxisomal
.beta.-oxidation of fatty acids; apolipoprotein A-I; medium chain
acyl-CoA dehydrogenase, a key enzyme in mitochondrial
.beta.-oxidation; and aP2, a lipid binding protein expressed
exclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM,
4:291 296; see also Staels and Auwerx, 1998, Atherosclerosis 137
Suppl:S19 23). The nature of the PPAR target genes coupled with the
activation of PPARs by fatty acids and hypolipidemic drugs suggests
a physiological role for the PPARs in lipid homeostasis.
[0021] Pioglitazone, an antidiabetic compound of the
thiazolidinedione class, was reported to stimulate expression of a
chimeric gene containing the enhancer/promoter of the lipid binding
protein aP2 upstream of the chloroamphenicol acetyl transferase
reporter gene (Harris and Kletzien, 1994, Mol. Pharmacol. 45:439
445). Deletion analysis led to the identification of an
approximately 30 bp region accounting for pioglitazone
responsiveness. In an independent study, this 30 bp fragment was
shown to contain a PPRE (Tontonoz et al., 1994, Nucleic Acids Res.
22:5628 5634). Taken together, these studies suggested the
possibility that the thiazolidinediones modulate gene expression at
the transcriptional level through interactions with a PPAR and
reinforce the concept of the interrelatedness of glucose and lipid
metabolism.
2.5. Current Cholesterol Management Therapies
[0022] In the past two decades or so, the segregation of
cholesterolemic compounds into HDL and LDL regulators and
recognition of the desirability of decreasing blood levels of the
latter has led to the development of a number of drugs. However,
many of these drugs have undesirable side effects and/or are
contraindicated in certain patients, particularly when administered
in combination with other drugs.
[0023] Bile-acid-binding resins are a class of drugs that interrupt
the recycling of bile acids from the intestine to the liver.
Examples of bile-acid-binding resins are cholestyramine (QUESTRAN
LIGHT, Bristol-Myers Squibb), and colestipol hydrochloride
(COLESTID, Pharmacia & Upjohn Company). When taken orally,
these positively charged resins bind to negatively charged bile
acids in the intestine. Because the resins cannot be absorbed from
the intestine, they are excreted, carrying the bile acids with
them. The use of such resins, however, at best only lowers serum
cholesterol levels by about 20%. Moreover, their use is associated
with gastrointestinal side-effects, including constipation and
certain vitamin deficiencies. Moreover, since the resins bind to
drugs, other oral medications must be taken at least one hour
before or four to six hours subsequent to ingestion of the resin,
complicating heart patients' drug regimens.
[0024] The statins are inhibitors of cholesterol synthesis.
Sometimes, the statins are used in combination therapy with
bile-acid-binding resins. Lovastatin (MEVACOR, Merck & Co.,
Inc.), a natural product derived from a strain of Aspergillus;
pravastatin (PRAVACHOL, Bristol-Myers Squibb Co.); and atorvastatin
(LIPITOR, Warner Lambert) block cholesterol synthesis by inhibiting
HMGCoA reductase, the key enzyme involved in the cholesterol
biosynthetic pathway. Lovastatin significantly reduces serum
cholesterol and LDL-serum levels. However, serum HDL levels are
only slightly increased following lovastatin administration. The
mechanism of the LDL-lowering effect may involve both reduction of
VLDL concentration and induction of cellular expression of
LDL-receptor, leading to reduced production and/or increased
catabolism of LDL. Side effects, including liver and kidney
dysfunction are associated with the use of these drugs.
[0025] Nicotinic acid, also known as niacin, is a water-soluble
vitamin B-complex used as a dietary supplement and
antihyperlipidemic agent. Niacin diminishes the production of VLDL
and is effective at lowering LDL. It is used in combination with
bile-acid-binding resins. Niacin can increase HDL when administered
at therapeutically effective doses; however, its usefulness is
limited by serious side effects.
[0026] Fibrates are a class of lipid-lowering drugs used to treat
various forms of hyperlipidemia, elevated serum triglycerides,
which may also be associated with hypercholesterolemia. Fibrates
appear to reduce the VLDL fraction and modestly increase HDL;
however, the effects of these drugs on serum cholesterol is
variable. In the United States, fibrates have been approved for use
as antilipidemic drugs, but have not received approval as
hypercholesterolemia agents. For example, clofibrate (ATROMID-S,
Wyeth-Ayerst Laboratories) is an antilipidemic agent that acts to
lower serum triglycerides by reducing the VLDL fraction. Although
ATROMID-S may reduce serum cholesterol levels in certain patient
subpopulations, the biochemical response to the drug is variable,
and is not always possible to predict which patients will obtain
favorable results. ATROMID-S has not been shown to be effective for
prevention of coronary heart disease. The chemically and
pharmacologically related drug, gemfibrozil (LOPID, Parke-Davis),
is a lipid regulating agent which moderately decreases serum
triglycerides and VLDL cholesterol. LOPID also increases HDL
cholesterol, particularly the HDL2 and HDL3 subfractions, as well
as both the AI/AII-HDL fractions. However, the lipid response to
LOPID is heterogeneous, especially among different patient
populations. Moreover, while prevention of coronary heart disease
was observed in male patients between the ages of 40 and 55 without
history or symptoms of existing coronary heart disease, it is not
clear to what extent these findings can be extrapolated to other
patient populations (e.g., women, older and younger males). Indeed,
no efficacy was observed in patients with established coronary
heart disease. Serious side-effects are associated with the use of
fibrates, including toxicity; malignancy, particularly malignancy
of gastrointestinal cancer; gallbladder disease; and an increased
incidence in non-coronary mortality. These drugs are not indicated
for the treatment of patients with high LDL or low HDL as their
only lipid abnormality.
[0027] Oral estrogen replacement therapy may be considered for
moderate hypercholesterolemia in post-menopausal women. However,
increases in HDL may be accompanied with an increase in
triglycerides. Estrogen treatment is, of course, limited to a
specific patient population, postmenopausal women, and is
associated with serious side effects, including induction of
malignant neoplasms; gall bladder disease; thromboembolic disease;
hepatic adenoma; elevated blood pressure; glucose intolerance; and
hypercalcemia.
[0028] Long chain carboxylic acids, particularly long chain
.alpha.,.omega.-dicarboxylic acids with distinctive substitution
patterns, and their simple derivatives and salts, have been
disclosed for treating atherosclerosis, obesity, and diabetes (See,
e.g., Bisgaier et al., 1998, J. Lipid Res. 39:17-30, and references
cited therein; International Patent Publication WO 98/30530; U.S.
Pat. No. 4,689,344; International Patent Publication WO 99/00116;
and U.S. Pat. No. 5,756,344). However, some of these compounds, for
example the .alpha.,.omega.-dicarboxylic acids substituted at their
.alpha.,.alpha.'-carbons (U.S. Pat. No. 3,773,946), while having
serum triglyceride and serum cholesterol-lowering activities, have
no value for treatment of obesity and hypercholesterolemia (U.S.
Pat. No. 4,689,344).
[0029] U.S. Pat. No. 4,689,344 discloses
.beta.,.beta.,.beta.',.beta.'-tetrasubstituted-.alpha.,.omega.-alkanedioi-
c acids that are optionally substituted at their
.alpha.,.alpha.,.alpha.',.alpha.'-positions, and alleges that they
are useful for treating obesity, hyperlipidemia, and diabetes.
According to this reference, both triglycerides and cholesterol are
lowered significantly by compounds such as
3,3,14,14-tetramethylhexadecane-1,16-dioic acid. U.S. Pat. No.
4,689,344 further discloses that the
.beta.,.beta.,.beta.',.beta.'-tetramethyl-alkanediols of U.S. Pat.
No. 3,930,024 also are not useful for treating hypercholesterolemia
or obesity.
[0030] Other compounds are disclosed in U.S. Pat. No. 4,711,896. In
U.S. Pat. No. 5,756,544, .alpha.,.omega.-dicarboxylic
acid-terminated dialkane ethers are disclosed to have activity in
lowering certain plasma lipids, including Lp(a), triglycerides,
VLDL-cholesterol, and LDL-cholesterol, in animals, and elevating
others, such as HDL-cholesterol. The compounds are also stated to
increase insulin sensitivity. In U.S. Pat. No. 4,613,593,
phosphates of dolichol, a polyprenol isolated from swine liver, are
stated to be useful in regenerating liver tissue, and in treating
hyperuricuria, hyperlipemia, diabetes, and hepatic diseases in
general.
[0031] U.S. Pat. No. 4,287,200 discloses azolidinedione derivatives
with anti-diabetic, hypolipidemic, and anti-hypertensive
properties. However, the administration of these compounds to
patients can produce side effects such as bone marrow depression,
and both liver and cardiac cytotoxicity. Further, the compounds
disclosed by U.S. Pat. No. 4,287,200 stimulate weight gain in obese
patients.
[0032] It is clear that none of the commercially available
cholesterol management drugs has a general utility in regulating
lipid, lipoprotein, insulin and glucose levels in the blood. Thus,
compounds that have one or more of these utilities are clearly
needed. Further, there is a clear need to develop safer drugs that
are efficacious at lowering serum cholesterol, increasing HDL serum
levels, preventing coronary heart disease, and/or treating existing
disease such as atherosclerosis, obesity, diabetes, and other
diseases that are affected by lipid metabolism and/or lipid levels.
There is also a clear need to develop drugs that may be used with
other lipid-altering treatment regimens in a synergistic manner.
There is still a further need to provide useful therapeutic agents
whose solubility and Hydrophile/Lipophile Balance (HLB) can be
readily varied.
[0033] The recitation of any reference in Section 2 of this
application is not an admission that the reference is available as
prior art to this application.
3. SUMMARY OF THE INVENTION
[0034] In one embodiment, the invention encompasses compounds of
formula I: ##STR1## or a pharmaceutically acceptable salt, hydrate,
solvate, or a mixture thereof, wherein [0035] (a) each occurrence
of Z is independently CH.sub.2, CH.dbd.CH, or phenyl, wherein each
occurrence of m is independently an integer ranging from 1 to 9,
but when Z is phenyl then its associated m is 1; [0036] (b) G is
(CH.sub.2).sub.x, CH.sub.2CH.dbd.CHCH.sub.2, CH.dbd.CH,
CH.sub.2-phenyl-CH.sub.2, or phenyl, wherein x is 2, 3, or 4;
[0037] (c) W.sup.1 and W.sup.2 are independently L, V,
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-(R.sup.1)(R.sup.2)--(CH.sub.2).sub.-
n-Y, or C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V, wherein c is 1 or
2 and n is an independent integer ranging from 0 to 4; [0038] (d)
R.sup.1 and R.sup.2 are independently (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl or when W.sup.1 or W.sup.2 is
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c---C(R.sup.3)(R.sup.4)--Y,
then R.sup.1 and R.sup.2 can both be H, or R.sup.1 and R.sup.2 and
the carbon to which they are both attached are taken together to
form a (C.sub.3-C.sub.7)cycloakyl group; [0039] (e) R.sup.3 and
R.sup.4 are independently H, OH, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO.sub.2, or
CF.sub.3, with the proviso that when R.sup.1 and R.sup.2 are both
H, then one of R.sup.3 or R.sup.4 is not H or R.sup.3 and R.sup.4
and the carbon to which they are both attached are taken together
to form a (C.sub.3-C.sub.7)cycloakyl group; [0040] (f) L is
C(R.sup.1)(R.sup.2)--CH.sub.2).sub.n-Y; [0041] (g) V is ##STR2##
[0042] (h) Y is (C.sub.1C.sub.6)alkyl, OH, COOH, CHO, COOR.sup.5,
SO.sub.3H, ##STR3## [0043] where [0044] (I) R.sup.5 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, [0045] (ii) each occurrence of R.sup.6 is
independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
or (C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted
with one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups;
and [0046] (iii) each occurrence of R.sup.7 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl.
[0047] Preferred compounds of formula I are those wherein: [0048]
(a) W.sup.1 and W.sup.2 are independently L, V, or
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V, where c is 1 or2; and
[0049] (b) R.sup.1 and R.sup.2 are independently
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl.
[0050] Other preferred compounds of formula I are those wherein
W.sup.1 is L.
[0051] Other preferred compounds of formula I are those wherein
W.sup.1 is V.
[0052] Other preferred compounds of formula I are those wherein
W.sup.1 is
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-C(R.sup.3)(R.sup.4)--(CH.sub.2).-
sub.n-Y.
[0053] Other preferred compounds of formula I are those wherein
W.sup.1 is C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V.
[0054] Other preferred compounds of formula I are those wherein
W.sup.1 and W.sup.2 are independent L groups.
[0055] Other preferred compounds of formula I are those wherein
each occurrence of Y is independently OH, COOR.sup.5, or COOH.
[0056] In another embodiment, the invention encompasses compounds
of formula Ia: ##STR4## or a pharmaceutically acceptable salt,
hydrate, solvate, or a mixture thereof, wherein [0057] (a) each
occurrence of Z is independently CH.sub.2 or CH.dbd.CH, wherein
each occurrence of m is independently an integer ranging from 1 to
9; [0058] (b) G is (CH.sub.2).sub.x, CH.sub.2CH.dbd.CHCH.sub.2, or
CH.dbd.CH, where x is 2, 3, or 4; [0059] (c) W.sup.1 and W.sup.2
are independently L, V, or C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.c-V,
where c is 1 or 2; [0060] (d) each occurrence of R.sup.1 and
R.sup.2 is independently (C.sub.1-.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, benzyl,
or R.sup.1 and R.sup.2 and the carbon to which they are both
attached are taken together to form a (C.sub.3-C.sub.7)cycloakyl
group; [0061] (e) L is C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.n-Y,
where n is an independent integer ranging from 0 to 4; [0062] (f) V
is ##STR5## [0063] (g) each occurrence of Y is independently
(C.sub.1-C.sub.6)alkyl, OH, COOH, CHO, (CH.sub.2).sub.nCOOR.sup.3,
SO.sub.3H, ##STR6## [0064] where [0065] (I) R.sup.3 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, [0066] (ii) each occurrence of R.sup.4 is
independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
or (C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted
with one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups;
and [0067] (iii) each occurrence of R.sup.5 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl.
[0068] Preferably, in formula Ia each occurrence of Y is
independently (C.sub.1-C.sub.6)alkyl, OH, COOR.sup.3, or COOH.
[0069] In yet another embodiment, the invention encompasses
compounds formula Ib ##STR7## or a pharmaceutically acceptable
salt, hydrate, solvate, or a mixture thereof, wherein: [0070] (a)
each occurrence of m is independently an integer ranging from 1 to
9; [0071] (b) x is 2, 3, or 4; [0072] (c) n is an independent
integer ranging from 0 to 4; [0073] (d) each occurrence of R.sup.1
and R.sup.2 is independently (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, benzyl,
or R.sup.1 and R.sup.2 and the carbon to which they are both
attached are taken together to form a (C.sub.3-C.sub.7)cycloakyl
group; [0074] (e) each occurrence of R.sup.11 and R.sup.12 is
independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, benzyl, or R.sup.11 and R.sup.12
and the carbon to which they are both attached are taken together
to form a (C.sub.3-C.sub.7)cycloakyl group; [0075] (f) each
occurrence of Y is independently (C.sub.1-C.sub.6)alkyl, OH, COOH,
CHO, COOR.sup.3, SO.sub.3H, ##STR8## [0076] where [0077] (I)
R.sup.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, [0078] (ii) each occurrence of R.sup.4 is
independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
or (C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted
with one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups;
and [0079] (iii) each occurrence of R.sup.5 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl.
[0080] Preferably in formula Ib, each occurrence of Y is
independently OH, COOR.sup.3, or COOH.
[0081] In still another embodiment, the invention encompasses
compounds of formula Ic ##STR9## or a pharmaceutically acceptable
salt, hydrate, solvate, or a mixture thereof, wherein: [0082] (a)
each occurrence of m is an independent integer ranging from 1 to 9;
[0083] (b) x is 2, 3, or 4; [0084] (c) V is ##STR10##
[0085] In another embodiment, the invention encompasses compounds
of formula II: ##STR11## or a pharmaceutically acceptable salt,
hydrate, solvate, or a mixture thereof, wherein [0086] (a) R.sup.1
and R.sup.2 are independently (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl; or R.sup.1, R.sup.2, and the carbon to which they are both
attached are taken together to form a (C.sub.3-C.sub.7)cycloalkyl
group; [0087] (b) R.sup.11 and R.sup.12 are independently
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl; or R.sup.11, R.sup.12,
and the carbon to which they are both attached are taken together
to form a (C.sub.3-C.sub.7)cycloalkyl group; [0088] (c) n is an
integer ranging from 1 to 5; [0089] (d) each occurrence of m is
independently an integer ranging from 0 to 4; [0090] (e) W.sup.1
and W.sup.2 are independently (C.sub.1-C.sub.6)alkyl, CH.sub.2OH,
C(O)OH, CHO, OC(O)R.sup.3, C(O)OR.sup.3, SO.sub.3H, ##STR12##
[0091] where [0092] (I) R.sup.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl and is unsubstituted or substituted with one or more halo,
OH, (C.sub.1-C.sub.6)alkoxy, or phenyl groups, [0093] (ii) each
ocurrence of R.sup.4 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl, and is
unsubstituted or substituted with one or two halo, OH,
C.sub.1-C.sub.6 alkoxy, or phenyl groups; and [0094] (iii) each
occurrence of R.sup.5 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl.
[0095] Preferred compounds of formula II are those wherein each
occurrence of W is independently OH, COOR.sup.3, or COOH.
[0096] Other preferred compounds of formula II are those wherein
R.sup.1 and R.sup.2 are independent (C.sub.1-C.sub.6)alkyl
groups.
[0097] Other preferred compounds of formula II are those wherein m
is 0.
[0098] Other preferred compounds of formula II are those wherein m
is 1.
[0099] Other preferred compounds of formula II are those wherein
R.sup.1 and R.sup.2 are each independently
(C.sub.1-C.sub.6)alkyl.
[0100] Other preferred compounds of formula II are those wherein
R.sup.1 and R.sup.2 are each methyl.
[0101] Other preferred compounds of formula II are those wherein
W.sup.1 and/or W.sup.2 is C(O)OH or CH.sub.2OH.
[0102] In another embodiment, the invention encompasses compounds
of formula IIa: ##STR13## or a pharmaceutically acceptable salt,
hydrate, solvate, or a mixture thereof, wherein [0103] (a) R.sup.1
and R.sup.2 are OH, COOH, CHO, COOR.sup.7, SO.sub.3H, ##STR14##
[0104] where [0105] (I) R.sup.7 is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl and is unsubstituted or substituted with one or more halo,
OH, (C.sub.1-C.sub.6)alkoxy, or phenyl groups, [0106] (ii) each
occurrence of R.sup.8 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl and is
unsubstituted or substituted with one or two halo, OH,
C.sub.1-C.sub.6 alkoxy, or phenyl groups, [0107] (iii) each
occurrence of R.sup.9 is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, or (C.sub.2-C.sub.6)alkynyl; [0108] (b)
R.sup.3 and R.sup.4 are (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, phenyl, or
benzyl; [0109] (c) R.sup.5 and R.sup.6 are hydrogen, halogen,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, (C6)aryloxy, CN,
or NO.sub.2, N(R.sup.5).sub.2 where R.sup.5 is H,
(C.sub.1-C.sub.4)alkyl, phenyl, or benzyl; [0110] (d) each
occurrence of m is independently an integer ranging from 1 to 5;
[0111] (e) each occurrence of n is independently an integer ranging
from 0 to 4; and [0112] (f) *.sup.1 and *.sup.2 represent
independent chiral-carbon centers, wherein each center may
independently be R or S.
[0113] Preferred compounds of formula Ia are those wherein each
occurrence of R.sup.1 and R.sup.2 is independently OH, COOR.sup.7,
or COOH.
[0114] Other preferred compounds of formula IIa are those wherein m
is 0.
[0115] Other preferred compounds of formula IIa are those wherein m
is 1.
[0116] Other preferred compounds of formula IIa are those wherein
R.sup.1 and/or R.sup.2 is C(O)OH or CH.sub.2OH.
[0117] Other preferred compounds of formula IIa are those wherein
R.sup.3 and R.sup.4 are each independently
(C.sub.1-C.sub.6)alkyl.
[0118] Other preferred compounds of formula IIa are those wherein
R.sup.3 and R.sup.4 are each methyl.
[0119] Other preferred compounds of formula IIa are those wherein
*.sup.1 is of the stereochemical configuration R or substantially
R.
[0120] Other preferred compounds of formula IIa are those wherein
*.sup.1 is of the stereochemical configuration S or substantially
S.
[0121] Other preferred compounds of formula IIa are those wherein
*.sup.2 is of the stereochemical configuration R or substantially
R.
[0122] Other preferred compounds of formula IIa are those wherein
*.sup.2 is of the stereochemical configuration S or substantially
S.
[0123] In a particular embodiment, compounds of formula IIa are
those wherein *.sup.1 *.sup.2 are of the stereochemical
configuration (S.sup.1,S.sup.2) or substantially
(S.sup.1,S.sup.2).
[0124] In another particular embodiment, compounds of formula IIa
are those wherein *.sup.1 *.sup.2 are of the stereochemical
configuration (S.sup.1,R.sup.2) or substantially
(S.sup.1,R.sup.2).
[0125] In another particular embodiment, compounds of formula IIa
are those wherein *.sup.1 *.sup.2 are of the stereochemical
configuration (R,R.sup.2) or substantially (R.sup.1 ,R.sup.2).
[0126] In another particular embodiment, compounds of formula IIa
are those wherein *.sup.1 *.sup.2 are of the stereochemical
configuration (R.sup.1,S.sup.2) or substantially
(R.sup.1,S.sup.2).
[0127] In still another embodiment, the invention encompasses
compounds of formula III: ##STR15## or a pharmaceutically
acceptable salt, hydrate, solvate, or a mixture thereof, wherein
[0128] (a) each occurrence of Z is independently CH.sub.2,
CH.dbd.CH, or phenyl, where each occurrence of m is independently
an integer ranging from 1 to 5, but when Z is phenyl then its
associated m is 1; [0129] (b) G is (CH.sub.2).sub.x,
CH.sub.2CH.dbd.CHCH.sub.2, CH.dbd.CH, CH.sub.2-phenyl-CH.sub.2, or
phenyl, where x is an integer ranging from 1 to 4; [0130] (c)
W.sup.1 and W.sup.2 are independently
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.n-Y where n is an integer
ranging from 0 to 4; [0131] (d) R.sup.1 and R.sup.2 are
independently (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl or R.sup.1 and R.sup.2
are both H, or R.sup.1, R.sup.1, and the carbon to which they are
both attached are taken together to form a
(C.sub.3-C.sub.7)cycloalkyl group; [0132] (e) Y is
(C.sub.1-C.sub.6)alkyl, (CH.sub.2).sub.nOH, (CH.sub.2).sub.nCOOH,
(CH.sub.2).sub.nCHO, (CH.sub.2).sub.nCOOR.sup.3, SO.sub.3H,
##STR16## ##STR17## [0133] where [0134] (I) R.sup.3 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, phenyl, or benzyl and is unsubstituted or
substituted with one or more halo, OH, (C.sub.1-C.sub.6)alkoxy, or
phenyl groups, [0135] (ii) each occurrence of R.sup.4 is
independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
or (C.sub.2-C.sub.6)alkynyl and is unsubstituted or substituted
with one or two halo, OH, C.sub.1-C.sub.6 alkoxy, or phenyl groups,
[0136] (iii) each occurrence of R.sup.5 is independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl; and [0137] (f) each occurrence of p is
independently 2 or 3 where the broken line represents an optional
presence of one or more additional carbon-carbon bonds that when
present complete one or more carbon-carbon double bonds.
[0138] Preferred compounds of formula III are those wherein each
occurrence of Y is independently OH, COOR.sup.3, or COOH.
[0139] Other preferred compounds of formula III are those wherein p
is 2.
[0140] Other preferred compounds of formula III are those wherein p
is 3.
[0141] In yet another embodiment, the invention encompasses
compounds of formula IIIa: ##STR18##
[0142] or a pharmaceutically acceptable salt, hydrate, solvate,
thereof, wherein W.sup.1, W.sup.2 and Z.sub.m are the same as
compound III. Preferably in compound IIIa, W.sup.1 and W.sup.2 are
independent C(R.sup.1)(R.sup.2)--Y groups and each occurrence of Y
is independently OH, COOR.sup.3, or COOH. Illustrative compounds
are illustrated below in Table 1. TABLE-US-00001 TABLE 1 Compounds
of the Invention ##STR19## I-1
5-Hydroxy-1-[4-(5-hydroxy-5-methyl-2-oxo-hexyl)-phenyl]-5-methyl-hexan-2-o-
ne ##STR20## I-2
6-Hydroxy-1-[4-(6-hydroxy-5,5-dimethyl-2-oxo-hexyl)-phenyl]-5,5-dimethyl-h-
exan-2-one ##STR21## I-3
6-[4-(5-Carboxy-5-methyl-2-oxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo-hexanoic
acid ##STR22## I-4
6-[4-(5,5-Dimethyl-2,6-dioxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo-hexanal
##STR23## I-5
6-[4-(5-Methoxycarbonyl-5-methyl-2-opxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo--
hexanoic acid methyl ester ##STR24## I-6
2,2-Dimethyl-6-[4-(5-methyl-oxo-5-phenoxycarbonyl-hexyl)-phenyl]-5-oxo-hex-
anoic acid phenyl ester ##STR25## I-7
6-[4-(5-Benzyloxycarbonyl-5-methyl-2-oxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo-
-hexanoic acid benzyl ester ##STR26## I-8
2-Methyl-6-[4-(5-methyl-2-oxo-5-sulfo-hexyl)-phenyl]-5-oxo-hexane-2-sulfon-
ic acid ##STR27## I-9 Phosphoric acid
mono-{1,1-dimethyl-5-[4-(5-methyl-2-oxo-5-phosphonooxy-hexyl)-
phenyl]-4-oxo-pentyl} ester ##STR28## I-10
4-Hydroxy-1-[4-(4-hydroxy-4-methyl-pentanoyl)-phenyl]-4-methyl-pentan-1-on-
e ##STR29## I-11
5-Hydroxy-1-[4-(5-hydroxy-4,4-dimethyl-pentanoyl)-phenyl]-4,4-dimethyl-pen-
tan-1-one ##STR30## I-12
5-[4-(4-Carboxy-4-methyl-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-pentanoic
acid ##STR31## I-13
5-[4-(4,4-Dimethyl-5-oxo-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-pentanal
##STR32## I-14
5-[4-(4-Methoxycarbonyl-4-methyl-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-pen-
tanoic acid methyl ester ##STR33## I-15
2,2-Dimethyl-6-[4-(5-methyl-2-oxo-5-phenoxycarbonyl-hexyl)-phenyl]-5-oxo-h-
exanoic acid phenyl ester ##STR34## I-16
5-[4-(4-Benzyloxycarbonyl-4-methyl-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-p-
entanoic acid benzyl ester ##STR35## I-17
2-Methyl-5-[4-(4-methyl-4-sulfo-pentanoyl)-phenyl]-5-oxo-pentane-2-sulfoni-
c acid ##STR36## I-18 Phosphoric acid
mono-{1,1-dimethyl-4-[4-(4-methyl-4-phosphonoxy-pentanoyl)-phenyl]-
4-oxo-butyl} ester ##STR37## Ib-1
2,12-Dihydroxy-2,12-dimethyl-tridecane-5,9-dione ##STR38## Ib-2
1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecane-5,9-dione ##STR39##
Ib-3 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid ##STR40##
Ib-4 2,2,12,12-Tetramethyl-5,9-dioxo-tridecandial ##STR41## Ib-5
2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dimethyl ester
##STR42## Ib-6 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid
diphenyl ester ##STR43## Ib-7
2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dibenzyl ester
##STR44## Ib-8 2,12-Dimethyl-5,9-dioxo-tridecane-2,12-disulfonic
acid ##STR45## Ib-9 Phosphoric acid
mono(1,1,11-trimethyl-4,8-dioxo-11-phosphonooxy-dodecyl) ester
##STR46## Ib-10
2,12-Bis(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12--
dimethyl- tridecane-5,9-dione ##STR47## Ib-11
2,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,12-dimethyl- tridecane-5,9-dione ##STR48## Ib-12
2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dicyanimide
##STR49## Ib-13 Phosphoramidic acid
mono[11-(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-4,8-
dioxo-dodecyl] ester ##STR50## Ib-14
2,12-Dimethyl-2,12-bis-(amino-hydroxy-phosphoryloxy)-tridecane-5,9-dione
##STR51## Ib-15
2,12-Dimethyl-2,12-bis-tetrazol-1-yl-tridecane-5,9-dione ##STR52##
Ib-16 2,12-Dimethyl-2,12-bis(1H-tetrazol-5-yl)-tridecane-5,9-dione
##STR53## Ib-17
2,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,12-dimethyl-tridecane-5,9-dione
##STR54## Ib-18
2,12-Bis(3-hydroxy-isoxazol-4-yl)-2,12-dimethyl-tridecane-5,9-dione
##STR55## Ib-19
2,12-Bis(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,12-dimethyl-tridecane-5,9-dione
##STR56## Ib-20
2,12-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,12-dimethyl-tridecane-5,9-dione
##STR57## Ib-21
1-Ethyl-3-[11-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-1,1,11-trimethyl-4,-
8-dioxo- dodecyl]-imidazolidine-2,4-dione ##STR58## Ib-22
2,12-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,12-dimethyl-tridecane-5,9-
-dione ##STR59## Ib-23
2,12-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,12-dimethyl-tridecan-
e-5,9-dione ##STR60## Ib-24
2,12-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,12-dimethyl-tridecan-
e-5,9-dione ##STR61## Ib-25
1,15-Dihydroxy-3,3,13,13-tetramethyl-pentadecane-6,10-dione
##STR62## Ib-26 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic
acid ##STR63## Ib-27
3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedial ##STR64## Ib-28
3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanesioic acid dimethyl
ester ##STR65## Ib-29
2,2,12,12-Tetramethyl-5,9-dioxo-tetradecanedioic acid diphenyl
ester ##STR66## Ib-30
3,3,13,13-Tetramethyl-6,10,14-trioxo-16-phenyl-hexadecanoic acid
benzyl ester ##STR67## Ib-31
2,2,12,12-Tetramethyl-5,9-dioxo-tridecane-1,13-disulfonic acid
##STR68## Ib-32 Phosphoric acid
mono-(2,2,12,12-tetramethyl-5,9-dioxo-13-phosphonooxy-tridecyl)
ester ##STR69## Ib-33
1,13-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2,-
12,12- tetramethyl-tridecane-5,9-dione ##STR70## Ib-34
1,13-Bis(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,-
2,12,12- tetramethyl-tridecane-5,9-dione ##STR71## Ib-35
3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic acid dicyanimide
##STR72## Ib-36 Phosphoramidic acid
mono-[13-(amino-hydroxy-phosphoryloxy)-2,2,12,12-tetramethyl-6,9-
dioxo-tridecyl] ester ##STR73## Ib-37 Phosphoramidic acid
mono-[11-(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-4,8-dioxo-dodecyl]
ester ##STR74## Ib-38
2,2,12,12-Tetramethyl-1,13-bis-tetrazol-1-yl-tridecane-5,9-dione
##STR75## Ib-39
1,13-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dio-
ne ##STR76## Ib-40
1,13-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dio-
ne ##STR77## Ib-41
1,13-Bis-(3-hydroxy-isoxazol-4-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dio-
ne ##STR78## Ib-42
1-(5-Hydroxy-4-oxo-4H-pyran-3-yl)-13-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,1-
2,12- tetramethyl-tridecane-5,9-dione ##STR79## Ib-43
1,13-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,12,12-tetramethyl-tridecane-5-
,9-dione ##STR80## Ib-44
1,13-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,12,12-tetramethyl-tridecane-5-
,9-dione ##STR81## Ib-45
1-Ethyl-3-[13-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,12,12-tetrameth-
yl-5,9-dioxo- tridecyl]-imidazolidine-2,4-dione ##STR82## Ib-46
1,13-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl-tride-
cane-5,9-dione ##STR83## Ib-47
1,13-Bis-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl-tr-
idecane-5,9-dione ##STR84## Ib-48
1,13-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl--
tridecane-5,9- dione ##STR85## Ib-49
1,13-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl--
tridecane-5,9- dione ##STR86## Ib-50
2,11-Dihydroxy-2,11-dimethyl-dodecane-5,8-dione ##STR87## Ib-51
1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione ##STR88##
Ib-52 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid ##STR89##
Ib-53 2,11-Dimethyl-5,8-dioxo-dodecane-2,11-disulfonic acid
##STR90## Ib-54 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedial
##STR91## Ib-55 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid
dimethyl ester ##STR92## Ib-56
2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid diphenyl ester
##STR93## Ib-57 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid
dibenzyl ester ##STR94## Ib-58 Phosphoric acid
mono-(1,1,10-trimethyl-4,7-dioxo-10-phosphonooxy-undecyl) ester
##STR95## Ib-59 2,14-Dihydroxy-2,14-dimethyl-pentadecane-6,10-dione
##STR96## Ib-60
1,15-Dihydroxy-2,2,14,14-tetramethyl-pentadecane-6,10-dione
##STR97## Ib-61 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic
acid ##STR98## Ib-62
2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedial ##STR99## Ib-63
2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid dimethyl
ester ##STR100## Ib-64
2,2,14,14-Tetramethyl-6,10-dioxo-hexadecanedioic acid diphenyl
ester ##STR101## Ib-65
2,2,14,14-Tetramethyl-6,10-dioxo-hexandecanedioic acid dibenzyl
ester ##STR102## Ib-66
2,14-Dimethyl-6,10-dioxo-pentadecane-2,1-4disulfonic acid
##STR103## Ib-67 Phosphoric acid
mono-(1,1,13-trimethyl-5,9-dioxo-13-phosphonooxy-tetradecyl) ester
##STR104##
Ib-68
2,14-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,14-
-dimethyl- pentadecane-6,10-dione ##STR105## Ib-69
2,14-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,14-dimethyl- pentadecane-6,10-dione ##STR106## Ib-70
2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid dicyanimide
##STR107## Ib-71 Phosphoroamidic acid
mono[13-(amino-hydroxy-phosphoryloxy)-1,1,13-trimethyl-5,9-
dioxo-tetradecyl] ester ##STR108## Ib-72
2,14-Dimethyl-2,14-bis(amino-hydroxy-phosphoryloxy)-pentadecane-6,10-dione
##STR109## Ib-73
2,14-Dimethyl-2,14-bis-tetrazol-1-yl-pentadecane-6,10-dione
##STR110## Ib-74
2,14-Dimethyl-2,14-bis-(1H-tetrazol-5-yl)pentadecane-6,10-dione
##STR111## Ib-75
2,14-Bis-(3-hydroxy-isoxazol-5-yl)-2,14-dimethyl-pentadecane-6,10-dione
##STR112## Ib-76
2,14-Bis-(3-hydroxy-isoxazol-4-yl)-2,14-dimethyl-pentadecane-6,10-dione
##STR113## Ib-77
2,14-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,14-dimethyl-pentadecane-6,10-di-
one ##STR114## Ib-78
2-(5-Hydroxy-4-oxo-4H-pyran-2-yl)-2,14-dimethyl-14-(5-methyl-4-oxo-4H-pyra-
n-2-yl)- pentadecane-6,10-dione ##STR115## Ib-79
2,14-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadecane-6-
,10-dione ##STR116## Ib-80
2,14-Bis-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadecan-
e-6,10-dione ##STR117## Ib-81
2,14-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadec-
ane-6,10-dione ##STR118##
2,14-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadec-
ane-6,10-dione ##STR119## Ib-83
1,14-Dihydroxy-3,3,12,12-tetramethyl-tetradecane-6,9-dione
##STR120## Ib-84 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic
acid ##STR121## Ib-85
3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedial ##STR122## Ib-86
3,3,12,12-Tetramethyl-6,9-dioxo-tetradecaendioic acid dimethyl
ester ##STR123## Ib-87
3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanioic acid diphenyl ester
##STR124## Ib-88 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic
acid dibenzyl ester ##STR125## Ib-89
2,2,11,11-Tetramethyl-5,8-dioxo-dodecane-1,12-disulfonic acid
##STR126## Ib-90 Phosphoric acid
mono-(2,2,11,11-tetramethyl-5,8-dioxo-12-phosphonooxy-dodecyl)
ester ##STR127## Ib-91
1,12-Bis-(4,6-dithiooxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)--
2,2,11,11- tetramethyl-dodecane-5,8-dione ##STR128## Ib-92
1,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,2,11,11- tetramethyl-dodecane-5,8-dithione ##STR129## Ib-93
3,3,12,12-Tetramethyl-6,9-dioxo-tetradecaedioic acid dicyanimide
##STR130## Ib-94 Phosphoramidic acid
mono-[12-(amino-hydroxy-phosphoryloxy)-2,2,11,11-tetramethyl-5,8-
dioxo-dodecyl] ester ##STR131## Ib-95
2,2,11,11-Tetramethyl-1,12-bis-(aminohydroxyphosphoryloxy)-dodecane-5,8-di-
one ##STR132## Ib-96
2,2,11,11-Tetramethyl-1,12-bis-(1H-tetrazol-5-yl)-dodecane-5,8-dione
##STR133## Ib-97
1,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dion-
e ##STR134## Ib-98
1,12-Bis-(3-hydroxy-isoxaol-4-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione
##STR135## Ib-99
1-(5-Hydroxy-4-oxo-4H-pyran-3-yl)-12-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,1-
1,11- tetramethyl-dodecane-5,8-dione ##STR136## Ib-100
1,12-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,11,11-tetramethyl-dodecane-5,-
8-dione ##STR137## Ib-101
1,12-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,11,11-tetramethyl-dodecane-5,-
8-dione ##STR138## Ib-102
1-Ethyl-3-[12-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,11,11-tetrameth-
yl-5,8-dioxo- dodecyl]-imidazolidine-2,4-dione ##STR139## Ib-103
1-Ethyl-3-[12-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,2,11,11-tetramethyl--
5,8-dioxo- dodecyl]-imidazolidine-2,4-dione ##STR140## Ib-104
1,12-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,2,11,11-tetramethyl--
dodecane-5,8- dione ##STR141## Ib-105
1,12-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,2,11,11-tetramethyl--
dodecane-5,8- dione ##STR142## Ib-106
1,16-Dihydroxy-4,4,13,13-tetramethyl-hexadecane-7,10-dione
##STR143## Ib-107 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic
acid ##STR144## Ib-108
4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedial ##STR145## Ib-109
4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dimethyl
ester ##STR146## Ib-110
4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid diphenyl
ester ##STR147## Ib-111
4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dibenzyl
ester ##STR148## Ib-112
3,3,12,12-Tetramethyl-6,9-dioxo-tetradecane-1,14-disulfonic acid
##STR149## Ib-113 Phosphoric acid
mono-(3,3,12,12-tetramethyl-6,9-dioxo-14-phosphonooxy-tetradecyl)
ester ##STR150## Ib-114
1,14-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-3,3,-
12,12- tetramethyl-tetradecane-6,9-dione ##STR151## Ib-115
1,14-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
,3,12,12- tetramethyl-tetradecane-6,9-dione ##STR152## Ib-116
4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dicyanimide
##STR153## Ib-117 Phosphoramidic acid
mono-[14-(amino-hydroxy-phosphoryloxy)-3,3,12,12-tetramethyl-6,9-
dioxo-tetradecyl] ester ##STR154## Ib-118
3,3,12,12-Tetramethyl-1,14-bis-(amino-hydroxy-phosphoryloxy)-tetradecane-6-
,9-dione ##STR155## Ib-119
1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione ##STR156##
Ib-120 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid
##STR157## Ib-121 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedial
##STR158## Ib-122 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic
acid dimethyl ester ##STR159## Ib-123
2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid diphenyl ester
##STR160## Ib-124 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic
acid dibenzyl ester ##STR161## Ib-125
2,11-Dimethyl-5,8-dioxo-dodecane-2,11-disulfonic acid ##STR162##
Ib-126 Phosphoric acid
mono-(1,1,10-trimethyl-4,7-dioxo-10-phosphonooxy-undecyl) ester
##STR163## Ib-127
2,11-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,11-
-dimethyl- dodecane-5,8-dione ##STR164## Ib-128
2,11-Bis-(4,6-dithio-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,1-
1-dimethyl- dodecane-5,8-dione ##STR165## Ib-129
2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dicyanimide
##STR166## Ib-120 Phosphoramidic acid
mono-[10-(amino-hydroxy-phosphoryloxy)-1,1,10-trimethyl-4,7-
dioxo-undecyl] ester ##STR167##
2,2,11,11-Tetramethyl-1,12-(amino-hydroxy-phosphoryloxy)-dodecane-5,8-dion-
e ##STR168## Ib-132
3,3,12,12-Tetramethyl-1,14-bis-tetrazol-1-yl-tetradecane-6,9-dione
##STR169## Ib-133
3,3,12,12-Tetramethyl-1,14-bis-(1H-tetrazol-5-yl)-tetradecane-6,9-dione
##STR170## Ib-134
1,14-Bis-(3-hydroxy-isoxazol-5-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-d-
ione ##STR171## Ib-135
1,14-Bis-(3-hydroxy-isoxazol-4-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-d-
ione ##STR172## Ib-136
1-(5-Hydroxy-4-oxo-4H-pyran-2-yl)-14-(5-hydroxy-4-oxo-4H-pyran-3-yl)-3,3,1-
2,12- tetramethyl-tetradecane-6,9-dione ##STR173## Ib-137
1,14-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-3,3,12,12-tetramethyl-tetradecane-
-6,9-dione ##STR174## Ib-138
1,14-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-3,3,12,12-tetramethyl-tetradecane-
-6,9-dione ##STR175## Ib-139
1-Ethyl-3-[14-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-3,3,12,12-tetrameth-
yl-6,9-dioxo- tetradecyl]-imidazolidine-2,4-dione ##STR176## Ib-140
1-Ethyl-3-[14-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl--
6,9-dioxo- tetradecyl]-imidazolidine-2,4-dione ##STR177## Ib-141
1-Ethyl-3-[14-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-3,3,12,12-tetrameth-
yl-6,9-dioxo- tetradecyl]-imidazolidine-2,4-dithione ##STR178##
Ib-142
1,14-Bis(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl-t-
etradecane-6,9- dione ##STR179## Ib-143
1,14-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl--
tetradecane-6,9- dione ##STR180## Ib-144
1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione
##STR181## Ib-145 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedial
##STR182## Ib-146 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic
acid dimethyl ester ##STR183## Ib-147
1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione
##STR184## Ib-148 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic
acid diphenyl ester ##STR185## Ib-149
3,3,15,15-Tetramethyl-7,11-dioxo-heptanedioic acid dibenzyl ester
##STR186## Ib-150
2,11-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-2,11-dimet-
hyl- dodecane-5,8-dione ##STR187## Ib-151
2,11-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,11-dimethyl- dodecane-5,8-dione ##STR188## Ib-152
2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dicyanamide
##STR189## Ib-153 Phosphoramidic acid
mono-[10--(amino-hydroxy-phosphoryloxy)-1,1,10-trimethyl-4,7-
dioxo-undecyl] ester ##STR190##
Ib-154
2,11-Dimethyl-2,11-bis-(amino-hydroxy-phosphoryloxy)-dodecane-5,8-dione
##STR191## Ib-155
2,11-Dimethyl-2,11-bis-tetrazol-1-yl-dodecane-5,8-dione ##STR192##
Ib-156 2,11-Dimethyl-2,11-bis-(1H-tetrazol-5-yl)-dodecane-5,8-dione
##STR193## Ib-157
2,2,14,14-Tetramethyl-6,10-dioxo-pentadecane-1,15-disulfonic acid
##STR194## Ib-158 Phosphoric acid
mono-(2,2,14,14-0tetramethyl-6,10-dioxo-15-phosphonooxy-pentadecyl)
ester ##STR195## Ib-159
1,15-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,2,14,14- tetramethyl-pentadecane-6,10-dione ##STR196## Ib-160
1,15-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,2,14,14- tetramethyl-pentadecane-6,10-dione ##STR197## Ib-161
3,3,15,15-Tetramethyl-7,11-dioxo-heptanedioic acid dicyanamide
##STR198## Ib-162 Phosphoramidic acid
mono-[16-(amino-hydroxy-phosphoryloxy)-4,4,15,15-tetramethyl-
7,11-dioxo-hexadecyl] ester ##STR199## Ib-163
2,2,14,14-Tetramethyl-1,15-bis-(amino-hydroxy-phosphoryloxy)-pentadecane-6-
,10-dione ##STR200## Ib-164
2,2,14,14-Tetramethyl-1,15-bis-tetrazol-1-yl-pentadecane-6,10-dione
##STR201## Ib-165
2,2,14,14-Tetramethyl-1,15-bis-(1H-tetrazol-5-yl)-pentadecane-6,10-dione
##STR202## Ib-166
1,15-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,14,14-tetramethyl-pentadecane-6,10--
dione ##STR203## Ib-167
1,15-Bis-(3-hydroxy-isoxazol-4-yl)-2,2,14,14-tetramethyl-pentadecane-6,10--
dione ##STR204## Ib-168
1-(5-Hydroxy-4-oxo-4H-pyran-3-yl)-15-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,1-
4,14- tetramethyl-pentadecane-6,10-dione ##STR205## Ib-169
1,15-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,14,14-tetramethyl-pentadecane-
-6,10-dione ##STR206## Ib-170
1,15-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,14,14-tetramethyl-pentadecane-
-6,10-dione ##STR207## Ib-171
1,15-Bis-(3-ethyl-2,5-dithio-imidazolidin-1-yl)-2,2,14,14-tetramethyl-pent-
adecane-6,10- dione ##STR208## Ib-172
1-Ethyl-3-[15-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,14,14-tetrameth-
yl-6,10-dioxo- pentadecyl]-imidazolidine-2,4-dione ##STR209##
Ib-173
1,15-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,2,14,14-tetramethyl-penta-
decane-6,10- dione ##STR210## Ib-174
1,15-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,2,14,14-tetramethyl--
pentadecane-6,10- dione ##STR211## Ib-175
1,15-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,2,14,14-tetramethyl--
pentadecane-6,10- dione ##STR212## Ic-1
1,9-Bis-(tetrahydro-pyran-2-yloxy)-nonane-3,7-dione ##STR213## Ic-2
1,9-Bis-(4-oxo-oxetan-2-yl)-nonane-3,7-dione ##STR214## Ic-3
1,9-Bis-(2-oxo-oxetan-3-yl)-nonane-3,7-dione ##STR215## Ic-4
1,9-Bis-(5-oxo-tetrahydrofuran-2-yl)-nonane-3,7-dione ##STR216##
Ic-5 1,9-Bis-(5-oxo-tetrahydrofuran-3-yl)-nonane-3,7-dione
##STR217## Ic-6
1,9-Bis-(2-oxo-tetrahydrofuran-3-yl)-nonane-3,7-dione ##STR218##
{2-[9-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-3,7-dioxo-no-
nyl]-4- hydroxy-6-oxo-tetrahydropyran-4-yl)-acetic acid ##STR219##
Ic-8 1,9-Bis-(6-oxo-tetrahydropyran-2-yl)-nonane-3,7-dione
##STR220## Ic-9
1,9-Bis-(6-oxo-tetrahydropyran-3-yl)-nonane-3,7-dione ##STR221##
Ic-10 1,9-Bis-(2-oxo-tetrahydropyran-4-yl)-nonane-3,7-dione
##STR222## Ic-11
1,9-Bis-(2-oxo-tetrahydropyran-3-yl)-nonane-3,7-dione ##STR223##
Ic-12 1,11-Bis-(tetrahydro-pyran-2-yloxy)-undecane-4,8-dione
##STR224## Ic-13 1,11-Bis-(2-oxo-oxetan-3-yl)-undecane-4,8-dione
##STR225## Ic-14 1,11-Bis-(2-oxo-oxetan-3-yl)-undecane-4,8-dione
##STR226## Ic-15
1,11-Bis-(5-oxo-tetrahydrofuran-2-yl)-undecane-4,8-dione ##STR227##
Ic-16 1,11-Bis-(5-oxo-tetrahydrofuran-3-yl)-undecane-4,8-dione
##STR228## Ic-17
1,11-Bis-(2-oxo-tetrahydrofuran-3-yl)-undecane-4,8-dione ##STR229##
Ic-18
{2-[11-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-4,8-dioxo-u-
ndecyl]-4- hydroxy-6-oxo-tetrahydropyran-4-yl}-acetic acid
##STR230## Ic-19
1,11-Bis-(6-oxo-tetrahydropyran-2-yl)-undecane-4,8-dione ##STR231##
Ic-20 1,11-Bis-(6-oxo-tetrahydropyran-3-yl)-undecane-4,8-dione
##STR232## Ic-21
1,11-Bis-(2-oxo-tetrahydropyran-4-yl)-undecane-4,8-dione ##STR233##
Ic-22 1,11-Bis-(2-oxo-tetrahydropyran-3-yl)-undecane-4,8-dione
##STR234## IC-23
1,8-Bis-(tetrahydropyran-2-yloxy)-octane-3,6-dione
##STR235## IC-24 1,8-Bis-(4-oxo-oxetan-2-yl)-octane-3,6-dione
##STR236## IC-25 1,8-Bis-(2-oxo-oxetan-3-yl)-octane-3,6-dione
##STR237## IC-26
1,8-Bis-(5-oxo-tetrahydro-furan-2-yl)-octane-3,6-dione ##STR238##
IC-27 1,8-Bis-(5-oxo-tetrahydro-furan-3-yl)-octane-3,6-dione
##STR239## IC-28
1,8-Bis-(2-oxo-tetrahydro-furan-3-yl)-octane-3,6-dione ##STR240##
IC-29
{2-[8-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-3,6-dioxo-oc-
tyl]-4- hydroxy-6-oxo-tetrahydro-pyran-4-yl}-acetic acid ##STR241##
IC-30 1,8-Bis-(6-oxo-tetrahydropyran-2-yl)-octane-3,6-dione
##STR242## IC-31
1,8-Bis-(6-oxo-tetrahydropyran-3-yl)-octane-3,6-dione ##STR243##
IC-32 1,8-Bis-(2-oxo-tetrahydropyran-4-yl)-octane-3,6-dione
##STR244## IC-33
1,8-Bis-(2-oxo-tetrahydropyran-3-yl)-octane-3,6-dione ##STR245##
II-1 1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecan-7-ene ##STR246##
II-2 12-Hydroxy-2,2,12-trimethyl-7-oxo-tridecanoic acid; compound
with formaldehyde ##STR247## II-3
11-Hydroperoxy-2,2,10,10-tetramethyl-6-oxo-undecanoic acid
##STR248## II-4 1,11-Dihydroxy-2,2,10,10-tetramethyl-undecan-6-one
##STR249## II-5 11-Hydroxy-2,2,10,10-tetramethyl-6-oxo-undecanoic
acid ##STR250## II-6 2,2,10,10-Tetramethyl-6-oxo-undecanedioic acid
##STR251## II-7
1,15-Dihydroxy-2,2,14,14-tetramethyl-pentadecan-8-one ##STR252##
II-8 15-Hydroxy-2,2,14,14-tetramethyl-8-oxo-pentadecanoic acid
##STR253## II-9 2,2,14,14-Tetramethyl-8-oxo-pentadecanedioic acid
##STR254## II-10 2,2,12,12-Tetramethyl-7-oxo-tridecanedial
##STR255## II-11 2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid
dimethyl ester ##STR256## II-12
2,2,12,12-Tetramethyl-1,13-diphenyl-tridecane-1,7,13-trione
##STR257## II-13
3,3,13,13-Tetramethyl-1,15-diphenyl-pentadecane-2,8,14-trione
##STR258## II-14 2,12-Dimethyl-7-oxo-tridecane-2,12-disulfonic acid
##STR259## II-15 Phosphoric acid
mono-(1,1,11-trimethyl-6-oxo-11-phosphonooxy-dodecyl) ester
##STR260## II-16 2,2,14,14-Tetramethyl-8-oxo-pentadecanedial
##STR261## II-17 2,2,14,14-Tetramethyl-8-oxo-pentadecanedioic acid
dimethyl ester ##STR262## II-18
2,2,14,14-Tetramethyl-1,15-diphenyl-pentadecane-1,8,15-trione
##STR263## II-19
3,3,15,15-Tetramethyl-1,17-diphenyl-heptadecane-2,9,16-trione
##STR264## II-20 2,14-Dimethyl-8-oxo-pentadecane-2,14-disulfonic
acid ##STR265## II-21 Phosphoric acid
mono-(1,1,13-trimethyl-7-oxo-13-phosphonooxy-tetradecyl) ester
##STR266## II-22
1,15-Dihydroxy-3,3,13,13-tetramethyl-pentadecan-8-one ##STR267##
II-23 15-Hydroxy-3,3,13,13-tetramethyl-8-oxo-pentadecanoic acid
##STR268## II-24 3,3,13,13-Tetramethyl-8-oxo-pentadecanedioic acid
##STR269## II-25
1,13-Dihydroxy-3,3,11,11-tetramethyl-tridecan-7-one ##STR270##
II-26 13-Hydroxy-3,3,11,11-tetramethyl-7-oxo-tridecanoic acid
##STR271## II-27 3,3,11,11-Tetramethyl-7-oxo-tridecanedioic acid
##STR272## II-28
1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecan-9-one ##STR273##
II-29 17-Hydroxy-3,3,15,15-tetramethyl-9-oxo-heptadecanoic acid
##STR274## II-30 3,3,15,15-Tetramethyl-9-oxo-heptadecanedioic acid
##STR275## II-31
1,17-Dihydroxy-4,4,14,14-tetramethyl-heptadecan-9-one ##STR276##
II-32 17-Hydroxy-4,4,14,14-tetramethyl-9-oxo-heptadecanoic acid
##STR277## II-33
4,4,14,14-Tetramethyl-heptadecan-9-oxo-1,17-dicarboxylic acid
##STR278## II-34
1,15-Dihydroxy-4,4,14,14-tetramethyl-pentadecan-8-one ##STR279##
II-35 15-Hydroxy-4,4,12,12-tetramethyl-8-oxo-pentadecanoic acid
##STR280## II-36 4,412,12-Tetramethyl-8-oxo-pentadecanedioic acid
##STR281## II-37
1,19-Dihydroxy-4,4,16,16-tetramethyl-nondecan-10-one ##STR282##
II-38 19-Hydroxy-4,4,16,16-tetramethyl-10-oxo-nonadecanoic acid
##STR283## II-39 4,4,16,16-Tetramethyl-10-oxo-nonadecanedioic acid
##STR284##
II-40
5-[9-(4-Mercapto-3-methyl-2,6-dioxo-3,6-dihydro-2H-pyridin-1-yl)-1,1,9-tri-
methyl-5-
oxo-decyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-dione
##STR285## II-41
2,10-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,10- dimethyl-undecan-6-one ##STR286## II-42
2,2,10,10-Tetramethyl-6-oxo-undecanedioic acid bis-cyanoamide
##STR287## II-43 Phosphoramidic acid mono-
[9-(amino-hydroxy-phosphoryloxy)-1,1,9-trimethyl-5-oxo-decyl] ester
##STR288## II-44 Phosphoramidic acid
mono-]9-(amino-hydroxy-phosphoryloxy)-1,1,9-trimethyl-5-oxo- decyl]
ester ##STR289## II-45
2,12-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12-
-dimethyl- tridecan-7-one ##STR290## II-46
2,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridi-5-yl)-2,-
12-dimethyl- tridecan-7-one ##STR291## II-47
2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid bis-cyanoamide
##STR292## II-48 Phosphoramidic acid
mono-[11-(amino-hydroxy-phosphoryloxy)-
1,1,11-trimethyl-6-oxo-dodecyl] ester ##STR293## II-49
Phosphoramidic acid
mono-[11(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-6-oxo-
dodecyl] ester ##STR294## II-50
2,12-Dimethyl-2,12-bis-tetrazol-1-yl-tridecan-7-one ##STR295##
II-51 2,12-Dimethyl-2,12-bis-(1H-tetrazol-5-yl)-tridecan-7-one
##STR296## II-52
2,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,12-dimethyl-tridecan-7-one
##STR297## II-53
2,12-Bis-(3-hydroxy-isoxazol-4-yl)-2,12-dimethyl-tridecan-7-one
##STR298## II-54
4-[11-(4-oxo-oxetan-2-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-oxetan-2-one
##STR299## II-55
3-[11-(4-oxo-oxetan-2-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-oxetan-2-one
##STR300## II-56
5-[11-(5-oxo-tetrahydro-furan-3-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-dihydr-
o-furan-2-one ##STR301## II-57
3-[11-(5-oxo-tetrahydro-furan-3-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-dihydr-
o-furan-2-one ##STR302## II-58
4-[11-(5-oxo-tetrahydro-furan-3-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-dihydr-
o-furan-2-one ##STR303## II-59
2,12-Dimethyl-2,12-bis-(tetrahydro-pyran-2-yloxy)-tridecan-7-one
##STR304## II-60
{2-[11-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-1,1,11-
trimethyl-6-oxo-dodecyl]-4-hydroxy-
6-oxo-tetrahydro-pyran-4-yl}-acetic acid ##STR305## IIa-1
1,15-Dihydroxy-2,14-dimethyl-2,14-diphenyl-pentadecan-8-one
##STR306## IIa-2
15-Hydroxy-2,14-dimethyl-8-oxo-2,14-diphenyl-pentadecanoic acid
##STR307## IIa-3 2,14-Dimethyl-8-oxo-2,14-diphenyl-pentadecanedioic
acid ##STR308## IIa-4
1,13-Dihydroxy-2,12-dimethyl-2,12-diphenyl-tridecan-7-one
##STR309## IIa-5
13-Hydroxy-2,12-dimethyl-7-oxo-2,12-diphenyl-tridecanoic acid
##STR310## IIa-6 2,12-Dimethyl-7-oxo-2,12-diphenyl-tridecanedioic
acid ##STR311## IIa-7
1,11-Dihydroxy-2,10-dimethyl-2,10-diphenyl-undecn-6-one ##STR312##
IIa-8 11-Hydroxy-2,10-dimethyl-6-oxo-2,10-diphenyl-undecanoic acid
##STR313## IIa-9 2,10-Dimethyl-6-oxo-2,10-diphenyl-undecandioic
acid ##STR314## IIa-10
2,14-Dimethyl-8-oxo-2,14-diphenyl-pentadecanedial ##STR315## IIa-11
2,14-Dimethyl-8-oxo-2,14-diphenyl-pentadecanedioic acid dimethyl
ester ##STR316## IIa-12
2,14-Dimethyl-1,2,14,15-tetraphenyl-pentadecane-1,8,15-trione
##STR317## IIa-13
3,15-Dimethyl-1,3,15,17-tetraphenyl-heptadecane-2,9,16-trione
##STR318## IIa-14 8-Oxo-2,14-diphenyl-pentadecane-2,14-disulfonic
acid ##STR319## IIa-15 Phosphoric acid
mono-(1-methyl-7-oxo-1,13-diphenyl-13-phosphonooxy-tetradecyl)
ester ##STR320## IIa-16
1,17-Dihydroxy-3,15-dimethyl-3,15-diphenyl-heptadecan-9-one
##STR321## IIa-17
17-Hydroxy-3,15-dimethyl-9-oxo-3,15-diphenyl-heptadecanoic acid
##STR322## IIa-18
3,15-Dimethyl-9-oxo-3,15-diphenyl-heotadecanedioic acid ##STR323##
IIa-19 1,15-Dihydroxy-3,13-dimethyl-3,13-diphenyl-pentadecan-8-one
##STR324## IIa-20
15-Hydroxy-3,13-dimethyl-8-oxo-3,13-diphenyl-pentadecanoic acid
##STR325## IIa-21
3,13-Dimethyl-8-oxo-3,13-diphenyl-pentadecanedioic acid ##STR326##
IIa-22 1,13-Dihydroxy-3,11-dimethyl-3,11-diphenyl-tridecan-7-one
##STR327## IIa-23
13-Hydroxy-3,11-dimethyl-7-oxo-3,11-diphenyl-tridecanoic acid
##STR328## IIa-24 3,11-Dimethyl-7-oxo-3,11-diphenyl-tridecanedioic
acid ##STR329## IIa-25
13-Hydroxy-3,11-dimethyl-7-oxo-3,11-diphenyl-tridecanoic acid
##STR330##
IIa-26 3,11-Dimethyl-7-oxo-3,11-diphenyl-tridecanedioic acid
##STR331## IIa-27
1,19-Dihydroxy-4,16-dimethyl-4,16-diphenyl-nonadecan-10-one
##STR332## IIa-28
19-Hydroxy-4,16-dimethyl-10-oxo-4,16-diphenyl-nonadecanoic acid
##STR333## IIa-29
4,16-Dimethyl-10-oxo-4,16-diphenyl-nonadecanedioic acid ##STR334##
IIa-30 1,17-Dihydroxy-4,14-dimethyl-4,14-diphenyl-heptadecan-9-one
##STR335## IIa-31
17-Hydroxy-4,14-dimethyl-9-oxo-4,14-diphenyl-heptadecanoic acid
##STR336## IIa-32
4,14-Dimethyl-9-oxo-4,14-diphenyl-heptadecanedioic acid ##STR337##
IIa-33 1,15-Dihydroxy-4,12-dimethyl-4,12-diphenyl-pentadecan-8-one
##STR338## IIa-34
15-Hydroxy-4,12-dimethyl-8-oxo-4,12-diphenyl-pentadecanoic acid
##STR339## IIa-35
4,12-Dimethyl-8-oxo-4,12-diphenyl-pentadecanedioic acid ##STR340##
IIa-36
2,12-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12-
-diphenyl- tridecan-7-one ##STR341## IIa-37
2,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2-
,12- diphenyl-tridecan-7-one ##STR342## IIa-38
2,12-Dimethyl-2,12-diphenyl-7-oxo-tridecanedioic acid
bis-cyanoamide ##STR343## IIa-39 Phosphoramidic acid
mono-[11-(amino-hydroxy-phosphoryloxy)-
1-methyl-6-oxo-1,11-diphenyl-dodecyl] ester ##STR344## IIa-40
Phosphoramidic acid
mono-[11(amino-hydroxy-phosphoryloxy)-1,11-diphenyl-1-methyl-6-
oxo-dodecyl] ester ##STR345## IIa-41
2,12-Diphenyl-2,12-bis-tetrazol-1-yl-tridecan-7-one ##STR346##
IIa-42 2,12-Diphenyl-2,12-bis-(1H-tetrazol-5-yl)-tridecan-7-one
##STR347## IIa-43
2,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,12-diphenyl-tridecan-7-one
##STR348## IIa-44
2,12-Bis-(3-hydroxy-isoxazol-4-yl)-2,12-diphenyl-tridecan-7-one
##STR349## IIa-45
2,12-Diphenyl-2,12-bis-(tetrahydrop-pyran-2-yloxy)-tridecan-7-one
##STR350## IIa-46
5-[11-(5-oxo-tetrahydro-furan-2-yl)-1,11-Diphenyl-1-methyl-6-oxo-dodecyl]--
dihydro-furan- 2-one ##STR351## IIa-47
4-[11-(4-oxo-oxetan-2-yl)-1,11-diphenyl-1-methyl-6-oxo-dodecyl]-oxetan-2-o-
ne ##STR352## IIa-48
4-[11-(5-oxo-tetrahydro-furan-2-yl)-1,11-Diphenyl-1-methyl-6-oxo-dodecyl]--
dihydro-furan- 2-one ##STR353## IIa-49
3-[11-(5-oxo-tetrahydro-furan-2-yl)-1,11-Diphenyl-1-methyl-6-oxo-dodecyl]--
dihydro-furan- 2-one ##STR354## IIa-50
{2-[11-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-
1-methyl-6-oxo-1,11-diphenyl-dodecyl]-
4-hydroxy-6-oxo-tetrahydro-pyran-4-yl}-acetic acid ##STR355## III-1
5-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl)-p-
ropyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol
##STR356## III-2
5-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-p-
ropyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR357## III-3
5-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-propy-
l}-1,4-dioxo- cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR358## III-4
5-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol
##STR359## III-5
5-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic
acid ##STR360## III-6
5-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2--
yl]propyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR361## III-7
6-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-pr-
opyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol
##STR362## III-8
6-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-pr-
opyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR363## III-9
6-(6-{3-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-propyl-
}-1,4-dioxo- cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR364## III-10
6-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-
propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol
##STR365## III-11
6-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-
propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic
acid ##STR366## III-12
6-(6-{3-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-y-
l]-propyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR367## III-13
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1--
oxo- cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol ##STR368## II-14
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]vinyl}-1-o-
xo- cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid ##STR369## III-15
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclohexan-2-yl]-cinyl}-1-oxo--
cyclohexan- 2-yl)-2,2-dimethyl-hexanoic acid ##STR370## III-16
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-vi-
nyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol
##STR371## III-17
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-ci-
nyl}-1,4- dioxo-cyclohexadien-2-yl}-2,2-dimethyl-hexanoic acid
##STR372## III-18
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-vinyl}-
-1,4-dioxo- cyclohexadien-2-yl}-2,2-dimethyl-hexanoic acid
##STR373## III-19
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-
vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol
##STR374## III-20
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-
vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic
acid ##STR375## III-21
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-y-
l]-vinyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR376## III-22
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1-
-oxo- cyclohexan-2-yl)-2,2dimethyl-pentan-1-ol ##STR377## III-23
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid ##STR378##
III-24
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1-oxo-
-cyclohexan- 2-yl)-2,2-dimethyl-pentanoic acid ##STR379## III-25
5-(6-{2-[6-(5-Hydroxy-4,4-dimthyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-vi-
nyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol
##STR380## III-26
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-v-
inyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR381## III-27
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-vinyl-
}-1,4-dioxo- cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR382## III-28
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol
##STR383## III-29
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2dimethyl-pentanoic
acid ##STR384## III-30
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2--
yl]-vinyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR385## III-31
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-et-
hyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol
##STR386## III-32
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-et-
hyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR387## III-33
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-ethyl}-
-1,4-dioxo- cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR388## III-34
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-ethyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol
##STR389## III-35
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-ethyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR390## III-36
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-y-
l]-ethyl}-4,4-
dimethyl-1-oxo-cyclohexadien-2yl)-2,2-dimethyl-hexanoic acid
##STR391## III-37
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-e-
thyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol
##STR392## III-38
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-e-
thyl}-1,4- dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR393## III-39
5-(6-{2-[6-(4-Carboxy-4-4methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-ethy-
l}-1,4-dioxo- cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR394## III-40
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol
##STR395## III-41
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic
acid ##STR396## III-42
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2--
yl]-ethyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR397## III-43
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol ##STR398## III-44
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid ##STR399## III-45
6-(6-{2-[6-(6-Carboxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid ##STR400## III-46
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-ph-
enyl}-1-oxo- cyclohexan-2-yl)-2,2-dimethyl-hexan-2-ol ##STR401##
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]phe-
nyl}-1-oxo- cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol III-47
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-ph-
enyl}-1,4-dio ##STR402##
xo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid II-48
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-phenyl-
}-1,4-dioxo-c ##STR403## yclohexadien-2-yl)-2,2-dimethyl-hexanoic
acid III-49
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-phenyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol
##STR404## III-50
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-
-2-yl]-phenyl ##STR405## III-51
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-y-
l]-phenyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR406## III-52
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-phenyl}--
1-oxo- cyclohexan-2-yl)-2,2-dimethyl-pentan-1-ol ##STR407## III-53
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-phenyl}--
1-oxo- cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid ##STR408##
III-54
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-ox-
o- cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid ##STR409## III-55
5-(6-{2-[6-(5-Hydroxy-4-methyl-pentyl)-1,4-dioxo-cyclohex-2-yl]-phenyl}-1,-
4-dioxo- cyclohex-2-yl)-2,2-dimethyl-pentan-1-ol ##STR410##
5-(6-{2-[6-(5-Hydroxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-pheny-
l}-1,4-dioxo- cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR411## III-57
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-pheny-
l}-1,4-dioxo- cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR412## III-58
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
phenyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol
##STR413## III-59
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadie-
n-2-yl]-
phenyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic
acid ##STR414## III-60
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2--
yl]-phenyl}-
4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR415## III-61
5-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-prop-
yl}-1-oxo- cyclopentan-2-yl)-2,2-dimethyl-pentan-1-ol ##STR416##
III-62
5-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-prop-
yl}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR417## III-63
5-(5-{3-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentadien-2-yl]-propyl}--
1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid ##STR418##
III-64
6-(5-{3-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-propy-
l}-1-oxo- cyclopentandien-2-yl)-2,2-dimethyl-hexan-1-ol ##STR419##
III-65
6-(5-{3-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-propy-
l}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid
##STR420##
6-(5-{3-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentadien-2-yl]-propyl}-1-
-oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid ##STR421##
III-67
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-
-oxo- cyclopentan-2-yl)-2,2-dimethyl-hexan-1-ol ##STR422## III-68
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-
-oxo- cyclopentan-2-yl)-2,2-dimethyl-hexanoic acid ##STR423##
III-69
6-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-
-cyclopentan- 2-yl)-2,2-dimethyl-hexanoic acid ##STR424## III-70
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl-
}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexan-1-ol ##STR425##
III-71
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl-
}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid ##STR426##
III-72
6-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1--
oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid ##STR427##
III-73
5-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]-vinyl}--
1-oxo- cyclopentan-2-yl)-2,2-dimethyl-pentan-1-ol ##STR428## III-74
5-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]-vinyl}--
1-oxo- cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid ##STR429##
III-75
5-(5-{2-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-ox-
o- cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid ##STR430## III-76
5-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-viny-
l}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentan-1-ol ##STR431##
III-77
5-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentandien-2-yl]-vin-
yl}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR432## III-78
5-(5-{2-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-
-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid ##STR433##
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-
-oxo- cyclopentan-2-yl)-2,2-dimethyl-hexan-1-ol ##STR434##
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]vinyl}-1--
oxo- cyclopentan-2-yl)-2,2-dimethyl-hexanoic acid ##STR435## III-81
6-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-
-cyclopentan- 2-yl)-2,2-dimethyl-hexanoic acid ##STR436## III-82
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]vinyl}-
-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexan-1-ol ##STR437##
III-83
6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl-
}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid ##STR438##
III-84
6-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1--
oxo- cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid ##STR439##
III-85
5-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-ethy-
l}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentan-1-ol ##STR440##
III-86
5-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-ethy-
l}-1-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid
##STR441## III-87
5-(5-{2-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentadien-2-yl]-ethyl}-1-
-oxo- cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid ##STR442##
IIIa-1
5-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-propyl}--
1-oxo-
cyclohexan-2-yl)-2,2-dimethyl-pentan-1-ol ##STR443## IIIa-2
5-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-ox-
o- cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid ##STR444## IIIa-3
5-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-ox-
o- cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid ##STR445## IIIa-4
6-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol ##STR446## IIIa-5
6-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid ##STR447## IIIa-6
6-(6-{3-[6-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-oxo-
-cyclohexan- 2-yl)-2,2-dimethyl-hexanoic acid ##STR448## IIIa-7
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1--
oxo- cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol ##STR449## IIIa-8
6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1--
oxo- cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid ##STR450## IIIa-9
6-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo--
cyclohexan- 2-yl)-2,2-dimethyl-hexanoic acid ##STR451## IIIa-10
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-pentan-1-ol ##STR452## IIIa-11
5-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-
-oxo- cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid ##STR453##
IIIa-12
5-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo-
-cyclohexan- 2-yl)-2,2-dimethyl-pentanoic acid ##STR454## IIIa-13
5-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]-propyl}-
-1-oxo- cyclopentan-2-yl)-2,2-dimethyl-pentan-1-ol ##STR455##
IIIa-14
5-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]propyl}--
1-oxo- cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid ##STR456##
IIIa-15
5-(5-{3-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentan-2-yl]propyl}-1-ox-
o- cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid
[0143] The compounds of the invention are useful in medical
applications for treating or preventing cardiovascular diseases,
dyslipidemias, dyslipoproteinemias, disorders of glucose
metabolism, Alzheimer's Disease, Syndrome X, PPAR-associated
disorders, septicemia, thrombotic disorders, obesity, pancreatitis,
hypertension, renal diseases, cancer, inflammation, and impotence.
As used herein, the phrase "compounds of the invention" means,
collectively, the compounds of formulas I, II, and III and
pharmaceutically acceptable salts, hydrates, solvates, clathrates,
enantiomers, diasteriomers, racemates, or mixtures of steroisomers
thereof. Compounds of formula I encompass subgroup formulas Ia, Ib,
and Ic. Compounds of formula II encompass subgroup formula IIa and
compounds of formula III encompass subgroup of formula IIIa. Thus,
"compound of the invention" collectively means compound of formulas
I, Ia, Ib, Ic, II, IIa, III, and IIIa and pharmaceutically
acceptable salts, hydrates, solvates, clathrates, enantiomers,
diasteriomers, racemates, or mixtures of steroisomers thereof. The
compounds of the invention are identified herein by their chemical
structure and/or chemical name. Where a compound is referred to by
both a chemical structure and a chemical name, and the chemical
structure and chemical name conflict, the chemical structure is
determinative of the compound's identity.
[0144] The present invention further provides pharmaceutical
compositions comprising one or more compounds of the invention and
a pharmaceutically acceptable vehicle, excipient, or diluent. A
pharmaceutically acceptable vehicle can comprise a carrier,
excipient, diluent, or a mixture thereof. These pharmaceutical
compositions are useful for treating or preventing a disease or
disorder including, but not limited to, aging, Alzheimer's Disease,
cancer, cardiovascular disease, diabetic nephropathy, diabetic
retinopathy, a disorder of glucose metabolism, dyslipidemia,
dyslipoproteinemia, hypertension, impotence, inflammation, insulin
resistance, lipid elimination in bile, modulating C reactive
protein, obesity, oxysterol elimination in bile, pancreatitis,
Parkinson's disease, a peroxisome proliferator activated
receptor-associated disorder, phospholipid elimination in bile,
renal disease, septicemia, metabolic syndrome disorders (e.g.,
Syndrome X), a thrombotic disorder, or enhancing bile production,
or enhancing reverse lipid transport, inflammatory processes and
diseases like gastrointestinal disease, irritable bowel syndrome
(IBS), inflammatory bowel disease (e.g., Crohn's Disease,
ulcerative colitis), arthritis (e.g., rheumatoid arthritis,
osteoarthritis), autoimmune disease (e.g., systemic lupus
erythematosus), scleroderma, ankylosing spondylitis, gout and
pseudogout, muscle pain: polymyositis/polymyalgia
rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue rheumatism.
These pharmaceutical composition are also useful for reducing the
fat content of meat in livestock and reducing the cholesterol
content of eggs.
[0145] The present invention provides a method for treating or
preventing a aging, Alzheimer's Disease, cancer, cardiovascular
disease, diabetic nephropathy, diabetic retinopathy, a disorder of
glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension,
impotence, inflammation, insulin resistance, lipid elimination in
bile, modulating C reactive protein, obesity, oxysterol elimination
in bile, pancreatitis, Parkinson's disease, a peroxisome
proliferator activated receptor-associated disorder, phospholipid
elimination in bile, renal disease, septicemia, metabolic syndrome
disorders (e.g., Syndrome X), a thrombotic disorder, or enhancing
bile production, or enhancing reverse lipid transport, inflammatory
processes and diseases like gastrointestinal disease, irritable
bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's
Disease, ulcerative colitis), arthritis (e.g., rheumatoid
arthritis, osteoarthritis), autoimmune disease (e.g., systemic
lupus erythematosus), scleroderma, ankylosing spondylitis, gout and
pseudogout, muscle pain: polymyositis/polymyalgia
rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue rheumatism,
comprising administering to a patient in need of such treatment or
prevention a therapeutically effective amount of a compound of the
invention or a pharmaceutical composition comprising a compound of
the invention and a pharmaceutically acceptable vehicle, excipient,
or diluent.
[0146] The present invention further encompasses a method for
reducing the fat content of meat in livestock comprising
administering to livestock in need of such fat-content reduction a
therapeutically effective amount of a compound of the invention or
a pharmaceutical composition comprising a compound of the invention
and a pharmaceutically acceptable vehicle, excipient, or
diluent.
[0147] The invention also encompasses a method for inhibited
hepatic fatty acid and sterol synthesis comprising administering to
a patient in need thereof a therapeutically effective amount of a
compound of the invention or a pharmaceutical composition
comprising a compound of the invention and a pharmaceutically
acceptable vehicle, excipient, or diluent.
[0148] The invention also encompasses a method of treating or
preventing a disease or disorder that is capable of being treated
or prevented by increasing HDL levels, which comprises
administering to a patient in need of such treatment or prevention
a therapeutically effective amount of a compound of the invention
and a pharmaceutically acceptable vehicle, excipient, or
diluent.
[0149] The invention also encompasses a method of treating or
preventing a disease or disorder that is capable of being treated
or prevented by lowering LDL levels, which comprises administering
to such patient in need of such treatment or prevention a
therapeutically effective amount of a compound of the invention and
a pharmaceutically acceptable vehicle, excipient, or diluent.
[0150] The compounds of the invention favorably alter lipid
metabolism in animal models of dyslipidemia at least in part by
enhancing oxidation of fatty acids through the
ACC/malonyl-CoA/CPT-I regulatory axis and therefore the invention
also encompasses methods of treatment or prevention of metabolic
syndrome disorders.
[0151] The present invention provides a method for reducing the
cholesterol content of a fowl egg comprising administering to a
fowl species a therapeutically effective amount of a compound of
the invention or a pharmaceutical composition comprising a compound
of the invention and a pharmaceutically acceptable vehicle,
excipient, or diluent.
[0152] Thus, the compounds of the present invention are useful for
the treatment of vascular disease, such as cardiovascular disease,
stroke, and peripheral vascular disease; dyslipidemia;
dyslipoproteinemia; a disorder of glucose metabolism; Alzheimer's
Disease; Syndrome X; a peroxisome proliferator activated
receptor-associated disorder; septicemia; a thrombotic disorder;
obesity; pancreatitis; hypertension; renal disease; cancer;
inflammation; inflammatory muscle diseases, such as polymylagia
rheumatica, polymyositis, and fibrositis; impotence;
gastrointestinal disease; irritable bowel syndrome; inflammatory
bowel disease; inflammatory disorders, such as asthma, vasculitis,
ulcerative colitis, Crohn's disease, Kawasaki disease, Wegener's
granulomatosis, (RA), systemic lupus erythematosus (SLE), multiple
sclerosis (MS), and autoimmune chronic hepatitis; arthritis, such
as rheumatoid arthritis, juvenile rheumatoid arthritis, and
osteoarthritis; osteoporosis, soft tissue rheumatism, such as
tendonitis; bursitis; autoimmune disease, such as systemic lupus
and erythematosus; scleroderma; ankylosing spondylitis; gout;
pseudogout; non-insulin dependent diabetes mellitus; polycystic
ovarian disease; hyperlipidemias, such as familial
hypercholesterolemia (FH), familial combined hyperlipidemia (FCH);
lipoprotein lipase deficiencies, such as hypertriglyceridemia,
hypoalphalipoproteinemia, and hypercholesterolemia; lipoprotein
abnormalities associated with diabetes; lipoprotein abnormalities
associated with obesity; and lipoprotein abnormalities associated
with Alzheimer's Disease. The compounds and compositions of the
invention are useful for treatment or prevention of high levels of
blood triglycerides, high levels of low density lipopotein
cholesterol, high levels of apolipoprotein B, high levels of
lipoprotein Lp(a) cholesterol, high levels of very low density
lipoprotein cholesterol, high levels of fibrinogen, high levels of
insulin, high levels of glucose, and low levels of high density
lipoprotein cholesterol. The compounds and compositions of the
invention also have utility for treatment of NIDDM without
increasing weight gain. The sulfoxide and bis-sulfoxide compounds
and compositions of the invention may also be used to reduce the
fat content of meat in livestock and reduce the cholesterol content
of eggs.
[0153] The present invention may be understood more fully by
reference to the detailed description and examples, which are
intended to exemplify non-limiting embodiments of the
invention.
3.1. BRIEF DESCRIPTION OF THE DRAWINGS
[0154] Various aspects of the invention can be understood with
reference to the figures described below:
[0155] FIGS. 1a to 1v illustrates various preferred compounds of
the invention;
[0156] FIG. 2 illustrates the effect of one week of daily oral
gavage treatment on lipoprotein total cholesterol in chow-fed male
Sprague-Dawly rats.
[0157] FIG. 3 illustrates the effect of one week of daily oral
gavage treatment on serum lipids in chow-fed male Sprague-Dawly
rats;
[0158] FIG. 4 illustrates the effect of two weeks of daily oral
gavage treatment on lipoprotein total cholesterol in chow-fed obese
female Zucker rats;
[0159] FIG. 5 is a table illustrating the effect of two weeks of
daily oral gavage treatment using a specific compound of the
invention in chow-fed obese female Zucker rats; and
4. DETAILED DESCRIPTION OF THE INVENTION
[0160] The present invention provides novel compounds useful for
treating or preventing a aging, Alzheimer's Disease, cancer,
cardiovascular disease, diabetic nephropathy, diabetic retinopathy,
a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,
hypertension, impotence, inflammation, insulin resistance, lipid
elimination in bile, modulating C reactive protein, obesity,
oxysterol elimination in bile, pancreatitis, Parkinson's disease, a
peroxisome proliferator activated receptor-associated disorder,
phospholipid elimination in bile, renal disease, septicemia,
metabolic syndrome disorders (e.g., Syndrome X), a thrombotic
disorder, or enhancing bile production, or enhancing reverse lipid
transport, inflammatory processes and diseases like
gastrointestinal disease, irritable bowel syndrome (IBS),
inflammatory bowel disease (e.g., Crohn's Disease, ulcerative
colitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis),
autoimmune disease (e.g., systemic lupus erythematosus),
scleroderma, ankylosing spondylitis, gout and pseudogout, muscle
pain: polymyositis/polymyalgia rheumatica/fibrositis; infection and
arthritis, juvenile rheumatoid arthritis, tendonitis, bursitis and
other soft tissue rheumatism.
[0161] In this regard, the compounds of the invention are
particularly useful when incorporated in a pharmaceutical
composition having a carrier, excipient, diluent, or a mixture
thereof. A composition of the invention need not contain additional
ingredients, such as an excipient, other than a compound of the
invention. Accordingly, in one embodiment, the compositions of the
invention can omit pharmaceutically acceptable excipients and
diluents and can be delivered in a gel cap or drug delivery device.
Accordingly, the present invention provides methods for treating or
preventing aging, Alzheimer's Disease, cancer, cardiovascular
disease, diabetic nephropathy, diabetic retinopathy, a disorder of
glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension,
impotence, inflammation, insulin resistance, lipid elimination in
bile, modulating C reactive protein, obesity, oxysterol elimination
in bile, pancreatitis, Parkinson's disease, a peroxisome
proliferator activated receptor-associated disorder, phospholipid
elimination in bile, renal disease, septicemia, metabolic syndrome
disorders (e.g., Syndrome X), a thrombotic disorder, or enhancing
bile production, or enhancing reverse lipid transport, inflammatory
processes and diseases like gastrointestinal disease, irritable
bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's
Disease, ulcerative colitis), arthritis (e.g., rheumatoid
arthritis, osteoarthritis), autoimmune disease (e.g., systemic
lupus erythematosus), scleroderma, ankylosing spondylitis, gout and
pseudogout, muscle pain: polymyositis/polymyalgia
rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue rheumatism,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound or composition of
the invention.
[0162] In certain embodiments of the invention, a compound of the
invention is administered in combination with another therapeutic
agent. The other therapeutic agent provides additive or synergistic
value relative to the administration of a compound of the invention
alone. The therapeutic agent can be a lovastatin; a
thiazolidinedione or fibrate; a bile-acid-binding-resin; a niacin;
an anti-obesity drug; a hormone; a tyrophostine; a
sulfonylurea-based drug; a biguanide; an a-glucosidase inhibitor;
an apolipoprotein A-I agonist; apolipoprotein E; a cardiovascular
drug; an HDL-raising drug; an HDL enhancer; or a regulator of the
apolipoprotein A-I, apolipoprotein A-IV and/or apolipoprotein
genes.
4.1. Definitions and Abbreviations
[0163] Apo(a): apolipoprotein(a) [0164] Apo A-I: apolipoprotein A-I
[0165] Apo B: apolipoprotein B [0166] Apo E: apolipoprotein E
[0167] FH: Familial hypercholesterolemia [0168] FCH: Familial
combined hyperlipidemia [0169] GDM: Gestational diabetes mellitus
[0170] HDL: High density lipoprotein [0171] IDL: Intermediate
density lipoprotein [0172] IDDM: Insulin dependent diabetes
mellitus [0173] LDH: Lactate dehdyrogenase [0174] LDL: Low density
lipoprotein [0175] Lp(a): Lipoprotein (a) [0176] MODY: Maturity
onset diabetes of the young [0177] NIDDM: Non-insulin dependent
diabetes mellitus [0178] PPAR: Peroxisome proliferator activated
receptor [0179] RXR: Retinoid X receptor [0180] VLDL: Very low
density lipoprotein
[0181] The term "compound A" means the compound
1,13-dihydroxy-2,2,12,12-tetramethyl-tridecan-7-one having the
structure: ##STR457##
1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecan-7-one
[0182] The compounds of the invention can contain one or more
chiral centers and/or double bonds and, therefore, exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers, or diastereomers. According to the
invention, the chemical structures depicted herein, and therefore
the compounds of the invention, encompass all of the corresponding
compound's enantiomers and stereoisomers, that is, both the
stereomerically pure form (e.g., geometrically pure,
enantiomerically pure, or diastereomerically pure) and enantiomeric
and stereoisomeric mixtures.
[0183] A compound of the invention is considered optically active
or enantiomerically pure (i.e., substantially the R-form or
substantially the S-form) with respect to a chiral center when the
compound is about 90% ee (enantiomeric excess) or greater,
preferably, equal to or greater than 95% ee with respect to a
particular chiral center. A compound of the invention is considered
to be in enantiomerically-enriched form when the compound has an
enantiomeric excess of greater than about 1% ee, preferably greater
than about 5% ee, more preferably, greater than about 10% ee with
respect to a particular chiral center. A compound of the invention
is considered diastereomerically pure with respect to multiple
chiral centers when the compound is about 90% de (diastereomeric
excess) or greater, preferably, equal to or greater than 95% de
with respect to a particular chiral center. A compound of the
invention is considered to be in diastereomerically-enriched form
when the compound has an diastereomeric excess of greater than
about 1% de, preferably greater than about 5% de, more preferably,
greater than about 10% de with respect to a particular chiral
center. As used herein, a racemic mixture means about 50% of one
enantiomer and about 50% of is corresponding enantiomer relative to
all chiral centers in the molecule. Thus, the invention encompasses
all enantiomerically-pure, enantiomerically-enriched,
diastereomerically pure, diastereomerically enriched, and racemic
mixtures of compounds of Formulas I through III.
[0184] Enantiomeric and diastereomeric mixtures can be resolved
into their component enantiomers or stereoisomers by well known
methods, such as chiral-phase gas chromatography, chiral-phase high
performance liquid chromatography, crystallizing the compound as a
chiral salt complex, or crystallizing the compound in a chiral
solvent. Enantiomers and diastereomers can also be obtained from
diastereomerically- or enantiomerically-pure intermediates,
reagents, and catalysts by well known asymmetric synthetic
methods.
[0185] The compounds of the invention are defined herein by their
chemical structures and/or chemical names. Where a compound is
referred to by both a chemical structure and a chemical name, and
the chemical structure and chemical name conflict, the chemical
structure is determinative of the compound's identity.
[0186] When administered to a patient, e.g., to an animal for
veterinary use or for improvement of livestock, or to a human for
clinical use, the compounds of the invention are administered in
isolated form or as the isolated form in a pharmaceutical
composition. As used herein, "isolated" means that the compounds of
the invention are separated from other components of either (a) a
natural source, such as a plant or cell, preferably bacterial
culture, or (b) a synthetic organic chemical reaction mixture.
Preferably, via conventional techniques, the compounds of the
invention are purified. As used herein, "purified" means that when
isolated, the isolate contains at least 95%, preferably at least
98%, of a single ether compound of the invention by weight of the
isolate.
[0187] The phrase "pharmaceutically acceptable salt(s)," as used
herein includes, but are not limited to, salts of acidic or basic
groups that may be present in the compounds of the invention.
Compounds that are basic in nature are capable of forming a wide
variety of salts with various inorganic and organic acids. The
acids that may be used to prepare pharmaceutically acceptable acid
addition salts of such basic compounds are those that form
non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, including but not limited to
sulfuric, citric, maleic, acetic, oxalic, hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate,
acid phosphate, isonicotinate, acetate, lactate, salicylate,
citrate, acid citrate, tartrate, oleate, tannate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate))salts. Compounds of the
invention that include an amino moiety also can form
pharmaceutically acceptable salts with various amino acids, in
addition to the acids mentioned above. Compounds of the invention
that are acidic in nature are capable of forming base salts with
various pharmacologically acceptable cations. Examples of such
salts include alkali metal or alkaline earth metal salts and,
particularly, calcium, magnesium, sodium lithium, zinc, potassium,
and iron salts.
[0188] As used herein, the term "solvate" means a compound of the
invention or a salt thereof, that further includes a stoichiometric
or non-stoichiometric amount of a solvent bound by non-covalent
intermolecular forces. Preferred solvents are volatile, non-toxic,
and/or acceptable for administration to humans in trace
amounts.
[0189] As used herein, the term "hydrate" means a compound of the
invention or a salt thereof, that further includes a stoichiometric
or non-stoichiometric amount of water bound by non-covalent
intermolecular forces.
[0190] As used herein, the term "clathrate" means a compound of the
invention or a salt thereof in the form of a crystal lattice that
contains spaces (e.g., channels) that have a guest molecule (e.g.,
a solvent or water) trapped within.
[0191] "Altering lipid metabolism" indicates an observable
(measurable) change in at least one aspect of lipid metabolism,
including but not limited to total blood lipid content, blood HDL
cholesterol, blood LDL cholesterol, blood VLDL cholesterol, blood
triglyceride, blood Lp(a), blood apo A-I, blood apo E and blood
non-esterified fatty acids.
[0192] "Altering glucose metabolism" indicates an observable
(measurable) change in at least one aspect of glucose metabolism,
including but not limited to total blood glucose content, blood
insulin, the blood insulin to blood glucose ratio, insulin
sensitivity, and oxygen consumption.
[0193] As used herein, the term "alkyl group" means a saturated,
monovalent unbranched or branched hydrocarbon chain. Examples of
alkyl groups include, but are not limited to,
(C.sub.1-C.sub.6)alkyl groups, such as methyl, ethyl, propyl,
isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,
2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-3-methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,
isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and
longer alkyl groups, such as heptyl, and octyl. An alkyl group can
be unsubstituted or substituted with one or two suitable
substituents.
[0194] An "alkenyl group" means a monovalent unbranched or branched
hydrocarbon chain having one or more double bonds therein. The
double bond of an alkenyl group can be unconjugated or conjugated
to another unsaturated group. Suitable alkenyl groups include, but
are not limited to (C.sub.2-C.sub.6)alkenyl groups, such as vinyl,
allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,
hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,
4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be
unsubstituted or substituted with one or two suitable
substituents.
[0195] An "alkynyl group" means monovalent unbranched or branched
hydrocarbon chain having one or more triple bonds therein. The
triple bond of an alkynyl group can be unconjugated or conjugated
to another unsaturated group. Suitable alkynyl groups include, but
are not limited to, (C.sub.2-C.sub.6)alkynyl groups, such as
ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-I-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An
alkynyl group can be unsubstituted or substituted with one or two
suitable substituents.
[0196] An "aryl group" means a monocyclic or polycyclic-aromatic
radical comprising carbon and hydrogen atoms. Examples of suitable
aryl groups include, but are not limited to, phenyl, tolyl,
anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as
benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or
substituted with one or two suitable substituents. Preferably, the
aryl group is a monocyclic ring, wherein the ring comprises 6
carbon atoms, referred to herein as "(C.sub.6)aryl".
[0197] A "heteroaryl group" means a monocyclic- or polycyclic
aromatic ring comprising carbon atoms, hydrogen atoms, and one or
more heteroatoms, preferably 1 to 3 heteroatoms, independently
selected from nitrogen, oxygen, and sulfur. Illustrative examples
of heteroaryl groups include, but are not limited to, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl,
imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl,
tetrazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, furyl,
phenyl, isoxazolyl, and oxazolyl. A heteroaryl group can be
unsubstituted or substituted with one or two suitable substituents.
Preferably, a heteroaryl group is a monocyclic ring, wherein the
ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred
to herein as "(C.sub.2-C.sub.5)heteroaryl".
[0198] A "cycloalkyl group" means a monocyclic or polycyclic
saturated ring comprising carbon and hydrogen atoms and having no
carbon-carbon multiple bonds. Examples of cycloalkyl groups
include, but are not limited to, (C.sub.3-C.sub.7)cycloalkyl
groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cycloheptyl, and saturated cyclic and bicyclic terpenes. A
cycloalkyl group can be unsubstituted or substituted by one or two
suitable substituents. Preferably, the cycloalkyl group is a
monocyclic ring or bicyclic ring.
[0199] A "heterocycloalkyl group" means a monocyclic or polycyclic
ring comprising carbon and hydrogen atoms and at least one
heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen,
oxygen, and sulfur, and having no unsaturation. Examples of
heterocycloalkyl groups include pyrrolidinyl, pyrrolidino,
piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl,
morpholino, thiomorpholinyl, thiomorpholino, and pyranyl. A
heterocycloalkyl group can be unsubstituted or substituted with one
or two suitable substituents. Preferably, the heterocycloalkyl
group is a monocyclic or bicyclic ring, more preferably, a
monocyclic ring, wherein the ring comprises from 3 to 6 carbon
atoms and form 1 to 3 heteroatoms, referred to herein as
(C.sub.1-.sub.6)heterocycloalkyl.
[0200] As used herein a "heterocyclic radical" or "heterocyclic
ring" means a heterocycloalkyl group or a heteroaryl group.
[0201] The term "alkoxy group" means an --O-alkyl group, wherein
alkyl is as defined above. An alkoxy group can be unsubstituted or
substituted with one or two suitable substituents. Preferably, the
alkyl chain of an alkyloxy group is from 1 to 6 carbon atoms in
length, referred to herein as "(C.sub.1-C.sub.6)alkoxy".
[0202] The term "aryloxy group" means an --O-aryl group, wherein
aryl is as defined above. An aryloxy group can be unsubstituted or
substituted with one or two suitable substituents. Preferably, the
aryl ring of an aryloxy group is a monocyclic ring, wherein the
ring comprises 6 carbon atoms, referred to herein as
"(C.sub.6)aryloxy".
[0203] The term "benzyl" means --CH.sub.2-phenyl.
[0204] The term "phenyl" means --C.sub.6H.sub.5. A phenyl group can
be unsubstituted or substituted with one or two suitable
substituents.
[0205] A "hydrocarbyl" group means a monovalent group selected from
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, and
(C.sub.2-C.sub.8)alkynyl, optionally substituted with one or two
suitable substituents. Preferably, the hydrocarbon chain of a
hydrocarbyl group is from 1 to 6 carbon atoms in length, referred
to herein as "(C.sub.1-C.sub.6)hydrocarbyl".
[0206] A "carbonyl" group is a divalent group of the formula
--C(O)--.
[0207] An "alkoxycarbonyl" group means a monovalent group of the
formula --C(O)-- alkoxy. Preferably, the hydrocarbon chain of an
alkoxycarbonyl group is from 1 to 8 carbon atoms in length,
referred to herein as a "lower alkoxycarbonyl" group.
[0208] A "carbamoyl" group means the radical --C(O)N(R').sub.2,
wherein R' is chosen from the group consisting of hydrogen, alkyl,
and aryl.
[0209] As used herein, "halogen" means fluorine, chlorine, bromine,
or iodine. Correspondingly, the meaning of the terms "halo" and
"Hal" encompass fluoro, chloro, bromo, and iodo.
[0210] As used herein, a "suitable substituent" means a group that
does not nullify the synthetic or pharmaceutical utility of the
compounds of the invention or the intermediates useful for
preparing them. Examples of suitable substituents include, but are
not limited to: (C.sub.1-C.sub.8)alkyl; (C.sub.1-C.sub.8)alkenyl;
(C.sub.1-C.sub.8)alkynyl; (C.sub.6)aryl;
(C.sub.2-C.sub.5)heteroaryl; (C.sub.3-C.sub.7)cycloalkyl;
(C.sub.1-C.sub.8)alkoxy; (C.sub.6)aryloxy; --CN; --OH; oxo; halo,
--CO.sub.2H; --NH.sub.2; --NH((C.sub.1-C.sub.8)alkyl);
--N((C.sub.1-C.sub.8)alkyl).sub.2; --NH((C.sub.6)aryl);
--N((C.sub.6)aryl).sub.2; --CHO; --CO((C.sub.1-C.sub.8)alkyl);
--CO((C.sub.6)aryl); --CO.sub.2((C.sub.1-C.sub.8)alkyl); and
--CO.sub.2((C.sub.6)aryl). One of skill in the art can readily
choose a suitable substituent based on the stability and
pharmacological and synthetic activity of the compound of the
invention.
4.2. Synthesis of the Compounds of the Invention
[0211] The compounds of the invention can be obtained via the
synthetic methodology illustrated in Schemes 1-8. Starting
materials useful for preparing the compounds of the invention and
intermediates thereof, are commercially available or can be
prepared from commercially available materials using known
synthetic methods and reagents. ##STR458##
[0212] Scheme 1 illustrates the synthesis of mono-protected diols
of the formula X, wherein n is an integer ranging from 0 to 4 and
R.sup.1 and R.sup.2 are as defined above, and E is a leaving group
as defined below. Scheme 1 first outlines the synthesis of
mono-protected diols X, wherein n is 0, where esters 4 are
successively reacted with a first ((R.sup.1).sub.p-M) then a second
((R.sup.2).sub.p-M) organometallic reagent providing ketones 5 and
alcohols 6, respectively. M is a metal group and p is the metal's
valency value (e.g., the valency of Li is 1 and that of Zn is 2).
Suitable metals include, but are not limited to, Zn, Na, Li, and
--Mg-Hal, wherein Hal is a halide selected from iodo, bromo, or
chloro. Preferably, M is --Mg-Hal, in which case the organometallic
reagents, (R.sup.1).sub.p-Mg-Hal and (R.sup.2).sub.p-Mg-Hal, are
known in the art as a Grignard reagents. Esters 4 are available
commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or can
be prepared by well-known synthetic methods, for example, via
esterification of the appropriate 5-halovaleric acid (commercially
available, e.g., Aldrich Chemical Co., Milwaukee, Wis.). Both
(R.sup.1).sub.p-M and (R.sup.2).sub.p-M are available commercially
(e.g., Aldrich Chemical Co., Milwaukee, Wis.) or can be prepared by
well-known methods (see e.g., Kharasch et al., Grignard Reactions
of Non-Metallic Substances; Prentice-Hall, Englewood Cliffs, N.J.,
pp. 138-528 (1954) and Hartley; Patai, The Chemistry of the
Metal-Carbon Bond, Vol. 4, Wiley: New York, pp. 159-306 and pp.
162-175 (1989), both citations are hereby expressly incorporated
herein by reference). The reaction of a first ((R.sup.1)).sub.p-M)
then a second ((R.sup.2).sub.p-M) organometallic reagent with
esters 4 can be performed using the general procedures referenced
in March, J. Advanced Organic Chemistry; Reactions Mechanisms, and
Structure, 4th ed., 1992, pp. 920-929 and Eicher, Patai, The
Chemistry of the Carbonyl Group, pt. 1, pp. 621-693; Wiley: New
York, (1966), hereby expressly incorporated herein by reference.
For example, the synthetic procedure described in Comins et al.,
1981, Tetrahedron Lett. 22:1085, hereby expressly incorporated
herein by reference, can be used. As one example, the reaction can
be performed by adding an organic solution of (R.sup.1).sub.p-M
(about 0.5 to about 1 equivalents) to a stirred, cooled (about
0.degree. C. to about -80.degree. C.) solution comprising esters 4,
under an inert atmosphere (e.g., nitrogen) to give a reaction
mixture comprising ketones 5. Preferably, (R.sup.1).sub.p-M is
added at a rate such that the reaction-mixture temperature remains
within about one to two degrees of the initial reaction-mixture
temperature. The progress of the reaction can be followed by using
an appropriate analytical method, such as thin-layer chromatography
or high-performance-liquid chromatography. Next, an organic
solution of (R.sup.2).sub.p-M (about 0.5 to about 1 equivalent) is
added to the reaction mixture comprising ketones 5 in the same
manner used to add (R.sup.1).sub.p-M. After the reaction providing
alcohols 6 is substantially complete, the reaction mixture can be
quenched and the product can be isolated by workup. Suitable
solvents for obtaining alcohols 6 include, but are not limited to,
dichloromethane, diethyl ether, tetrahydrofuran, benzene, toluene,
xylene, hydrocarbon solvents (e.g., pentane, hexane, and heptane),
and mixtures thereof. Preferably, the organic solvent is diethyl
ether or tetrahydrofuran. Next, alcohols 6 are converted to
mono-protected diols X, wherein n is 0, using the well-known
Williamson ether synthesis. This involves reacting alcohols 6 with
--O--PG, wherein --PG is a hydroxy-protecting group. For a general
discussion of the Williamson ether synthesis, See March, J.
Advanced Organic Chemistry; Reactions Mechanisms, and Structure,
4th ed., 1992, pp. 386-387, and for a list of procedures and
reagents useful in the Williamson ether synthesis, See, for
example, Larock Comprehensive Organic Transformations; VCH: New
York, 1989, pp. 446-448, both of which references are incorporated
herein by reference. As used herein, a "hydroxy-protecting group"
means a group that is reversibly attached to a hydroxy moiety that
renders the hydroxy moiety unreactive during a subsequent
reaction(s) and that can be selectively cleaved to regenerate the
hydroxy moiety once its protecting purpose has been served.
Examples of hydroxy-protecting groups are found in Greene, T. W.,
Protective Groups in Organic Synthesis, 3rd edition 17-237 (1999),
hereby expressly incorporated herein by reference. Preferably, the
hydroxy-protecting group is stable in a basic reaction medium, but
can be cleaved by acid. Examples of suitable base-stable
acid-labile hydroxy-protecting groups suitable for use with the
invention include, but are not limited to, ethers, such as methyl,
methoxy methyl, methylthiomethyl, methoxyethoxymethyl,
bis(2-chloroethoxy)methyl, tetrahydropyranyl,
tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl,
1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl,
o-nitrobenzyl, triphenylmethyl, .alpha.-naphthyldiphenylmethyl,
p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,
trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, tribenzylsilyl, and triisopropylsilyl; and
esters, such as pivaloate, adamantoate, and
2,4,6-trimethylbenzoate. Ethers are preferred, particularly
straight chain ethers, such as methyl ether, methoxymethyl ether,
methylthiomethyl ether, methoxyethoxymethyl ether,
bis(2-chloroethoxy)methyl ether. Preferably --PG is methoxymethyl
(CH.sub.3OCH.sub.2--). Reaction of alcohols 6 with --O--PG under
the conditions of the Williamson ether synthesis involves adding a
base to a stirred organic solution comprising HO--PG (e.g.,
methoxymethanol), maintained at a constant temperature within the
range of about 0.degree. C. to about 80.degree. C., preferably at
about room temperature. Preferably, the base is added at a rate
such that the reaction-mixture temperature remains within about one
to two degrees of the initial reaction-mixture temperature. The
base can be added as an organic solution or in undiluted form.
Preferably, the base will have a base strength sufficient to
deprotonate a proton, wherein the proton has a pK.sub.a of greater
than about 15, preferably greater than about 20. As is well known
in the art, the pK.sub.a is a measure of the acidity of an acid
H-A, according to the equation pK.sub.a=-log K.sub.a, wherein
K.sub.a is the equilibrium constant for the proton transfer. The
acidity of an acid H-A is proportional to the stability of its
conjugate base -A. For tables listing pK.sub.a values for various
organic acids and a discussion on pK.sub.a measurement, see March,
J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure,
4th ed., 1992, pp. 248-272, incorporated herein by reference.
Suitable bases include, but are not limited to, alkylmetal bases
such as methyllithium, n-butyllithium, tert-butyllithium,
sec-butyllithium, phenyllithium, phenyl sodium, and phenyl
potassium; metal amide bases such as lithium amide, sodium amide,
potassium amide, lithium tetramethylpiperidide, lithium
diisopropylamide, lithium diethylamide, lithium dicyclohexylamide,
sodium hexamethyldisilazide, and lithium hexamethyldisilazide; and
hydride bases such as sodium hydride and potassium hydride. The
preferred base is lithium diisopropylamide. Solvents suitable for
reacting alcohols 6 with --OPG include, but are not limited, to
dimethyl sulfoxide, dichloromethane, ethers, and mixtures thereof,
preferably tetrahydrofuran. After addition of the base, the
reaction mixture can be adjusted to within a temperature range of
about 0.degree. C. to about room temperature and alcohols 6 can be
added, preferably at a rate such that the reaction-mixture
temperature remains within about one to two degrees of the initial
reaction-mixture temperature. Alcohols 6 can be diluted in an
organic solvent or added in their undiluted form. The resulting
reaction mixture is stirred until the reaction is substantially
complete as determined by using an appropriate analytical method,
preferably by gas chromatography, then the mono-protected diols X
can be isolated by workup and purification.
[0213] Next, Scheme 1 outlines a method useful for synthesizing
mono-protected diols X, wherein n is 1. First, compounds 7, wherein
E is a suitable leaving group, are reacted with compounds 8,
wherein R.sup.1 and R.sup.2 are as defined above and R.sup.8 is H,
(C.sub.1-C.sub.6)alkyl or (C.sub.6)aryl, providing compounds 9.
Suitable leaving groups are well known in the art, for example, but
not limited to halides, such as chloride, bromide, and iodide;
aryl- or alkylsulfonyloxy, substituted arylsulfonyloxy (e.g.,
tosyloxy or mesyloxy); substituted alkylsulfonyloxy (e.g.,
haloalkylsulfonyloxy); (C.sub.6)aryloxy or subsituted
(C.sub.6)aryloxy; and acyloxy groups. Compounds 7 are available
commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or can
be prepared by well-known methods such as halogenation or
sulfonation of butanediol. Compounds 8 are also available
commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or by
well-known methods, such as those listed in Larock Comprehensive
Organic Transformations; Wiley-VCH: New York, 1999, pp. 1754-1755
and 1765. A review on alkylation of esters of type 8 is given by J.
Mulzer in Comprehensive Organic Functional Transformations,
Pergamon, Oxford 1995, pp. 148-151 and exemplary synthetic
procedures for reacting compounds 7 with compounds 8 are described
in U.S. Pat. No. 5,648,387, column 6 and Ackerly, et al., J. Med.
Chem. 1995, pp. 1608, all of which citations are hereby expressly
incorporated herein by reference. The reaction requires the
presence of a suitable base. Preferably, a suitable base will have
a pK.sub.a of greater than about 25, more preferably greater than
about 30. Suitable bases include, but are not limited to,
alkylmetal bases such as methyllithium, n-butyllithium,
tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium,
and phenyl potassium; metal amide bases such as lithium amide,
sodium amide, potassium amide, lithium tetramethylpiperidide,
lithium diisopropylamide, lithium diethylamide, lithium
dicyclohexylamide, sodium hexamethyldisilazide, and lithium
hexamethyldisilazide; hydride bases such as sodium hydride and
potassium hydride. Metal amide bases, such as lithium
diisopropylamide are preferred. Preferably, to react compounds 7
with compounds 8, a solution of about 1 to about 2 equivalents of a
suitable base is added to a stirred solution comprising esters 8
and a suitable organic solvent, under an inert atmosphere, the
solution maintained at a constant temperature within the range of
about -95.degree. C. to about room temperature, preferably at about
-78.degree. C. to about -20.degree. C. Preferably, the base is
diluted in a suitable organic solvent before addition. Preferably,
the base is added at a rate of about 1.5 moles per hour. Organic
solvents suitable for the reaction of compounds 7 with the
compounds 8 include, but are not limited to, dichloromethane,
diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl
sulfoxide, benzene, toluene, xylene, hydrocarbon solvents (e.g.,
pentane, hexane, and heptane), and mixtures thereof. After addition
of the base, the reaction mixture is allowed to stir for about 1 to
about 2 hours, and a compound 7, preferably dissolved in a suitable
organic solvent, is added, preferably at a rate such that the
reaction-mixture temperature remains within about one to two
degrees of the initial reaction-mixture temperature. After addition
of compounds 7, the reaction-mixture temperature can be adjusted to
within a temperature range of about -20.degree. C. to about room
temperature, preferably to about room temperature, and the reaction
mixture is allowed to stir until the reaction is substantially
complete as determined by using an appropriated analytical method,
preferably thin-layer chromatography or high-performance liquid
chromatography. Then the reaction mixture is quenched and compounds
9, wherein n is 1 can be isolated by workup. Compounds 10 are then
synthesized by reacting compounds 9 with --O--PG according to the
protocol described above for reacting alcohols 6 with --O--PG.
Next, compounds 10 can be converted to mono-protected diols X,
wherein n is 1, by reduction of the ester group of compounds 10 to
an alcohol group with a suitable reducing agent. A wide variety of
reagents are available for reduction of such esters to alcohols,
e.g., see M. Hudlicky, Reductions in Organic Chemistry, 2nd ed.,
1996 pp. 212-217, hereby expressly incorporated herein by
reference. Preferably, the reduction is effected with a hydride
type reducing agent, for example, lithium aluminum hydride, lithium
borohydride, lithium triethyl borohydride, diisobutylaluminum
hydride, lithium trimethoxyaluminum hydride, or sodium
bis(2-methoxy)aluminum hydride. For exemplary procedures for
reducing esters to alcohols, see Nystrom et al., 1947, J. Am. Chem.
Soc. 69:1197; and Moffet et al., 1963, Org. Synth., Collect.
834(4), lithium aluminum hydride; Brown et al., 1965, J. Am. Chem.
Soc. 87:5614, lithium trimethoxyaluminum hydride; Cerny et al.,
1969, Collect. Czech. Chem. Commun. 34:1025, sodium
bis(2-methoxy)aluminum hydride; Nystrom et al., 1949, J. Am. Chem.
71:245, lithium borohydride; and Brown et al., 1980, J. Org. Chem.
45:1, lithium triethyl borohydride, all of which citations are
hereby expressly incorporated herein by reference. Preferably, the
reduction is conducted by adding an organic solution of compounds
10 to a stirred mixture comprising a reducing agent, preferably
lithium aluminum hydride, and an organic solvent. During the
addition, the reaction mixture is maintained at a constant
temperature within the range of about -20.degree. C. to about
80.degree. C., preferably at about room temperature. Organic
solvents suitable for reacting 9 with --OPG include, but are not
limited to, dichloromethane, diethyl ether, tetrahydrofuran or
mixtures thereof, preferably tetrahydrofuran. After the addition,
the reaction mixture is stirred at a constant temperature within
the range of about room temperature to about 60.degree. C., until
the reaction is substantially complete as determined by using an
appropriate analytical method, preferably thin-layer chromatography
or high-performance-liquid chromatography. Then the reaction
mixture can be quenched and mono-protected diols X, wherein n is 1,
can be isolated by workup and purification.
[0214] Scheme 1 next illustrates a three step synthetic sequence
for homologating mono-protected diols X comprising: (a)
halogenation (converting --CH.sub.2OH to --CH.sub.2-Hal); (b)
carbonylation (replacing -Hal with --CHO); and (c) reduction
(converting --CHO to --CH.sub.2OH), wherein a reaction sequence of
(a), (b), and (c) increases the value of n by 1. In step (a)
protected halo-alcohols 11, wherein Hal is a halide selected from
the group of chloro, bromo, or iodo, preferably iodo, can be
prepared by halogenating mono-protected diols X, by using
well-known methods (for a discussion of various methods for
conversion of alcohols to halides see March, J. Advanced Organic
Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp.
431-433, hereby expressly incorporated herein by reference). For
example, protected iodo-alcohols 11 can be synthesized starting
from mono-protected diols X by treatment with
Ph.sub.3/I.sub.2/imidazole (Garegg et al., 1980, J.C.S Perkin I
2866); 1,2-dipheneylene phosphorochloridite/I.sub.2 (Corey et al.,
1967, J. Org. Chem. 82:4160); or preferably with Me.sub.3SiCl/NaI
(Olah et al., 1979, J. Org. Chem. 44:8, 1247), all of which
citations are hereby expressly incorporated herein by reference.
Step (b); carbonylation of alkyl halides, such as protected
halo-alcohols 11, is reviewed in Olah et al., 1987, Chem Rev. 87:4,
671; and March, J., Advanced Organic Chemistry; Reactions
Mechanisms, and Structure, 4th ed., 1992, pp. 483-484, both of
which are hereby expressly incorporated herein by reference).
Protected halo-alcohols 11 can be carbonylated with
Li(BF.sub.3.Et.sub.2O)/HCONMe.sub.2 using the procedure described
in Maddaford et al., 1993, J. Org. Chem. 58:4132; Becker et al.,
1982, J. Org. Chem. 3297; or Myers et al., 1992, J. Am. Chem. Soc.
114:9369 or, alternatively, with an
organometallic/N-formylmorpholine using the procedure described in
Olah et al., 1984, J. Org. Chem. 49:3856 or Vogtle et al., 1987, J.
Org. Chem. 52:5560, all of which citations are hereby expressly
incorporated herein by reference. The method described in Olah et
al., 1984, J. Org. Chem. 49:3856 is preferred. Reduction step (c)
useful for synthesizing mono-protected diols X from aldehydes 12,
can be accomplished by well-known methods in the art for reduction
of aldehydes to the corresponding alcohols (for a discussion see M.
Hudlicky, Reductions in Organic Chemistry, 2nd ed., 1996 pp
137-139), for example, by catalytic hydrogenation (see e.g.,
Carothers, 1949, J. Am. Chem. Soc. 46:1675) or, preferably by
reacting aldehydes 12 with a hydride reducing agent, such as
lithium aluminum hydride, lithium borohydride, sodium borohydride
(see e.g., the procedures described in Chaikin et al., 1949, J. Am.
Chem. Soc. 71:3245; Nystrom et al., 1947, J. Am. Chem. Soc.
69:1197; and Nystrom et al., 1949, J. Am. Chem. 71:3245, all of
which are hereby expressly incorporated herein by reference).
Reduction with lithium aluminum hydride is preferred.
##STR459##
[0215] Scheme 2 outlines the method for the synthesis of protected
alcohols 12a wherein Y, R.sup.1, R.sup.2, Z, and m are defined as
above. Protected alcohols 12a correspond to compounds of the
formula W.sup.(1)(2)Zm-OPG, wherein W.sup.(1)(2)-is
C(R.sup.1)(R.sup.2)--Y.
[0216] Protected alcohols 16, wherein Y comprises a --C(O)OH group,
can be synthesized by oxidizing mono-protected diols X with an
agent suitable for oxidizing a primary alcohol to a carboxylic acid
(for a discussion see M. Hudlicky, Oxidations in Organic Chemistry,
ACS Monograph 186, 1990, pp. 127-130, hereby expressly incorporated
herein by reference). Suitable oxidizing agents include, but are
not limited to, pyridinium dichromate (Corey et al., 1979,
Tetrahedron Lett. 399); manganese dioxide (Ahrens et al., 1967, J.
Heterocycl. Chem. 4:625); sodium permanganate monohydrate (Menger
et al., 1981, Tetrahedron Lett. 22:1655); and potassium
permanganate (Sam et al., 1972, J. Am. Chem. Soc. 94:4024), all of
which citations are hereby expressly incorporated herein by
reference. The preferred oxidizing reagent is pyridinium
dichromate. In an alternative synthetic procedure, protected
alcohols 16, wherein Y comprises a --C(O)OH group, can be
synthesized by treatment of protected halo-alcohols 15, wherein X
is iodo, with CO or CO.sub.2, as described in Bailey et al., 1990,
J. Org. Chem. 55:5404 and Yanagisawa et al., 1994, J. Am. Chem.
Soc. 116:6130, the two of which citations are hereby expressly
incorporated herein by reference. Protected alcohols 16, wherein Y
comprises --C(O)OR.sup.5, wherein R.sup.5 is as defined above, can
be synthesized by oxidation of mono-protected diols X in the
presence of R.sup.5OH (see generally, March, J. Advanced Organic
Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p.
1196). An exemplary procedure for such an oxidation is described in
Stevens et al., 1982, Tetrahedron Lett. 23:4647 (HOCl);
Sundararaman et al., 1978, Tetrahedron Lett. 1627 (O.sub.3/KOH);
Wilson et al., 1982, J. Org. Chem. 47:1360 (t-BuOOH/Et.sub.3N); and
Williams et al., 1988, Tetrahedron Lett. 29:5087 (Br.sub.2), the
four of which citations are hereby expressly incorporated herein by
reference. Preferably, protected alcohols 16, wherein Y comprises a
--C(O)OR.sup.5 group are synthesized from the corresponding
carboxylic acid (i.e., 16, wherein Y comprises --C(O)OH) by
esterification with R.sup.5OH (e.g., see March, J., Advanced
Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed.,
1992, p. 393-394, hereby expressly incorporated herein by
reference). In another alternative synthesis, protected alcohols
16, wherein Y comprises --C(O)OR.sup.5, can be prepared from
protected halo-alcohols 14 by carbonylation with transition metal
complexes (see e.g., March, J. Advanced Organic Chemistry;
Reactions Mechanisms, and Structure, 4th ed., 1992, p. 484-486;
Urata et al., 1991, Tetrahedron Lett. 32:36, 4733); and Ogata et
al., 1969, J. Org. Chem. 3985, the three of which citations are
hereby expressly incorporated herein by reference).
[0217] Protected alcohols 16, wherein Y comprises --OC(O)R.sup.5,
wherein R.sup.5 is as defined above, can be prepared by acylation
of mono-protected diols X with a carboxylate equivalent such as an
acyl halide (i.e., R.sup.5C(O)-Hal, wherein Hal is iodo, bromo, or
chloro, see e.g., March, J. Advanced Organic Chemistry; Reactions
Mechanisms, and Structure, 4th ed., 1992, p. 392 and Org. Synth.
Coll. Vol. III, Wiley, NY, pp. 142, 144, 167, and 187 (1955)) or an
anhydride (i.e., R.sup.5C(O)--O--(O)CR.sup.5, see e.g., March, J.
Advanced Organic Chemistry; Reactions Mechanisms, and Structure,
4th ed., 1992, p. 392-393 and Org. Synth. Coll. Vol. III, Wiley,
NY, pp. 11, 127, 141, 169, 237, 281, 428, 432, 690, and 833 (1955),
all of which citations are hereby expressly incorporated herein by
reference). Preferably, the reaction is conducted by adding a base
to a solution comprising mono-protected diols X, a carboxylate
equivalent, and an organic solvent, which solution is preferably
maintained at a constant temperature within the range of 0.degree.
C. to about room temperature. Solvents suitable for reacting
mono-protected diols X with a carboxylate equivalent include, but
are not limited to, dichloromethane, toluene, and ether, preferably
dichloromethane. Suitable bases include, but are not limited to,
hydroxide sources, such as sodium hydroxide, potassium hydroxide,
sodium carbonate, or potassium carbonate; or an amine such as
triethylamine, pyridine, or dimethylaminopyridine, amines are
preferred. The progress of the reaction can be followed by using an
appropriate analytical technique, such as thin layer chromatography
or high performance liquid chromatography and when substantially
complete, the product can be isolated by workup and purified if
desired.
[0218] Protected alcohols 16, wherein Y comprises one of the
following phosphate ester groups ##STR460## wherein R.sup.6 is
defined as above, can be prepared by phosphorylation of
mono-protected diols X according to well-known methods (for a
general reviews, see Corbridge Phosphorus: An Outline of its
Chemistry, Biochemistry, and Uses, Studies in Inorganic Chemistry,
3rd ed., pp. 357-395 (1985); Ramirez et al., 1978, Acc. Chem. Res.
11:239; and Kalckare Biological Phosphorylations, Prentice-Hall,
New York (1969); J. B. Sweeny in Comprehensive Organic Functional
Group Transformations, A. R. Katritzky, O. Meth-Cohn and C. W.
Rees, Eds. Pergamon: Oxford, 1995, vol 2, pp. 104-109, the four of
which are hereby expressly incorporated herein by reference).
Protected alcohols 16 wherein Y comprises a monophosphate group of
the formula: ##STR461## wherein R.sup.6 is defined as above, can be
prepared by treatment of mono-protected diol X with phosphorous
oxychloride in a suitable solvent, such as xylene or toluene, at a
constant temperature within the range of about 100C to about
150.degree. C. for about 2 hours to about 24 hours. After the
reaction is deemed substantially complete, by using an appropriate
analytical method, the reaction mixture is hydrolyzed with
R.sup.6--OH. Suitable procedures are referenced in Houben-Weyl,
Methoden der Organische Chemie, Georg Thieme Verlag Stuttgart 1964,
vol. XII/2, pp. 143-210 and 872-879, hereby expressly incorporated
herein by reference. Alternatively, when both R.sup.6 are hydrogen,
can be synthesized by reacting mono-protected diols X with silyl
polyphosphate (Okamoto et al., 1985, Bull Chem. Soc. Jpn. 58:3393,
hereby expressly incorporated herein by reference) or by
hydrogenolysis of their benzyl or phenyl esters (Chen et al., 1998,
J. Org. Chem. 63:6511, hereby expressly incorporated herein by
reference). In another alternative procedure, when R.sup.6 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl, the monophosphate esters can be prepared
by reacting mono-protected diols X with appropriately substituted
phophoramidites followed by oxidation of the intermediate with
m-chloroperbenzoic acid (Yu et al., 1988, Tetrahedron Lett. 29:979,
hereby expressly incorporated herein by reference) or by reacting
mono-protected diols X with dialkyl or diaryl substituted
phosphorochloridates (Pop, et al, 1997, Org. Prep. and Proc. Int.
29:341, hereby expressly incorporated herein by reference). The
phosphoramidites are commercially available (e.g., Aldrich Chemical
Co., Milwaukee, Wis.) or readily prepared according to literature
procedures (see e.g., Uhlmann et al. 1986, Tetrahedron Lett.
27:1023 and Tanaka et al., 1988, Tetrahedron Lett. 29:199, both of
which are hereby expressly incorporated herein by reference). The
phosphorochloridates are also commercially available (e.g., Aldrich
Chemical Co., Milwaukee, Wis.) or prepared according to literature
methods (e.g., Gajda et al, 1995, Synthesis 25:4099. In still
another alternative synthesis, protected alcohols 16, wherein Y
comprises a monophosphate group and R.sup.6 is alkyl or aryl, can
be prepared by reacting IP.sup.+(OR.sup.6).sub.3 with
mono-protected diols X according to the procedure described in
Stowell et al., 1995, Tetrahedron Lett. 36:11, 1825 or by
alkylation of protected halo alcohols 14 with the appropriate
dialkyl or diaryl phosphates (see e.g., Okamoto, 1985, Bull Chem.
Soc. Jpn. 58:3393, hereby expressly incorporated herein by
reference).
[0219] Protected alcohols 16 wherein Y comprises a diphosphate
group of the formula ##STR462## wherein R.sup.6 is defined as
above, can be synthesized by reacting the above-discussed
monophosphates of the formula: ##STR463## with a phosphate of the
formula ##STR464## (commercially available, e.g., Aldrich Chemical
Co., Milwaukee, Wis.), in the presence of carbodiimide such as
dicyclohexylcarbodiimide, as described in Houben-Weyl, Methoden der
Organische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XII/2,
pp. 881-885. In the same fashion, protected alcohols 16, wherein Y
comprises a triphosphate group of the formula: ##STR465## can be
synthesized by reacting the above-discussed diphosphate protected
alcohols, of the formula: ##STR466## with a phosphate of the
formula: ##STR467## as described above. Alternatively, when R.sup.6
is H, protected alcohols 16 wherein Y comprises the triphosphate
group, can be prepared by reacting mono-protected diols X with
salicyl phosphorochloridite and then pyrophosphate and subsequent
cleavage of the adduct thus obtained with iodine in pyridine as
described in Ludwig et al., 1989, J. Org. Chem. 54:631, hereby
expressly incorporated herein by reference.
[0220] Protected alcohols 16, wherein Y is --SO.sub.3H or a
heterocyclic group selected from the group consisting of:
##STR468## can be prepared by halide displacement from protected
halo-alcohols 14. Thus, when Y is --SO.sub.3H, protected alcohols
16 can by synthesized by reacting protected halo-alcohols 14 with
sodium sulfite as described in Gilbert Sulfonation and Related
Reactions; Wiley: New York, 1965, pp. 136-148 and pp. 161-163; Org.
Synth. Coll. Vol. I, Wiley, NY, 558, 564 (1943); and Org. Synth.
Coll. Vol. IV, Wiley, NY, 529 (1963), all three of which are hereby
expressly incorporated herein by reference. When Y is one of the
above-mentioned heterocycles, protected alcohols 16 can be prepared
by reacting protected halo-alcohols 14 with the corresponding
heterocycle in the presence of a base. The heterocycles are
available commercially (e.g., Aldrich Chemical Co., Milwaukee,
Wis.) or prepared by well-known synthetic methods (see the
procedures described in Ware, 1950, Chem. Rev. 46:403-470, hereby
expressly incorporated herein by reference). Preferably, the
reaction is conducted by stirring a mixture comprising 14, the
heterocycle, and a solvent at a constant temperature within the
range of about room temperature to about 100.degree. C., preferably
within the range of about 50.degree. C. to about 70.degree. C. for
about 10 to about 48 hours. Suitable bases include hydroxide bases
such as sodium hydroxide, potassium hydroxide, sodium carbonate, or
potassium carbonate. Preferably, the solvent used in forming
protected alcohols 16 is selected from dimethylformamide;
formamide; dimethyl sulfoxide; alcohols, such as methanol or
ethanol; and mixtures thereof. The progress of the reaction can be
followed by using an appropriate analytical technique, such as thin
layer chromatography or high performance liquid chromatography and
when substantially complete, the product can be isolated by workup
and purified if desired.
[0221] Protected alcohols 16, wherein Y is a heteroaryl ring
selected from ##STR469## can be prepared by metallating the
suitable heteroaryl ring then reacting the resulting metallated
heteroaryl ring with protected halo-alcohols 14 (for a review, see
Katritzky Handbook of Heterocyclic Chemistry, Pergamon Press:
Oxford 1985). The heteroaryl rings are available commercially or
prepared by well-known synthetic methods (see e.g., Joule et al.,
Heterocyclic Chemistry, 3rd ed., 1995; De Sarlo et al., 1971, J.
Chem. Soc. (C) 86; Oster et al., 1983, J. Org. Chem. 48:4307; Iwai
et al., 1966, Chem. Pharm. Bull. 14:1277; and U.S. Pat. No.
3,152,148, all of which citations are hereby expressly incorporated
herein by reference). As used herein, the term "metallating" means
the forming of a carbon-metal bond, which bond may be substantially
ionic in character. Metallation can be accomplished by adding about
2 equivalents of strong organometallic base, preferably with a
pK.sub.a of about 25 or more, more preferably with a pK.sub.a of
greater than about 35, to a mixture comprising a suitable organic
solvent and the heterocycle. Two equivalents of base are required:
one equivalent of the base deprotonates the --OH group or the --NH
group, and the second equivalent metallates the heteroaryl ring.
Alternatively, the hydroxy group of the heteroaryl ring can be
protected with a base-stable, acid-labile protecting group as
described in Greene, T. W., Protective Groups in Organic Synthesis,
3rd edition 17-237 (1999), hereby expressly incorporated herein by
reference. Where the hydroxy group is protected, only one
equivalent of base is required. Examples of suitable base-stable,
acid-labile hydroxyl-protecting groups, include but are not limited
to, ethers, such as methyl, methoxy methyl, methylthiomethyl,
methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl,
tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl,
1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl,
o-nitrobenzyl, triphenylmethyl, .alpha.-naphthyldiphenylmethyl,
p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,
trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl; and
esters, such as pivaloate, adamantoate, and
2,4,6-trimethylbenzoate. Ethers are preferred, particularly
straight chain ethers, such as methyl ether, methoxymethyl ether,
methylthiomethyl ether, methoxyethoxymethyl ether,
bis(2-chloroethoxy)methyl ether. Preferably, the pK.sub.a of the
base is higher than the pK.sub.a of the proton of the heterocycle
to be deprotonated. For a listing of pK.sub.as for various
heteroaryl rings, see Fraser et al., 1985, Can. J. Chem. 63:3505,
hereby expressly incorporated herein by reference. Suitable bases
include, but are not limited to, alkylmetal bases such as
methyllithium, n-butyllithium, tert-butyllithium, sec-butyllithium,
phenyllithium, phenyl sodium, and phenyl potassium; metal amide
bases such as lithium amide, sodium amide, potassium amide, lithium
tetramethylpiperidide, lithium diisopropylamide, lithium
diethylamide, lithium dicyclohexylamide, sodium
hexamethyldisilazide, and lithium hexamethyldisilazide; and hydride
bases such as sodium hydride and potassium hydride. If desired, the
organometallic base can be activated with a complexing agent, such
as N,N,N',N'-tetramethylethylenediamine or hexamethylphosphoramide
(1970, J. Am. Chem. Soc. 92:4664, hereby expressly incorporated
herein by reference). Solvents suitable for synthesizing protected
alcohols 16, wherein Y is a heteroaryl ring include, but are not
limited to, diethyl ether; tetrahydrofuran; and hydrocarbons, such
as pentane. Generally, metallation occurs alpha to the heteroatom
due to the inductive effect of the heteroatom, however,
modification of conditions, such as the identity of the base and
solvents, order of reagent addition, reagent addition times, and
reaction and addition temperatures can be modified by one of skill
in the art to achieve the desired metallation position (see e.g.,
Joule et al., Heterocyclic Chemistry, 3rd ed., 1995, pp. 30-42,
hereby expressly incorporated herein by reference) Alternatively,
the position of metallation can be controlled by use of a
halogenated heteroaryl group, wherein the halogen is located on the
position of the heteroaryl ring where metallation is desired (see
e.g., Joule et al., Heterocyclic Chemistry, 3rd ed., 1995, p. 33
and Saulnier et al., 1982, J. Org. Chem. 47:757, the two of which
citations are hereby expressly incorporated herein by reference).
Halogenated heteroaryl groups are available commercially (e.g.,
Aldrich Chemical Co., Milwaukee, Wis.) or can be prepared by
well-known synthetic methods (see e.g., Joule et al., Heterocyclic
Chemistry, 3rd ed., 1995, pp. 78, 85, 122, 193, 234, 261, 280, 308,
hereby expressly incorporated herein by reference). After
metallation, the reaction mixture comprising the metallated
heteroaryl ring is adjusted to within a temperature range of about
0.degree. C. to about room temperature and protected halo-alcohols
14 (diluted with a solvent or in undiluted form) are added,
preferably at a rate such that the reaction-mixture temperature
remains within about one to two degrees of the initial
reaction-mixture temperature. After addition of protected
halo-alcohols 14, the reaction mixture is stirred at a constant
temperature within the range of about room temperature and about
the solvent's boiling temperature and the reaction's progress can
be monitored by the appropriate analytical technique, preferably
thin-layer chromatography or high-performance liquid
chromatography. After the reaction is substantially complete,
protected alcohols 16 can be isolated by workup and purification.
It is to be understood that conditions, such as the identity of
protected halo-alcohol 14, the base, solvents, orders of reagent
addition, times, and temperatures, can be modified by one of skill
in the art to optimize the yield and selectivity. Exemplary
procedures that can be used in such a transformation are described
in Shirley et al., 1995, J. Org. Chem. 20:225; Chadwick et al.,
1979, J. Chem. Soc., Perkin Trans. 1 2845; Rewcastle, 1993, Adv.
Het. Chem. 56:208; Katritzky et al., 1993, Adv. Het. Chem. 56:155;
and Kessar et al., 1997, Chem. Rev. 97:721. When Y is ##STR470##
protected alcohols 16 can be prepared from their corresponding
carboxylic acid derivatives (16, wherein Y is --CO.sub.2H) as
described in Belletire et al, 1988, Synthetic Commun. 18:2063 or
from the corresponding acylchlorides (16, wherein Y is --CO-halo)
as described in Skinner et al., 1995, J. Am. Chem. Soc. 77:5440,
both citations are hereby expressly incorporated herein by
reference. The acylhalides can be prepared from the carboxylic
acids by well known procedures such as those described in March,
J., Advanced Organic Chemistry; Reactions Mechanisms, and
Structure, 4th ed., 1992, pp. 437-438, hereby expressly
incorporated herein by reference. When Y is ##STR471## wherein
R.sup.7 is as defined above, protected alcohols 16 can be prepared
by first reacting protected halo-alcohols 15 with a trialkyl
phosphite according to the procedure described in Kosolapoff, 1951,
Org. React. 6:273 followed by reacting the derived phosphonic
diester with ammonia according to the procedure described in Smith
et al., 1957, J. Org. Chem. 22:265, hereby expressly incorporated
herein by reference. When Y is ##STR472## protected alcohols 16 can
be prepared by reacting their sulphonic acid derivatives (i.e., 16,
wherein Y is --SO.sub.3H ) with ammonia as described in Sianesi et
al., 1971, Chem. Ber. 104:1880 and Campagna et al., 1994, Farmaco,
Ed. Sci. 49:653, both of which citations are hereby expressly
incorporated herein by reference).
[0222] As further illustrated in Scheme 2, protected alcohols 16
can be deprotected providing alcohols 20a. The deprotection method
depends on the identity of the alcohol-protecting group, see e.g.,
the procedures listed in Greene, T. W., Protective Groups in
Organic Synthesis, 3rd edition 17-237 (1999), particularly see
pages 48-49, hereby expressly incorporated herein by reference. One
of skill in the art will readily be able to choose the appropriate
deprotection procedure. When the alcohol is protected as an ether
function (e.g., methoxymethyl ether), the alcohol is preferably
deprotected with aqueous or alcoholic acid. Suitable deprotection
reagents include, but are not limited to, aqueous hydrochloric
acid, p-toluenesulfonic acid in methanol,
pyridinium-p-toluenesulfonate in ethanol, Amberlyst H-15 in
methanol, boric acid in ethylene-glycol-monoethylether, acetic acid
in a water-tetrahydrofuran mixture, aqueous hydrochloric acid is
preferred. Examples of such procedures are described, respectively,
in Bemady et al., 1979, J. Org. Chem. 44:1438; Miyashita et al.,
1977, J. Org. Chem. 42:3772; Johnston et al., 1988, Synthesis 393;
Bongini et al., 1979, Synthesis 618; and Hoyer et al., 1986,
Synthesis 655; Gigg et al., 1967, J. Chem. Soc. C, 431; and Corey
et al., 1978, J. Am. Chem. Soc. 100:1942, all of which are hereby
expressly incorporated herein by reference. ##STR473##
[0223] Scheme 3 depicts the synthesis of protected lactone alcohols
20 and lactone alcohols 13a. Compounds 20 and 13a correspond to
compounds of the formula W.sup.(1)(2)-Zm-OPG and
W.sup.(1)(2)-Z.sub.m-OH respectively, wherein W.sup.(1)(2) is a
lactone group selected from: ##STR474## Protected lactone alcohols
20 can be prepared from compounds of the formula 17, 18, or 19 by
using well-known condensation reactions and variations of the
Michael reaction. Methods for the synthesis of lactones are
disclosed in Multzer in Comprehensive Organic Functional Group
Transformations, A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Eds.
Pergamon: Oxford, 1995, vol 5, pp. 161-173, hereby expressly
incorporated herein by reference. Mono-protected diols 19,
electrophilic protected alcohols 18, and aldehydes 19 are readily
available ether commercially (e.g., Aldrich Chemical Co.,
Milwaukee, Wis.) or by well known synthetic procedures.
[0224] When W.sup.(1)(2) is a beta-lactone group of the formula:
##STR475## protected lactone alcohols 20 can be prepared from
aldehydes 19 and electrophilic protected alcohols 18, respectively,
by a one-pot-addition-lactonization according to the procedure of
Masamune et al., 1976, J. Am. Chem. Soc. 98:7874 and Danheiser et
al., 1991, J. Org. Chem. 56:1176, both of which are hereby
expressly incorporated herein by reference. This
one-pot-addition-lactonization methodology has been reviewed by
Multzer in Comprehensive Organic Functional Group Transformations,
A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Eds. Pergamon:
Oxford, 1995, vol 5, pp. 161, hereby expressly incorporated herein
by reference When W.sup.(1)(2) is a gamma- or delta-lactone group
of the formula: ##STR476## protected lactone alcohols 20 can be
prepared from aldehydes 19 according to well known synthetic
methodology. For example, the methodology described in Masuyama et
al., 2000, J. Org. Chem. 65:494; Eisch et al., 1978, J. Organo.
Met. Chem. C8 160; Eaton et al., 1947, J. Org. Chem. 37:1947;
Yunker et al., 1978, Tetrahedron Lett. 4651; Bhanot et al., 1977,
J. Org. Chem. 42:1623; Ehlinger et al., 1980, J. Am. Chem. Soc.
102:5004; and Raunio et al., 1957, J. Org. Chem. 22:570, all of
which citations are hereby expressly incorporated herein by
reference. For instance, as described in Masuyama et al., 2000, J.
Org. Chem. 65:494, aldehydes 19 can be treated with about 1
equivalent of a strong organometallic base, preferably with a
pK.sub.a of about 25 or more, more preferably with a pK.sub.a of
greater than about 35, in a suitable organic solvent to give a
reaction mixture. Suitable bases include, but are not limited to,
alkylmetal bases such as methyllithium, n-butyllithium,
tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium,
and phenyl potassium; metal amide bases such as lithium amide,
sodium amide, potassium amide, lithium tetramethylpiperidide,
lithium diisopropylamide, lithium diethylamide, lithium
dicyclohexylamide, sodium hexamethyldisilazide, and lithium
hexamethyldisilazide; and hydride bases such as sodium hydride and
potassium hydride, preferably lithium tetramethylpiperidide.
Suitable solvents include, but are not limited to, diethyl ether
and tetrahydrofuran. The reaction-mixture temperature is adjusted
to within the range of about 0.degree. C. to about 100.degree. C.,
preferably about room temperature to about 50.degree. C., and a
halide of the formula: ##STR477## wherein z is 1 or 2 (diluted with
a solvent or in undiluted form) is added. The reaction mixture is
stirred for a period of about 2 hours to about 48 hours, preferably
about 5 to about 10 hours, during which time the reaction's
progress can be followed by using an appropriate analytical
technique, such as thin layer chromatography or high performance
liquid chromatography. When the reaction is deemed substantially
complete, protected lactone alcohols 20 can be isolated by workup
and purified if desired. When W.sup.(1)(2) is a gamma- or
delta-lactone group of the formula: ##STR478## protected lactone
alcohols 20 can be synthesized by deprotonating the corresponding
lactone with a strong base providing the lactone enolate and
reacting the enolate with electrophilic protected alcohols 20 (for
a detailed discussion of enolate formation of active methylene
compounds such as lactones, see House Modern Synthetic Reactions;
W. A. Benjamin, Inc. Philippines 1972 pp. 492-570, and for a
discussion of reaction of lactone enolates with electrophiles such
as carbonyl compounds, see March, J. Advanced Organic Chemistry;
Reactions Mechanisms and Structure, 4th ed., 1992, pp. 944-945,
both of which are hereby expressly incorporated herein by
reference). Lactone-enolate formation can be accomplished by adding
about 1 equivalent of a strong organometallic base, preferably with
a pK.sub.a of about 25 or more, more preferably with a pK.sub.a of
greater than about 35, to a mixture comprising a suitable organic
solvent and the lactone. Suitable bases include, but are not
limited to, alkylmetal bases such as methyllithium, n-butyllithium,
tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium,
and phenyl potassium; metal amide bases such as lithium amide,
sodium amide, potassium amide, lithium tetramethylpiperidide,
lithium diisopropylamide, lithium diethylamide, lithium
dicyclohexylamide, sodium hexamethyldisilazide, and lithium
hexamethyldisilazide; and hydride bases such as sodium hydride and
potassium hydride, preferably lithium tetramethylpiperidide.
Solvents suitable for lactone-enolate formation include, but are
not limited to, diethyl ether and tetrahydrofuran. After enolate
formation, the reaction-mixture temperature is adjusted to within
the range of about -78.degree. C. to about room temperature,
preferably about -50.degree. C. to about 0.degree. C., and
electrophilic protected alcohols 18 (diluted with a solvent or in
undiluted form) are added, preferably at a rate such that the
reaction-mixture temperature remains within about one to two
degrees of the initial reaction-mixture temperature. The reaction
mixture is stirred for a period of about 15 minutes to about 5
hours, during which time the reaction's progress can be followed by
using an appropriate analytical technique, such as thin layer
chromatography or high performance liquid chromatography. When the
reaction is deemed substantially complete, protected lactone
alcohols 20 can be isolated by workup and purified if desired. When
W.sup.(1)(2) is a lactone group of the formula: ##STR479##
protected lactone alcohols 20 can be prepared from aldehydes 19
according to the procedure described in U.S. Pat. No. 4,622,338,
hereby expressly incorporated herein by reference.
[0225] When W.sup.(1)(2) is a gamma- or delta-lactone group of the
formula: ##STR480## protected lactone alcohols 20 can be prepared
according to a three step sequence. The first step comprises
base-mediated reaction of electrophilic protected alcohols 18 with
succinic acid esters (i.e.,
R.sup.9O.sub.2CCH.sub.2CH.sub.2CO.sub.2R.sup.9, wherein R.sup.9 is
alkyl) or glutaric acid esters (i.e.,
R.sup.9O.sub.2CCH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.9, wherein
R.sup.9 is alkyl) providing a diester intermediate of the formula
21: ##STR481## wherein x is 1 or 2 depending on whether the gamma
or delta lactone group is desired. The reaction can be performed by
adding about 1 equivalent of a strong organometallic base,
preferably with a pK.sub.a of about 25 or more, more preferably
with a pK.sub.a of greater than about 35, to a mixture comprising a
suitable organic solvent and the succinic or glutaric acid ester.
Suitable bases include, but are not limited to, alkylmetal bases
such as methyllithium, n-butyllithium, tert-butyllithium,
sec-butyllithium, phenyllithium, phenyl sodium, and phenyl
potassium; metal amide bases such as lithium amide, sodium amide,
potassium amide, lithium tetramethylpiperidide, lithium
diisopropylamide, lithium diethylamide, lithium dicyclohexylamide,
sodium hexamethyldisilazide, and lithium hexamethyldisilazide; and
hydride bases such as sodium hydride and potassium hydride,
preferably lithium tetramethylpiperidide. Suitable solvents
include, but are not limited to, diethyl ether and tetrahydrofuran.
After enolate formation, the reaction-mixture temperature is
adjusted to within the range of about -78.degree. C. to about room
temperature, preferably about -50.degree. C. to about 0.degree. C.,
and electrophilic protected alcohols 18 (diluted with a solvent or
in undiluted form) are added, preferably at a rate such that the
reaction-mixture temperature remains within about one to two
degrees of the initial reaction-mixture temperature. The reaction
mixture is stirred for a period of about 15 minutes to about 5
hours, during which time the reaction's progress can be followed by
using an appropriate analytical technique, such as thin layer
chromatography or high performance liquid chromatography. When the
reaction is deemed substantially complete, the diester intermediate
be isolated by workup and purified if desired. In the second step,
the intermediate diester can be reduced, with a hydride reducing
agent, to yield a diol of the formula 22: ##STR482## The reduction
can be performed according to the procedures referenced in March,
J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure,
4th ed., 1992, p. 1214, hereby expressly incorporated herein by
reference). Suitable reducing agents include, but are not limited
to, lithium aluminum hydride, diisobutylaluminum hydride, sodium
borohydride, and lithium borohydride). In the third step, the diol
can be oxidatively cyclized with RuH.sub.2(PPh.sub.3).sub.4 to the
product protected lactone alcohols 20 according to the procedure of
Yoshikawa et al., 1986, J. Org. Chem. 51:2034 and Yoshikawa et al.,
1983, Tetrahedron Lett. 26:2677, both of which citations are hereby
expressly incorporated herein by reference. When W.sup.(1)(2) is a
lactone group of the formula: ##STR483## protected lactone alcohols
20 can be synthesized by reacting the Grignard salts of
electrophilic protected alcohols 18, where E is a halide, with
5,6-dihydro-2H-pyran-2-one, commercially available (e.g., Aldrich
Chemical Co., Milwaukee, Wis.), in the presence of catalytic
amounts of a
1-dimethylaminoacetyl)pyrolidine-2yl)methyl-diarylphosphine-copper(I)
iodide complex as described in Tomioka et al., 1995, Tetrahedron
Lett. 36:4275, hereby expressly incorporated herein by reference.
##STR484##
[0226] Scheme 4 outlines methodology for the synthesis of protected
alcohols 14. Compounds 14, wherein n is an integer ranging from 1
to 5, can be prepared from compounds 11 using general synthetic
strategy depicted and adapting the synthetic protocols from those
discussed for Scheme 1.
[0227] Next, Scheme 4 depicts the general strategy for the
synthesis of compounds 14 wherein n is 0. First, Esters 27, wherein
R.sup.8 is as defined above, are synthesized by oxidation of
mono-protected diols X in the presence of R.sup.8OH (see generally,
March, J. Advanced Organic Chemistry; Reactions Mechanisms, and
Structure, 4th ed., 1992, p. 1196). An exemplary procedure for such
an oxidation is described in Stevens et al., 1982, Tetrahedron
Lett. 23:4647 (HOCl); Sundararaman et al., 1978, Tetrahedron Lett.
1627 (O.sub.3/KOH); Wilson et al., 1982, J. Org. Chem. 47:1360
(t-BuOOH/Et.sub.3N); and Williams et al., 1988, Tetrahedron Lett.
29:5087 (Br.sub.2), the four of which citations are hereby
expressly incorporated herein by reference. Compounds 28 are
converted to compounds 14 wherein n is 0 by adapting the synthetic
procedures depicted in Scheme 1. ##STR485##
[0228] Scheme 5 outlines methodology for the synthesis of protected
alcohols 29 and alcohols 15a, which correspond to
W.sup.(1)(2)-Z.sub.m-OPG and W.sup.(1)(2)-Z.sub.m-OH, respectively,
wherein W.sup.(1)(2) is
C(R.sup.1)(R.sup.2)--(CH.sub.2).sub.cC(R.sup.3)(R.sup.4)--Y. The
synthesis of starting materials 14, 26, and 28 are depicted in
Scheme 4 and the synthetic methods and procedures can be adapted
from those described for Scheme 2. ##STR486##
[0229] Scheme 6 depicts the synthesis of protected lactone alcohols
30 and lactone alcohols 16a. Compounds 30 and 16a correspond to
compounds of the formula, which correspond to compounds
W.sup.(1)(2)-Z.sub.m-OH, Wherein W.sup.(1)(2) is
C(R.sup.1)(R.sup.2)(CH2).sub.c-V and V is a Group selected from:
##STR487## As shown in Scheme 6, protected lactone alcohols 30 and
lactone alcohols 16a can be synthesized from compounds of the
formula X, 11, or 12 by adaptation of the methods and procedures
discussed above for Scheme 3. ##STR488##
[0230] Scheme 7 depicts the synthesis of halides 17. Halides 17 can
be synthesized by a variety of methods. One method involves
conversion of the alcohol to a leaving group such as a sulfonic
ester, such as, for example, tosylate, brosylate, mesylate, or
nosylate. This intermediate is then treated with a source of
X.sup.-, wherein X.sup.- is I.sup.-, Br.sup.-, or Cl.sup.- in a
solvent such as THF or ether. A general method for converting vinyl
and phenyl alcohols to thiols involves initially converting the
alcohol to a leaving group (e.g., a tosylate) then treating with a
halide nucleophile. ##STR489##
[0231] Scheme 8 outlines the synthesis of compounds I. In the first
step, compounds I are synthesized by reacting compounds 17
(compounds X 11, 12, 13, 14, 15, and 16 are encompassed by 17) with
compounds 31 under the conditions suitable for the formation of
compounds I. The conditions and methods discussed in Scheme 1 above
for the synthesis of mono-protected diols X from alcohols 6 can be
adapted for the synthesis of compounds 17. Compounds 31, wherein Y
is a suitable leaving group as defined above, preferably an
anhydride, an ester, or an amide group, are readily obtained
commercially (e.g., Aldrich Chemical Co. Milwaukee Wis.) or by well
known synthetic methods. Compounds I are obtained by reacting
compounds 31 with compounds 17 under the conditions suitable for
alkyl-de-acyloxy substitution. (For a review, See Kharasch;
Reinmuth, Grignard Reactions of Nonmetallic Substances; Prentice
Hall: Englewood Cliffs, N.J., 1954, pp. 561-562 and 846-908. In a
preferred procedure, the conversion of anhydrides, carboxylic
esters, or amides to ketones with organometallic compounds. In a
particular procedure, anhydrides and carboxylic esters give ketones
when treated using inverse addition of Grignard reagents at low
temperature with the solvent HMPA. See Newman, J. Org. Chem. 1948,
13, 592; Huet; Empotz; Jubier Tetrahedron 1973, 29, 479; and
Comprehensive Organic Transformations; VCH: New York, 1989, pp.
685-686, 693-700. Ketones can also be prepare by the treatment of
thioamides with organolithium compounds (alkyl or aryl). See
Tominaga; Kohra; Hosomi Tetrahedron Lett. 1987, 28, 1529. Moreover,
alkyllithium compounds have been used to give ketones from
carboxylic esters. See Petrov; Kaplan; Tsir J. Gen. Chem. USSR
1962, 32, 691. The reaction must be carried out in a high-boiling
solvent such as toluene. Di-substituted amides also can be used to
synthesize ketones. See Evans J. Chem. Soc. 1956, 4691; and
Wakefield Organolithium Methods; Academic Press: New York, 1988,
pp. 82-88. ##STR490##
[0232] Scheme 9 illustrates the alpha disubstitution of an ester
containing a terminal protected hydroxyl moiety. Compounds that
contain strong electron withdrawing groups are easily converted to
the corresponding enolates. These enolate ions can readilt attack
an electrophile resulting in alpha substitution. See Some Modern
Methods of Organic Synthesis, 3.sup.rd Ed.; Cambridge University
Press: Cambridge, 1986, pp. 1-26, hereby expressly incorporated
herein by reference. The reaction is successful for primary and
secondary alkyl, allylic, and benzylic. The use of polar aprotic
solvents, e.g., dimethylformamide or dimethylsulfoxide, are
preferred. Phase transfer catalysts can also be used. See Tundo et
al. J. Chem. Soc., Perkin Trans. 1, 1987, 2159, which is hereby
expressly incorporated herein by reference.
[0233] The conversion to a carboxylic acid with an additional
carbon is achieved by treating an acyl halide with diazomethane to
generate an intermediate diazo ketone, which in the presence of
water and silver oxide rearranges through a ketene intermediate to
a carboxylic acid with an additional carbon atom 37. If the
reaction is done in an alcohol instead of water an ester is
recovered. See Meier et al. Angew. Chem. Int. Ed. Eng. 1975, 14,
32-43, which is hereby expressly incorporated herein by reference.
Alternatively, the carboxylic acid can be esterified by known
techniques. The reaction can be repeated to generate methylene
groups adjacent to the carboxylic acid. ##STR491##
[0234] Scheme 10 outlines methodology for the synthesis of
protected alcohols 42a wherein Y, R.sup.1, R.sup.2, Z, and m are
defined as above. Protected alcohols 42a correspond to compounds of
the formula W.sup.(1)(2)-Z.sub.m-OPG, wherein W.sup.(1)(2) is
C(R.sup.1)(R.sup.2)--Y.
[0235] Protected alcohols 42, wherein Y comprises a --C(O)OH group,
can be synthesized by oxidizing mono-protected diols 39 with an
agent suitable for oxidizing a primary alcohol to a carboxylic acid
(for a discussion see M. Hudlicky, Oxidations in Organic Chemistry,
ACS Monograph 186, 1990, pp. 127-130, hereby expressly incorporated
herein by reference). Suitable oxidizing agents include, but are
not limited to, pyridinium dichromate (Corey et al., 1979,
Tetrahedron Lett. 399); manganese dioxide (Ahrens et al., 1967, J.
Heterocycl. Chem. 4:625); sodium permanganate monohydrate (Menger
et al., 1981, Tetrahedron Lett. 22:1655); and potassium
permanganate (Sam et al., 1972, J. Am. Chem. Soc. 94:4024), all of
which citations are hereby expressly incorporated herein by
reference. The preferred oxidizing reagent is pyridinium
dichromate. In an alternative synthetic procedure, protected
alcohols 42, wherein Y comprises a --C(O)OH group, can be
synthesized by treatment of protected halo-alcohols 40, wherein X
is iodo, with CO or CO.sub.2, as described in Bailey et al., 1990,
J. Org. Chem. 55:5404 and Yanagisawa et al., 1994, J. Am. Chem.
Soc. 116:6130, the two of which citations are hereby expressly
incorporated herein by reference. Protected alcohols 42, wherein Y
comprises --C(O)OR.sup.5, wherein R.sup.5 is as defined above, can
be synthesized by oxidation of mono-protected diols 39 in the
presence of R.sup.5OH (see generally, March, J. Advanced Organic
Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p.
1196). An exemplary procedure for such an oxidation is described in
Stevens et al., 1982, Tetrahedron Lett. 23:4647 (HOCl);
Sundararaman et al., 1978, Tetrahedron Lett. 1627 (O.sub.3/KOH);
Wilson et al., 1982, J. Org. Chem. 47:1360 (t-BuOOH/Et.sub.3N); and
Williams et al., 1988, Tetrahedron Lett. 29:5087 (Br.sub.2), the
four of which citations are hereby expressly incorporated herein by
reference. Preferably, protected alcohols 42, wherein Y comprises a
--C(O)OR.sup.5 group are synthesized from the corresponding
carboxylic acid (i.e., 42, wherein Y comprises --C(O)OH) by
esterification with R.sup.5OH (e.g., see March, J., Advanced
Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed.,
1992, p. 393-394, hereby expressly incorporated herein by
reference). In another alternative synthesis, protected alcohols
42, wherein Y comprises --C(O)OR.sup.5, can be prepared from
protected halo-alcohols 40 by carbonylation with transition metal
complexes (see e.g., March, J. Advanced Organic Chemistry;
Reactions Mechanisms, and Structure, 4th ed., 1992, p. 484-486;
Urata et al., 1991, Tetrahedron Lett. 32:36, 4733); and Ogata et
al., 1969, J. Org. Chem. 3985, the three of which citations are
hereby expressly incorporated herein by reference).
[0236] Protected alcohols 42, wherein Y comprises --OC(O)R.sup.5,
wherein R.sup.5 is as defined above, can be prepared by acylation
of mono-protected diols 39 with a carboxylate equivalent such as an
acyl halide (i.e., R.sup.5C(O)-Hal, wherein Hal is iodo, bromo, or
chloro, see e.g., March, J. Advanced Organic Chemistry; Reactions
Mechanisms, and Structure, 4th ed., 1992, p. 392 and Org. Synth.
Coll. Vol. III, Wiley, NY, pp. 142, 144, 167, and 187 (1955)) or an
anhydride (i.e., R.sup.5C(O)--O--(O)CR.sup.5, see e.g., March, J.
Advanced Organic Chemistry; Reactions Mechanisms, and Structure,
4th ed., 1992, p. 392-393 and Org. Synth. Coll. Vol. III, Wiley,
NY, pp. 11, 127, 141, 169, 237, 281, 428, 432, 690, and 833 (1955),
all of which citations are incorporated herein by reference).
Preferably, the reaction is conducted by adding a base to a
solution comprising mono-protected diols 39, a carboxylate
equivalent, and an organic solvent, which solution is preferably
maintained at a constant temperature within the range of 0.degree.
C. to about room temperature. Solvents suitable for reacting
mono-protected diols 39 with a carboxylate equivalent include, but
are not limited to, dichloromethane, toluene, and ether, preferably
dichloromethane. Suitable bases include, but are not limited to,
hydroxide sources, such as sodium hydroxide, potassium hydroxide,
sodium carbonate, or potassium carbonate; or an amine such as
triethylamine, pyridine, or dimethylaminopyridine, amines are
preferred. The progress of the reaction can be followed by using an
appropriate analytical technique, such as thin layer chromatography
or high performance liquid chromatography and when substantially
complete, the product can be isolated by workup and purified if
desired.
[0237] Protected alcohols 42, wherein Y comprises one of the
following phosphate ester groups ##STR492## wherein R.sup.6 is
defined as above, can be prepared by phosphorylation of
mono-protected diols X according to well-known methods (for a
general reviews, see Corbridge Phosphorus: An Outline of its
Chemistry, Biochemistry, and Uses, Studies in Inorganic Chemistry,
3rd ed., pp. 357-395 (1985); Ramirez et al., 1978, Acc. Chem. Res.
11:239; and Kalckare Biological Phosphorylations, Prentice-Hall,
New York (1969); J. B. Sweeny in Comprehensive Organic Functional
Group Transformations, A. R. Katritzky, O. Meth-Cohn and C. W.
Rees, Eds. Pergamon: Oxford, 1995, vol 2, pp. 104-109, the four of
which are hereby expressly incorporated herein by reference).
Protected alcohols 42 wherein Y comprises a monophosphate group of
the formula: ##STR493## wherein R.sup.6 is defined as above, can be
prepared by treatment of mono-protected diol 39 with phosphorous
oxychloride in a suitable solvent, such as xylene or toluene, at a
constant temperature within the range of about 100.degree. C. to
about 150.degree. C. for about 2 hours to about 24 hours. After the
reaction is deemed substantially complete, by using an appropriate
analytical method, the reaction mixture is hydrolyzed with
R.sup.6-OH. Suitable procedures are referenced in Houben-Weyl,
Methoden der Organische Chemie, Georg Thieme Verlag Stuttgart 1964,
vol. XII/2, pp. 143-210 and 872-879, hereby expressly incorporated
herein by reference. Alternatively, when both R.sup.6 are hydrogen,
can be synthesized by reacting mono-protected diols X with silyl
polyphosphate (Okamoto et al., 1985, Bull Chem. Soc. Jpn. 58:3393,
hereby expressly incorporated herein by reference) or by
hydrogenolysis of their benzyl or phenyl esters (Chen et al., 1998,
J. Org. Chem. 63:6511, incorporated herein by reference). In
another alternative procedure, when R.sup.6 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, or
(C.sub.2-C.sub.6)alkynyl, the monophosphate esters can be prepared
by reacting mono-protected diols 39 with appropriately substituted
phophoramidites followed by oxidation of the intermediate with
m-chloroperbenzoic acid (Yu et al., 1988, Tetrahedron Lett. 29:979,
incorporated herein by reference) or by reacting mono-protected
diols 39 with dialkyl or diaryl substituted phosphorochloridates
(Pop, et al, 1997, Org. Prep. and Proc. Int. 29:341, incorporated
herein by reference). The phosphoramidites are commercially
available (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or readily
prepared according to literature procedures (see e.g., Uhlmann et
al.1986, Tetrahedron Lett. 27:1023 and Tanaka et al., 1988,
Tetrahedron Lett. 29:199, both of which are incorporated herein by
reference). The phosphorochloridates are also commercially
available (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or prepared
according to literature methods (e.g., Gajda et al, 1995, Synthesis
25:4099. In still another alternative synthesis, protected alcohols
42, wherein Y comprises a monophosphate group and R.sup.6 is alkyl
or aryl, can be prepared by reacting IP.sup.+(OR.sup.6).sub.3 with
mono-protected diols 39 according to the procedure described in
Stowell et al., 1995, Tetrahedron Lett. 36:11, 1825 or by
alkylation of protected halo alcohols 40 with the appropriate
dialkyl or diaryl phosphates (see e.g., Okamoto, 1985, Bull Chem.
Soc. Jpn. 58:3393, incorporated herein by reference).
[0238] Protected alcohols 42 wherein Y comprises a diphosphate
group of the formula ##STR494## wherein R.sup.6 is defined as
above, can be synthesized by reacting the above-discussed
monophosphates of the formula: ##STR495## with a phosphate of the
formula ##STR496## (commercially available, e.g., Aldrich Chemical
Co., Milwaukee, Wis.), in the presence of carbodiimide such as
dicyclohexylcarbodiimide, as described in Houben-Weyl, Methoden der
Organische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XII/2,
pp. 881-885. In the same fashion, protected alcohols 42, wherein Y
comprises a triphosphate group of the formula: ##STR497## can be
synthesized by reacting the above-discussed diphosphate protected
alcohols, of the formula: ##STR498## with a phosphate of the
formula: ##STR499## as described above. Alternatively, when R.sup.6
is H, protected alcohols 42 wherein Y comprises the triphosphate
group, can be prepared by reacting mono-protected diols 39 with
salicyl phosphorochloridite and then pyrophosphate and subsequent
cleavage of the adduct thus obtained with iodine in pyridine as
described in Ludwig et al., 1989, J. Org. Chem. 54:631,
incorporated herein by reference.
[0239] Protected alcohols 42, wherein Y is --SO.sub.3H or a
heterocyclic group selected from the group consisting of:
##STR500## can be prepared by halide displacement from protected
halo-alcohols 40. Thus, when Y is --SO.sub.3H, protected alcohols
42 can by synthesized by reacting protected halo-alcohols 40 with
sodium sulfite as described in Gilbert Sulfonation and Related
Reactions; Wiley: New York, 1965, pp. 136-148 and pp. 161-163; Org.
Synth. Coll. Vol. II, Wiley, NY, 558, 564 (1943); and Org. Synth.
Coll. Vol. IV, Wiley, NY, 529 (1963), all three of which are
incorporated herein by reference. When Y is one of the
above-mentioned heterocycles, protected alcohols 42 can be prepared
by reacting protected halo-alcohols 40 with the corresponding
heterocycle in the presence of a base. The heterocycles are
available commercially (e.g., Aldrich Chemical Co., Milwaukee,
Wis.) or prepared by well-known synthetic methods (see the
procedures described in Ware, 1950, Chem. Rev. 46:403-470,
incorporated herein by reference). Preferably, the reaction is
conducted by stirring a mixture comprising 40, the heterocycle, and
a solvent at a constant temperature within the range of about room
temperature to about 100.degree. C., preferably within the range of
about 50.degree. C. to about 70.degree. C. for about 10 to about 48
hours. Suitable bases include hydroxide bases such as sodium
hydroxide, potassium hydroxide, sodium carbonate, or potassium
carbonate. Preferably, the solvent used in forming protected
alcohols 42 is selected from dimethylformamide; formamide; dimethyl
sulfoxide; alcohols, such as methanol or ethanol; and mixtures
thereof. The progress of the reaction can be followed by using an
appropriate analytical technique, such as thin layer chromatography
or high performance liquid chromatography and when substantially
complete, the product can be isolated by workup and purified if
desired.
[0240] Protected alcohols 42, wherein Y is a heteroaryl ring
selected from ##STR501## can be prepared by metallating the
suitable heteroaryl ring then reacting the resulting metallated
heteroaryl ring with protected halo-alcohols 40 (for a review, see
Katritzky Handbook of Heterocyclic Chemistry, Pergamon Press:
Oxford 1985). The heteroaryl rings are available commercially or
prepared by well-known synthetic methods (see e.g., Joule et al.,
Heterocyclic Chemistry, 3rd ed., 1995; De Sarlo et al., 1971, J.
Chem. Soc. (C) 86; Oster et al., 1983, J. Org. Chem. 48:4307; Iwai
et al., 1966, Chem. Pharm. Bull. 14:1277; and U.S. Pat. No.
3,152,148, all of which citations are incorporated herein by
reference). As used herein, the term "metallating" means the
forming of a carbon-metal bond, which bond may be substantially
ionic in character. Metallation can be accomplished by adding about
2 equivalents of strong organometallic base, preferably with a
pK.sub.a of about 25 or more, more preferably with a pK.sub.a of
greater than about 35, to a mixture comprising a suitable organic
solvent and the heterocycle. Two equivalents of base are required:
one equivalent of the base deprotonates the --OH group or the --NH
group, and the second equivalent metallates the heteroaryl ring.
Alternatively, the hydroxy group of the heteroaryl ring can be
protected with a base-stable, acid-labile protecting group as
described in Greene, T. W., Protective Groups in Organic Synthesis,
3rd edition 17-237 (1999), hereby expressly incorporated herein by
reference. Where the hydroxy group is protected, only one
equivalent of base is required. Examples of suitable base-stable,
acid-labile hydroxyl-protecting groups, include but are not limited
to, ethers, such as methyl, methoxy methyl, methylthiomethyl,
methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl,
tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl,
1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl,
o-nitrobenzyl, triphenylmethyl, .alpha.-naphthyldiphenylmethyl,
p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,
trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl; and
esters, such as pivaloate, adamantoate, and
2,4,6-trimethylbenzoate. Ethers are preferred, particularly
straight chain ethers, such as methyl ether, methoxymethyl ether,
methylthiomethyl ether, methoxyethoxymethyl ether,
bis(2-chloroethoxy)methyl ether. Preferably, the pK.sub.a of the
base is higher than the pK.sub.a of the proton of the heterocycle
to be deprotonated. For a listing of pK.sub.as for various
heteroaryl rings, see Fraser et al., 1985, Can. J. Chem. 63:3505,
incorporated herein by reference. Suitable bases include, but are
not limited to, alkylmetal bases such as methyllithium,
n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium,
phenyl sodium, and phenyl potassium; metal amide bases such as
lithium amide, sodium amide, potassium amide, lithium
tetramethylpiperidide, lithium diisopropylamide, lithium
diethylamide, lithium dicyclohexylamide, sodium
hexamethyldisilazide, and lithium hexamethyldisilazide; and hydride
bases such as sodium hydride and potassium hydride. If desired, the
organometallic base can be activated with a complexing agent, such
as N,N,N',N'-tetramethylethylenediamine or hexamethylphosphoramide
(1970, J. Am. Chem. Soc. 92:4664, hereby expressly incorporated
herein by reference). Solvents suitable for synthesizing protected
alcohols 42, wherein Y is a heteroaryl ring include, but are not
limited to, diethyl ether; tetrahydrofuran; and hydrocarbons, such
as pentane. Generally, metallation occurs alpha to the heteroatom
due to the inductive effect of the heteroatom, however,
modification of conditions, such as the identity of the base and
solvents, order of reagent addition, reagent addition times, and
reaction and addition temperatures can be modified by one of skill
in the art to achieve the desired metallation position (see e.g.,
Joule et al., Heterocyclic Chemistry, 3rd ed., 1995, pp. 30-42,
hereby expressly incorporated herein by reference) Alternatively,
the position of metallation can be controlled by use of a
halogenated heteroaryl group, wherein the halogen is located on the
position of the heteroaryl ring where metallation is desired (see
e.g., Joule et al., Heterocyclic Chemistry, 3rd ed., 1995, p. 33
and Saulnier et al., 1982, J. Org. Chem. 47:757, the two of which
citations are hereby expressly incorporated herein by reference).
Halogenated heteroaryl groups are available commercially (e.g.,
Aldrich Chemical Co., Milwaukee, Wis.) or can be prepared by
well-known synthetic methods (see e.g., Joule et al., Heterocyclic
Chemistry, 3rd ed., 1995, pp. 78, 85, 122, 193, 234, 261, 280, 308,
hereby expressly incorporated herein by reference). After
metallation, the reaction mixture comprising the metallated
heteroaryl ring is adjusted to within a temperature range of about
0.degree. C. to about room temperature and protected halo-alcohols
40 (diluted with a solvent or in undiluted form) are added,
preferably at a rate such that the reaction-mixture temperature
remains within about one to two degrees of the initial
reaction-mixture temperature. After addition of protected
halo-alcohols 40, the reaction mixture is stirred at a constant
temperature within the range of about room temperature and about
the solvent's boiling temperature and the reaction's progress can
be monitored by the appropriate analytical technique, preferably
thin-layer chromatography or high-performance liquid
chromatography. After the reaction is substantially complete,
protected alcohols 42 can be isolated by workup and purification.
It is to be understood that conditions, such as the identity of
protected halo-alcohol 40, the base, solvents, orders of reagent
addition, times, and temperatures, can be modified by one of skill
in the art to optimize the yield and selectivity. Exemplary
procedures that can be used in such a transformation are described
in Shirley et al., 1995, J. Org. Chem. 20:225; Chadwick et al.,
1979, J. Chem. Soc., Perkin Trans. 1 2845; Rewcastle, 1993, Adv.
Het. Chem. 56:208; Katritzky et al., 1993, Adv. Het. Chem. 56:155;
and Kessar et al., 1997, Chem. Rev. 97:721. When Y is ##STR502##
protected alcohols 42 can be prepared from their corresponding
carboxylic acid derivatives (42, wherein Y is --CO.sub.2H) as
described in Belletire et al, 1988, Synthetic Commun. 18:2063 or
from the corresponding acylchlorides (42, wherein Y is --CO-halo)
as described in Skinner et al., 1995, J. Am. Chem. Soc. 77:5440,
both citations are incorporated herein by reference. The
acylhalides can be prepared from the carboxylic acids by well known
procedures such as those described in March, J., Advanced Organic
Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp.
437-438, hereby expressly incorporated herein by reference. When Y
is ##STR503## wherein R.sup.7 is as defined above, protected
alcohols 42 can be prepared by first reacting protected
halo-alcohols 40 with a trialkyl phosphite according to the
procedure described in Kosolapoff, 1951, Org. React. 6:273 followed
by reacting the derived phosphonic diester with ammonia according
to the procedure described in Smith et al., 1957, J. Org. Chem.
22:265, incorporated herein by reference. When Y is ##STR504##
protected alcohols 42 can be prepared by reacting their sulphonic
acid derivatives (i.e., 42, wherein Y is --SO.sub.3H ) with ammonia
as described in Sianesi et al., 1971, Chem. Ber. 104:1880 and
Campagna et al., 1994, Farmaco, Ed. Sci. 49:653, both of which
citations are incorporated herein by reference). ##STR505##
[0241] As further illustrated in Scheme 11, protected alcohols 42
can be deprotected providing alcohols 42a. The deprotection method
depends on the identity of the alcohol-protecting group, see e.g.,
the procedures listed in Greene, T. W., Protective Groups in
Organic Synthesis, 3rd edition 17-237 (1999), particularly see
pages 48-49, incorporated herein by reference. One of skill in the
art will readily be able to choose the appropriate deprotection
procedure. When the alcohol is protected as an ether function
(e.g., methoxymethyl ether), the alcohol is preferably deprotected
with aqueous or alcoholic acid. Suitable deprotection reagents
include, but are not limited to, aqueous hydrochloric acid,
p-toluenesulfonic acid in methanol, pyridinium-p-toluenesulfonate
in ethanol, Amberlyst H-15 in methanol, boric acid in
ethylene-glycol-monoethylether, acetic acid in a
water-tetrahydrofuran mixture, aqueous hydrochloric acid is
preferred. Examples of such procedures are described, respectively,
in Bernady et al., 1979, J. Org. Chem. 44:1438; Miyashita et al.,
1977, J. Org. Chem. 42:3772; Johnston et al., 1988, Synthesis 393;
Bongini et al., 1979, Synthesis 618; and Hoyer et al., 1986,
Synthesis 655; Gigg et al., 1967, J. Chem. Soc. C, 431; and Corey
et al., 1978, J. Am. Chem. Soc. 100:1942, all of which are
incorporated herein by reference.
[0242] Scheme 11 depicts the synthesis of protected lactone
alcohols 46 and lactone. Compound 46 corresponds to compounds of
the formula W.sup.(1)(2)-Zm-OPG and, wherein W.sup.(1)(2) is a
lactone group selected from: ##STR506## Protected lactone alcohols
46 can be prepared from compounds of the formula 46, 45, or 44 by
using well-known condensation reactions and variations of the
Michael reaction. Methods for the synthesis of lactones are
disclosed in Multzer in Comprehensive Organic Functional Group
Transformations, A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Eds.
Pergamon: Oxford, 1995, vol 5, pp. 161-173, incorporated herein by
reference. Mono-protected diols 43, electrophilic protected
alcohols 44, and aldehydes 45 are readily available ether
commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or by
well known synthetic procedures.
[0243] When W.sup.(1)(2) is a beta-lactone group of the formula:
##STR507## protected lactone alcohols 46 can be prepared from
aldehydes 45 and electrophilic protected alcohols 44, respectively,
by a one-pot-addition-lactonization according to the procedure of
Masamune et al., 1976, J. Am. Chem. Soc. 98:7874 and Danheiser et
al., 1991, J. Org. Chem. 56:1176, both of which are incorporated
herein by reference. This one-pot-addition-lactonization
methodology has been reviewed by Multzer in Comprehensive Organic
Functional Group Transformations, A. R. Katritzky, O. Meth-Cohn and
C. W. Rees, Eds. Pergamon: Oxford, 1995, vol 5, pp. 161,
incorporated herein by reference When W.sup.(1)(2) is a gamma- or
delta-lactone group of the formula: ##STR508## protected lactone
alcohols 46 can be prepared from aldehydes 45 according to well
known synthetic methodology. For example, the methodology described
in Masuyama et al., 2000, J. Org. Chem. 65:494; Eisch et al., 1978,
J. Organo. Met. Chem. C8 160; Eaton et al., 1947, J. Org. Chem.
37:1947; Yunker et al., 1978, Tetrahedron Lett. 4651; Bhanot et
al., 1977, J. Org. Chem. 42:1623; Ehlinger et al., 1980, J. Am.
Chem. Soc. 102:5004; and Raunio et al., 1957, J. Org. Chem. 22:570,
all of which citations are incorporated herein by reference. For
instance, as described in Masuyama et al., 2000, J. Org. Chem.
65:494, aldehydes 45 can be treated with about 1 equivalent of a
strong organometallic base, preferably with a pK.sub.a of about 25
or more, more preferably with a pK.sub.a of greater than about 35,
in a suitable organic solvent to give a reaction mixture. Suitable
bases include, but are not limited to, alkylmetal bases such as
methyllithium, n-butyllithium, tert-butyllithium, sec-butyllithium,
phenyllithium, phenyl sodium, and phenyl potassium; metal amide
bases such as lithium amide, sodium amide, potassium amide, lithium
tetramethylpiperidide, lithium diisopropylamide, lithium
diethylamide, lithium dicyclohexylamide, sodium
hexamethyldisilazide, and lithium hexamethyldisilazide; and hydride
bases such as sodium hydride and potassium hydride, preferably
lithium tetramethylpiperidide. Suitable solvents include, but are
not limited to, diethyl ether and tetrahydrofuran. The
reaction-mixture temperature is adjusted to within the range of
about 0.degree. C. to about 100.degree. C., preferably about room
temperature to about 50.degree. C., and a halide of the formula:
##STR509## wherein z is 1 or 2 (diluted with a solvent or in
undiluted form) is added. The reaction mixture is stirred for a
period of about 2 hours to about 48 hours, preferably about 5 to
about 10 hours, during which time the reaction's progress can be
followed by using an appropriate analytical technique, such as thin
layer chromatography or high performance liquid chromatography.
When the reaction is deemed substantially complete, protected
lactone alcohols 46 can be isolated by workup and purified if
desired. When W.sup.(1)(2) is a ganmma- or delta-lactone group of
the formula: ##STR510## protected lactone alcohols 46 can be
synthesized by deprotonating the corresponding lactone with a
strong base providing the lactone enolate and reacting the enolate
with electrophilic protected alcohols 44 (for a detailed discussion
of enolate formation of active methylene compounds such as
lactones, see House Modern Synthetic Reactions; W. A. Benjamin,
Inc. Philippines 1972 pp. 492-570, and for a discussion of reaction
of lactone enolates with electrophiles such as carbonyl compounds,
see March, J. Advanced Organic Chemistry; Reactions Mechanisms, and
Structure, 4th ed., 1992, pp. 944-945, both of which are
incorporated herein by reference). Lactone-enolate formation can be
accomplished by adding about 1 equivalent of a strong
organometallic base, preferably with a pK.sub.a of about 25 or
more, more preferably with a pK.sub.a of greater than about 35, to
a mixture comprising a suitable organic solvent and the lactone.
Suitable bases include, but are not limited to, alkylmetal bases
such as methyllithium, n-butyllithium, tert-butyllithium,
sec-butyllithium, phenyllithium, phenyl sodium, and phenyl
potassium; metal amide bases such as lithium amide, sodium amide,
potassium amide, lithium tetramethylpiperidide, lithium
diisopropylamide, lithium diethylamide, lithium dicyclohexylamide,
sodium hexamethyldisilazide, and lithium hexamethyldisilazide; and
hydride bases such as sodium hydride and potassium hydride,
preferably lithium tetramethylpiperidide. Solvents suitable for
lactone-enolate formation include, but are not limited to, diethyl
ether and tetrahydrofuran. After enolate formation, the
reaction-mixture temperature is adjusted to within the range of
about -78.degree. C. to about room temperature, preferably about
-50.degree. C. to about 0.degree. C., and electrophilic protected
alcohols 44 (diluted with a solvent or in undiluted form) are
added, preferably at a rate such that the reaction-mixture
temperature remains within about one to two degrees of the initial
reaction-mixture temperature. The reaction mixture is stirred for a
period of about 15 minutes to about 5 hours, during which time the
reaction's progress can be followed by using an appropriate
analytical technique, such as thin layer chromatography or high
performance liquid chromatography. When the reaction is deemed
substantially complete, protected lactone alcohols 46 can be
isolated by workup and purified if desired. When W.sup.(1)(2) is a
lactone group group of the formula: ##STR511## protected lactone
alcohols 46 can be prepared from aldehydes 45 according to the
procedure described in U.S. Pat. No. 4,622,338, hereby expressly
incorporated herein by reference.
[0244] When W.sup.(1)(2) is a gamma- or delta-lactone group of the
formula: ##STR512## protected lactone alcohols 46 can be prepared
according to a three step sequence. The first step comprises
base-mediated reaction of electrophilic protected alcohols 44 with
succinic acid esters (i.e.,
R.sup.9O.sub.2CCH.sub.2CH.sub.2CO.sub.2R.sup.9, wherein R.sup.9 is
alkyl) or glutaric acid esters (i.e.,
R.sup.9O.sub.2CCH.sub.2CH.sub.2CH.sub.2CO.sub.2R.sup.9, wherein
R.sup.9 is alkyl) providing a diester intermediate of the formula
44i: ##STR513## wherein x is 1 or 2 depending on whether the gamma
or delta lactone group is desired. The reaction can be performed by
adding about 1 equivalent of a strong organometallic base,
preferably with a pK.sub.a of about 25 or more, more preferably
with a pK.sub.a of greater than about 35, to a mixture comprising a
suitable organic solvent and the succinic or glutaric acid ester.
Suitable bases include, but are not limited to, alkylmetal bases
such as methyllithium, n-butyllithium, tert-butyllithium,
sec-butyllithium, phenyllithium, phenyl sodium, and phenyl
potassium; metal amide bases such as lithium amide, sodium amide,
potassium amide, lithium tetramethylpiperidide, lithium
diisopropylamide, lithium diethylamide, lithium dicyclohexylamide,
sodium hexamethyldisilazide, and lithium hexamethyldisilazide; and
hydride bases such as sodium hydride and potassium hydride,
preferably lithium tetramethylpiperidide. Suitable solvents
include, but are not limited to, diethyl ether and tetrahydrofuran.
After enolate formation, the reaction-mixture temperature is
adjusted to within the range of about -78.degree. C. to about room
temperature, preferably about -50.degree. C. to about 0.degree. C.,
and electrophilic protected alcohols 44 (diluted with a solvent or
in undiluted form) are added, preferably at a rate such that the
reaction-mixture temperature remains within about one to two
degrees of the initial reaction-mixture temperature. The reaction
mixture is stirred for a period of about 15 minutes to about 5
hours, during which time the reaction's progress can be followed by
using an appropriate analytical technique, such as thin layer
chromatography or high performance liquid chromatography. When the
reaction is deemed substantially complete, the diester intermediate
be isolated by workup and purified if desired. In the second step,
the intermediate diester can be reduced, with a hydride reducing
agent, to yield a diol: ##STR514## The reduction can be performed
according to the procedures referenced in March, J. Advanced
Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed.,
1992, p. 1214, incorporated herein by reference). Suitable reducing
agents include, but are not limited to, lithium aluminum hydride,
diisobutylaluminum hydride, sodium borohydride, and lithium
borohydride). In the third step, the diol can be oxidatively
cyclized with RuH.sub.2(PPh.sub.3).sub.4 to the product protected
lactone alcohols 46 according to the procedure of Yoshikawa et al.,
1986, J. Org. Chem. 51:2034 and Yoshikawa et al., 1983, Tetrahedron
Lett. 26:2677, both of which citations are incorporated herein by
reference. When W.sup.(1)(2) is a lactone group of the formula:
##STR515## protected lactone alcohols 46 can be synthesized by
reacting the Grignard salts of electrophilic protected alcohols 44,
where E is a halide, with 5,6-dihydro-2H-pyran-2-one, commercially
available (e.g., Aldrich Chemical Co., Milwaukee, Wis.), in the
presence of catalytic amounts of a
1-dimethylaminoacetyl)pyrolidine-2yl)methyl-diarylphosphine-copper(I)
iodide complex as described in Tomioka et al., 1995, Tetrahedron
Lett. 36:4275, incorporated herein by reference. ##STR516##
[0245] 3Scheme 12 illustrates the synthesis of ketone II. The
alcohol 47 is intiallly converted to a halogen 48. See Larock,
Comprehensive Organic Transformations, VCH: New York, 1989, pp.
360-362; all references disclosed therein are incorporated herein
by reference. The halide 48 is then converted to a carboxylic acid
49 with subsequent conversion to a acyl halide 50. See Larock,
Comprehensive Organic Transformations, VCH: New York, 1989, pp.
850-851, 855-856, 859-860, 977, 980, and 985; all references
discloses therein are incorporated herein by reference. The acyl
halide 50 is then coupled with the halide to afford compound II.
See Rappoport, The Chemistry of the Functional Groups, Supp. D, pt.
2; Wiley: New York, 1983; House, Modern Synthetic Reactions,
2.sup.nd Ed. Benjamin: New York, 1972, pp. 691-694, 734-765, which
are incorporated herein by reference. ##STR517##
[0246] Scheme 13 depicts the synthesis of compounds IIIa, that is,
compounds III where a double bond is not present in the ring. In
the first step, compounds 53, prepared as discussed in Schemes 1 to
6 above, can be converted to compounds 54 by standard oxidation of
the primary alcohol to an aldehyde group. Such oxidations are
described in M. Hudlicky, Oxidations in Organic Chemistry, ACS
Monograph 186, 1990, pp. 114-127, hereby expressly incorporated
herein by reference. In the next step Grignard reaction of 54 with
55 followed by standard OH protection gives 57. Compounds 55 are
commercially available (e.g., from Aldrich Chemical Co. Milwakee,
Wis.) or readily prepared by standard synthetic methodology. For
exemplary procedures for Grignard reaction see March, J. Advanced
Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed.,
1992, pp. 920-929, incorporated herein by reference. Similarly, in
the next step, the Grignard salt of 57 is condensed with 58 to
provide 59. Next 59 is is oxidized and then cyclized to 60. When p
is one, exemplary cyclization procedures are found in Friedrichsen,
W. in Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.;
Rees, W. C.; Scriven, E. F. V. Eds.; Pergamon Press: Oxford, 1996;
Vol.2, p 351, and Comprehensive Heterocyclic Chemistry; Katritzky,
A. R.; Rees, W. C. Eds.; Pergamon Press: Oxford, 1986; Vol.3. When
p is 0, cyclization procedures are found in Hepworth, J. D. in
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, W.
C.; Scriven, E. F. V. Eds.; Pergamon Press: Oxford, 1996; Vol.5, p
351 and Comprehensive Heterocyclic Chemistry; Katritzky, A. R.;
Rees, W. C. Eds.; Pergamon Press: Oxford, 1986; Vol. 3, all of
which citations are hereby expressly incorporated herein by
reference.
[0247] The hydroxy ketone is subjected to cyclization, as described
in the above Hepworth, J. D. in Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R.; Rees, W. C.; Scriven, E. F. V.
Eds.; Pergamon Press: Oxford, 1996; Vol.5, p 386. For compounds III
where W.sup.(1)(2) is HO(CH.sub.2).sub.n-R.sup.1R.sup.2: The
hydroxy group is first deprotected as described in Greene, T. W.,
Protective Groups in Organic Synthesis, 3rd edition (1999). For
other structures, where Y is a group such as an acid, aldehydes,
etc., protection is needed (acids as esters, preferably pivaloyl,
aldehydes as silyl derivatives such as TIPS, stable in both basic
and acidic conditions). When W.sup.(1)(2) is a Lactone it can be
introduced as discussed in Scheme 3 above. The compounds are then
coupled to afford compound of the formula IIIa.
[0248] The reactions are performed under similar conditions for
substituted cyclic compounds. After the formation of the
mono-cyclic compounds, they are in situ reacted with electrophiles
(e.g., MeI) at temperatures between -40.degree. C. to +60.degree.
C., for a reaction time of 1 hr to 5 days. In addition, ing double
bonds can be selectively added or reduced or otherwise manipulated
by well known synthetic methods to give compounds III having one or
two selectively-placed double bonds (i.e., the double bond(s) can
be positioned in the desired location within the ring), for
example, the methods disclosed in March, J. Advanced Organic
Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp.
771-780, incorporated herein by reference.
4.3. Therapeutic Uses of Compounds or Compositions of the
Invention
[0249] In accordance with the invention, a compound of the
invention or a composition of the invention, comprising a compound
of the invention and a pharmaceutically acceptable vehicle, is
administered to a patient, preferably a human, with or at risk of
aging, Alzheimer's Disease, cancer, cardiovascular disease,
diabetic nephropathy, diabetic retinopathy, a disorder of glucose
metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile
production, enhancing reverse lipid transport, hypertension,
impotence, inflammation, insulin resistance, lipid elimination in
bile, modulating C reactive protein, obesity, oxysterol elimination
in bile, pancreatitis, Parkinson's disease, a peroxisome
proliferator activated receptor-associated disorder, phospholipid
elimination in bile, renal disease, septicemia, metabolic syndrome
disorders (e.g., Syndrome X), a thrombotic disorder,
gastrointestinal disease, irritable bowel syndrome (IBS),
inflammatory bowel disease (e.g., Crohn's Disease, ulcerative
colitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis),
autoimmune disease (e.g., systemic lupus erythematosus),
scleroderma, ankylosing spondylitis, gout and pseudogout, muscle
pain: polymyositis/polymyalgia rheumatica/fibrositis; infection and
arthritis, juvenile rheumatoid arthritis, tendonitis, bursitis and
other soft tissue rheumatism. In one embodiment, "treatment" or
"treating" refers to an amelioration of a disease or disorder, or
at least one discernible symptom thereof. In another embodiment,
"treatment" or "treating" refers to inhibiting the progression of a
disease or disorder, either physically, e.g., stabilization of a
discernible symptom, physiologically, e.g., stabilization of a
physical parameter, or both.
[0250] In certain embodiments, the compounds of the invention or
the compositions of the invention are administered to a patient,
preferably a human, as a preventative measure against such
diseases. As used herein, "prevention" or "preventing" refers to a
reduction of the risk of acquiring a given disease or disorder. In
a preferred mode of the embodiment, the compositions of the present
invention are administered as a preventative measure to a patient,
preferably a human having a genetic predisposition to a aging,
Alzheimer's Disease, cancer, cardiovascular disease, diabetic
nephropathy, diabetic retinopathy, a disorder of glucose
metabolism, dyslipidemia, dyslipoproteinemia, enhancing bile
production, enhancing reverse lipid transport, hypertension,
impotence, inflammation, insulin resistance, lipid elimination in
bile, modulating C reactive protein, obesity, oxysterol elimination
in bile, pancreatitis, Parkinson's disease, a peroxisome
proliferator activated receptor-associated disorder, phospholipid
elimination in bile, renal disease, septicemia, metabolic syndrome
disorders (e.g., Syndrome X), a thrombotic disorder, inflammatory
processes and diseases like gastrointestinal disease, irritable
bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's
Disease, ulcerative colitis), arthritis (e.g., rheumatoid
arthritis, osteoarthritis), autoimmune disease (e.g., systemic
lupus erythematosus), scleroderma, ankylosing spondylitis, gout and
pseudogout, muscle pain: polymyositis/polymyalgia
rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue rheumatism.
Examples of such genetic predispositions include but are not
limited to the .epsilon.4 allele of apolipoprotein E, which
increases the likelihood of Alzheimer's Disease; a loss of function
or null mutation in the lipoprotein lipase gene coding region or
promoter (e.g., mutations in the coding regions resulting in the
substitutions D9N and N291S; for a review of genetic mutations in
the lipoprotein lipase gene that increase the risk of
cardiovascular diseases, dyslipidemias and dyslipoproteinemias, see
Hayden and Ma, 1992, Mol. Cell Biochem. 113:171-176); and familial
combined hyperlipidemia and familial hypercholesterolemia.
[0251] In another preferred mode of the embodiment, the compounds
of the invention or compositions of the invention are administered
as a preventative measure to a patient having a non-genetic
predisposition to a aging, Alzheimer's Disease, cancer,
cardiovascular disease, diabetic nephropathy, diabetic retinopathy,
a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,
enhancing bile production, enhancing reverse lipid transport,
hypertension, impotence, inflammation, insulin resistance, lipid
elimination in bile, modulating C reactive protein, obesity,
oxysterol elimination in bile, pancreatitis, Parkinson's disease, a
peroxisome proliferator activated receptor-associated disorder,
phospholipid elimination in bile, renal disease, septicemia,
metabolic syndrome disorders (e.g., Syndrome X), a thrombotic
disorder, inflammatory processes and diseases like gastrointestinal
disease, irritable bowel syndrome (IBS), inflammatory bowel disease
(e.g., Crohn's Disease, ulcerative colitis), arthritis (e.g.,
rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g.,
systemic lupus erythematosus), scleroderma, ankylosing spondylitis,
gout and pseudogout, muscle pain: polymyositis/polymyalgia
rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue rheumatism.
Examples of such non-genetic predispositions include but are not
limited to cardiac bypass surgery and percutaneous transluminal
coronary angioplasty, which often lead to restenosis, an
accelerated form of atherosclerosis; diabetes in women, which often
leads to polycystic ovarian disease; and cardiovascular disease,
which often leads to impotence. Accordingly, the compositions of
the invention may be used for the prevention of one disease or
disorder and concurrently treating another (e.g., prevention of
polycystic ovarian disease while treating diabetes; prevention of
impotence while treating a cardiovascular disease).
4.4. Treatment of Cardiovascular Diseases
[0252] The present invention provides methods for the treatment or
prevention of a cardiovascular disease, comprising administering to
a patient a therapeutically effective amount of a compound or a
composition comprising a compound of the invention and a
pharmaceutically acceptable vehicle. As used herein, the term
"cardiovascular diseases" refers to diseases of the heart and
circulatory system. These diseases are often associated with
dyslipoproteinemias and/or dyslipidemias. Cardiovascular diseases
which the compositions of the present invention are useful for
preventing or treating include but are not limited to
arteriosclerosis; atherosclerosis; stroke; ischemia; endothelium
dysfunctions, in particular those dysfunctions affecting blood
vessel elasticity; peripheral vascular disease; coronary heart
disease; myocardial infarcation; cerebral infarction and
restenosis.
4.5. Treatment of Dyslipidemias
[0253] The present invention provides methods for the treatment or
prevention of a dyslipidemia comprising administering to a patient
a therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically
acceptable vehicle.
[0254] As used herein, the term "dyslipidemias" refers to disorders
that lead to or are manifested by aberrant levels of circulating
lipids. To the extent that levels of lipids in the blood are too
high, the compositions of the invention are administered to a
patient to restore normal levels. Normal levels of lipids are
reported in medical treatises known to those of skill in the art.
For example, recommended blood levels of LDL, HDL, free
triglycerides and others parameters relating to lipid metabolism
can be found at the web site of the American Heart Association and
that of the National Cholesterol Education Program of the National
Heart, Lung and Blood Institute
(http://www.americanheart.org/cholesterol/about_level.html and
http://www.nhlbi.nih.gov/health/public/heart/chol/hbc_what.html,
respectively). At the present time, the recommended level of HDL
cholesterol in the blood is above 35 mg/dL; the recommended level
of LDL cholesterol in the blood is below 130 mg/dL; the recommended
LDL:HDL cholesterol ratio in the blood is below 5:1, ideally 3.5:1;
and the recommended level of free triglycerides in the blood is
less than 200 mg/dL. Dyslipidemias which the compositions of the
present invention are useful for preventing or treating include but
are not limited to hyperlipidemia and low blood levels of high
density lipoprotein (HDL) cholesterol. In certain embodiments, the
hyperlipidemia for prevention or treatment by the compounds of the
present invention is familial hypercholesterolemia; familial
combined hyperlipidemia; reduced or deficient lipoprotein lipase
levels or activity, including reductions or deficiencies resulting
from lipoprotein lipase mutations; hypertriglyceridemia;
hypercholesterolemia; high blood levels of urea bodies (e.g.
.beta.-OH butyric acid); high blood levels of Lp(a) cholesterol;
high blood levels of low density lipoprotein (LDL) cholesterol;
high blood levels of very low density lipoprotein (VLDL)
cholesterol and high blood levels of non-esterified fatty
acids.
[0255] The present invention further provides methods for altering
lipid metabolism in a patient, e.g., reducing LDL in the blood of a
patient, reducing free triglycerides in the blood of a patient,
increasing the ratio of HDL to LDL in the blood of a patient, and
inhibiting saponified and/or non-saponified fatty acid synthesis,
said methods comprising administering to the patient a compound or
a composition comprising a compound of the invention in an amount
effective alter lipid metabolism.
4.6. Treatment of Dyslipoproteinemias
[0256] The present invention provides methods for the treatment or
prevention of a dyslipoproteinemia comprising administering to a
patient a therapeutically effective amount of a compound or a
composition comprising a compound of the invention and a
pharmaceutically acceptable vehicle.
[0257] As used herein, the term "dyslipoproteinemias" refers to
disorders that lead to or are manifested by aberrant levels of
circulating lipoproteins. To the extent that levels of lipoproteins
in the blood are too high, the compositions of the invention are
administered to a patient to restore normal levels. Conversely, to
the extent that levels of lipoproteins in the blood are too low,
the compositions of the invention are administered to a patient to
restore normal levels. Normal levels of lipoproteins are reported
in medical treatises known to those of skill in the art.
[0258] Dyslipoproteinemias which the compositions of the present
invention are useful for preventing or treating include but are not
limited to high blood levels of LDL; high blood levels of
apolipoprotein B (apo B); high blood levels of Lp(a); high blood
levels of apo(a); high blood levels of VLDL; low blood levels of
HDL; reduced or deficient lipoprotein lipase levels or activity,
including reductions or deficiencies resulting from lipoprotein
lipase mutations; hypoalphalipoproteinemia; lipoprotein
abnormalities associated with diabetes; lipoprotein abnormalities
associated with obesity; lipoprotein abnormalities associated with
Alzheimer's Disease; and familial combined hyperlipidemia.
[0259] The present invention further provides methods for reducing
apo C-II levels in the blood of a patient; reducing apo C-III
levels in the blood of a patient; elevating the levels of HDL
associated proteins, including but not limited to apo A-I, apo
A-II, apo A-IV and apo E in the blood of a patient; elevating the
levels of apo E in the blood of a patient, and promoting clearance
of triglycerides from the blood of a patient, said methods
comprising administering to the patient a compound or a composition
comprising a compound of the invention in an amount effective to
bring about said reduction, elevation or promotion,
respectively.
4.7. Treatment of Glucose Metabolism Disorders
[0260] The present invention provides methods for the treatment or
prevention of a glucose metabolism disorder, comprising
administering to a patient a therapeutically effective amount of a
compound or a composition comprising a compound of the invention
and a pharmaceutically acceptable vehicle. As used herein, the term
"glucose metabolism disorders" refers to disorders that lead to or
are manifested by aberrant glucose storage and/or utilization. To
the extent that indicia of glucose metabolism (i.e., blood insulin,
blood glucose) are too high, the compositions of the invention are
administered to a patient to restore normal levels. Conversely, to
the extent that indicia of glucose metabolism are too low, the
compositions of the invention are administered to a patient to
restore normal levels. Normal indicia of glucose metabolism are
reported in medical treatises known to those of skill in the
art.
[0261] Glucose metabolism disorders which the compositions of the
present invention are useful for preventing or treating include but
are not limited to impaired glucose tolerance; insulin resistance;
insulin resistance related breast, colon or prostate cancer;
diabetes, including but not limited to non-insulin dependent
diabetes mellitus (NIDDM), insulin dependent diabetes mellitus
(IDDM), gestational diabetes mellitus (GDM), and maturity onset
diabetes of the young (MODY); pancreatitis; hypertension;
polycystic ovarian disease; and high levels of blood insulin and/or
glucose.
[0262] The present invention further provides methods for altering
glucose metabolism in a patient, for example to increase insulin
sensitivity and/or oxygen consumption of a patient, said methods
comprising administering to the patient a compound or a composition
comprising a compound of the invention in an amount effective to
alter glucose metabolism.
4.8. Treatment of PPAR-Associated Disorders
[0263] The present invention provides methods for the treatment or
prevention of a PPAR-associated disorder, comprising administering
to a patient a therapeutically effective amount of a compound or a
composition comprising a compound of the invention and a
pharmaceutically acceptable vehicle. As used herein, "treatment or
prevention of PPAR associated disorders" encompasses treatment or
prevention of rheumatoid arthritis; multiple sclerosis; psoriasis;
inflammatory bowel diseases; breast; colon or prostate cancer; low
levels of blood HDL; low levels of blood, lymph and/or
cerebrospinal fluid apo E; low blood, lymph and/or cerebrospinal
fluid levels of apo A-I; high levels of blood VLDL; high levels of
blood LDL; high levels of blood triglyceride; high levels of blood
apo B; high levels of blood apo C-III and reduced ratio of
post-heparin hepatic lipase to lipoprotein lipase activity. HDL may
be elevated in lymph and/or cerebral fluid.
4.9. Treatment of Renal Diseases
[0264] The present invention provides methods for the treatment or
prevention of a renal disease, comprising administering to a
patient a therapeutically effective amount of a compound or a
composition comprising a compound of the invention and a
pharmaceutically acceptable vehicle. Renal diseases that can be
treated by the compounds of the present invention include
glomerular diseases (including but not limited to acute and chronic
glomerulonephritis, rapidly progressive glomerulonephritis,
nephrotic syndrome, focal proliferative glomerulonephritis,
glomerular lesions associated with systemic disease, such as
systemic lupus erythematosus, Goodpasture's syndrome, multiple
myeloma, diabetes, neoplasia, sickle cell disease, and chronic
inflammatory diseases), tubular diseases (including but not limited
to acute tubular necrosis and acute renal failure, polycystic renal
diseasemedullary sponge kidney, medullary cystic disease,
nephrogenic diabetes, and renal tubular acidosis),
tubulointerstitial diseases (including but not limited to
pyelonephritis, drug and toxin induced tubulointerstitial
nephritis, hypercalcemic nephropathy, and hypokalemic nephropathy)
acute and rapidly progressive renal failure, chronic renal failure,
nephrolithiasis, or tumors (including but not limited to renal cell
carcinoma and nephroblastoma). In a most preferred embodiment,
renal diseases that are treated by the compounds of the present
invention are vascular diseases, including but not limited to
hypertension, nephrosclerosis, microangiopathic hemolytic anemia,
atheroembolic renal disease, diffuse cortical necrosis, and renal
infarcts.
4.10. Treatment of Cancer
[0265] The present invention provides methods for the treatment or
prevention of cancer, comprising administering to a patient a
therapeutically effective amount of a compound or a composition
comprising a compound of the invention and a pharmaceutically
acceptable vehicle. Types of cancer that can be treated using a
Compound of the Invention include, but are not limited to, those
listed in Table 2. TABLE-US-00002 TABLE 2 Solid tumors, including
but not limited to fibrosarcoma myxosarcoma liposarcoma
chondrosarcoma osteogenic sarcoma chordoma angiosarcoma
endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma
synovioma mesothelioma Ewing's tumor leiomyosarcoma
rhabdomyosarcoma colon cancer colorectal cancer kidney cancer
pancreatic cancer bone cancer breast cancer ovarian cancer prostate
cancer esophogeal cancer stomach cancer oral cancer nasal cancer
throat cancer squamous cell carcinoma basal cell carcinoma
adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma
papillary carcinoma papillary adenocarcinomas cystadenocarcinoma
medullary carcinoma bronchogenic carcinoma renal cell carcinoma
hepatoma bile duct carcinoma choriocarcinoma seminoma embryonal
carcinoma Wilms' tumor cervical cancer uterine cancer testicular
cancer small cell lung carcinoma bladder carcinoma lung cancer
epithelial carcinoma glioma glioblastoma multiforme astrocytoma
medulloblastoma craniopharyngioma ependymoma pinealoma
hemangioblastoma acoustic neuroma oligodendroglioma meningioma skin
cancer melanoma neuroblastoma retinoblastoma Blood-borne cancers,
including but not limited to: acute lymphoblastic B-cell leukemia
acute lymphoblastic T-cell leukemia acute myeloblastic leukemia
"AML" acute promyelocytic leukemia "APL" acute monoblastic leukemia
acute erythroleukemic leukemia acute megakaryoblastic leukemia
acute myelomonocytic leukemia acute nonlymphocyctic leukemia acute
undifferentiated leukemia chronic myelocytic leukemia "CML" chronic
lymphocytic leukemia "CLL" hairy cell leukemia multiple myeloma
Acute and chronic leukemias Lymphoblastic myelogenous lymphocytic
myelocytic leukemias Lymphomas: Hodgkin's disease non-Hodgkin's
Lymphoma Multiple myeloma Waldenstrom's macroglobulinemia Heavy
chain disease Polycythemia vera
[0266] Cancer, including, but not limited to, a tumor, metastasis,
or any disease or disorder characterized by uncontrolled cell
growth, can be treated or prevented by administration of a Compound
of the Invention.
4.11. Treatment of Other Diseases
[0267] The present invention provides methods for the treatment or
prevention of aging, Alzheimer's Disease, cancer, cardiovascular
disease, diabetic nephropathy, diabetic retinopathy, a disorder of
glucose metabolism, dyslipidemia, dyslipoproteinemia, enhancing
bile production, enhancing reverse lipid transport, hypertension,
impotence, inflammation, insulin resistance, lipid elimination in
bile, modulating C reactive protein, obesity, oxysterol elimination
in bile, pancreatitis, Parkinson's disease, a peroxisome
proliferator activated receptor-associated disorder, phospholipid
elimination in bile, renal disease, septicemia, metabolic syndrome
disorders (e.g., Syndrome X), a thrombotic disorder, inflammatory
processes and diseases like gastrointestinal disease, irritable
bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's
Disease, ulcerative colitis), arthritis (e.g., rheumatoid
arthritis, osteoarthritis), autoimmune disease (e.g., systemic
lupus erythematosus), scleroderma, ankylosing spondylitis, gout and
pseudogout, muscle pain: polymyositis/polymyalgia
rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue rheumatism,
comprising administering to a patient a therapeutically effective
amount of a compound or a composition comprising a compound of the
invention and a pharmaceutically acceptable vehicle.
[0268] As used herein, "treatment or prevention of Alzheimer's
Disease" encompasses treatment or prevention of lipoprotein
abnormalities associated with Alzheimer's Disease.
[0269] As used herein, "treatment or prevention of Syndrome X or
Metabolic Syndrome" encompasses treatment or prevention of a
symptom thereof, including but not limited to impaired glucose
tolerance, hypertension and dyslipidemia/dyslipoproteinemia.
[0270] As used herein, "treatment or prevention of septicemia"
encompasses treatment or prevention of septic shock.
[0271] As used herein, "treatment or prevention of thrombotic
disorders" encompasses treatment or prevention of high blood levels
of fibrinogen and promotion of fibrinolysis. In addition to
treating or preventing obesity, the compositions of the invention
can be administered to an individual to promote weight reduction of
the individual.
[0272] As used herein, "treatment or prevention of diabetic
nephropathy" encompasses treating or preventing kidney disease that
develops as a result of diabetes mellitus (DM). Diabetes mellitus
is a disorder in which the body is unable to metabolize
carbohydrates (e.g., food starches, sugars, cellulose) properly.
The disease is characterized by excessive amounts of sugar in the
blood (hyperglycemia) and urine; inadequate production and/or
utilization of insulin; and by thirst, hunger, and loss of weight.
Thus, the compounds of the invention can also be used to treat or
prevent diabetes mellitus.
[0273] As used herein, "treatment or prevention of diabetic
retinopathy" encompasses treating or preventing complications of
diabetes that lead to or cause blindness. Diabetic retinopathy
occurs when diabetes damages the tiny blood vessels inside the
retina, the light-sensitive tissue at the back of the eye.
[0274] As used herein, "treatment or prevention of impotence"
includes treating or preventing erectile dysfunction, which
encompasses the repeated inability to get or keep an erection firm
enough for sexual intercourse. The word "impotence" may also be
used to describe other problems that interfere with sexual
intercourse and reproduction, such as lack of sexual desire and
problems with ejaculation or orgasm. The term "treatment or
prevention of impotence includes, but is not limited to impotence
that results as a result of damage to nerves, arteries, smooth
muscles, and fibrous tissues, or as a result of disease, such as,
but not limited to, diabetes, kidney disease, chronic alcoholism,
multiple sclerosis, atherosclerosis, vascular disease, and
neurologic disease.
[0275] As used herein, "treatment or prevention of hypertension"
encompasses treating or preventing blood flow through the vessels
at a greater than normal force, which strains the heart; harms the
arteries; and increases the risk of heart attack, stroke, and
kidney problems. The term hypertension includes, but is not limited
to, cardiovascular disease, essential hypertension, hyperpiesia,
hyperpiesis, malignant hypertension, secondary hypertension, or
white-coat hypertension.
[0276] As used herein, "treatment or prevention of inflammation"
encompasses treating or preventing inflammation diseases including,
but not limited to, chronic inflammatory disorders of the joints
including arthritis, e.g., rheumatoid arthritis and osteoarthritis;
respiratory distress syndrome, inflammatory bowel diseases such as
ileitis, ulcerative colitis and Crohn's disease; and inflammatory
lung disorders such as asthma and chronic obstructive airway
disease, inflammatory disorders of the eye such as corneal
dystrophy, trachoma, onchocerciasis, uveitis, sympathetic
ophthalmitis, and endophthalmitis; inflammatory disorders of the
gum, e.g., periodontitis and gingivitis; tuberculosis; leprosy;
inflammatory diseases of the kidney including glomerulonephritis
and nephrosis; inflammatory disorders of the skin including acne,
sclerodermatitis, psoriasis, eczema, photoaging and wrinkles;
inflammatory diseases of the central nervous system, including
AIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer's
disease, encephalomyelitis and viral or autoimmune encephalitis;
autoimmune diseases including immune-complex vasculitis, systemic
lupus and erythematodes; systemic lupus erythematosus (SLE); and
inflammatory diseases of the heart such as cardiomyopathy.
4.12. Combination Therapy
[0277] In certain embodiments of the present invention, the
compounds and compositions of the invention can be used in
combination therapy with at least one other therapeutic agent. The
compound of the invention and the therapeutic agent can act
additively or, more preferably, synergistically. In a preferred
embodiment, a compound or a composition comprising a compound of
the invention is administered concurrently with the administration
of another therapeutic agent, which can be part of the same
composition as the compound of the invention or a different
composition. In another embodiment, a compound or a composition
comprising a compound of the invention is administered prior or
subsequent to administration of another therapeutic agent. As many
of the disorders for which the compounds and compositions of the
invention are useful in treating are chronic disorders, in one
embodiment combination therapy involves alternating between
administering a compound or a composition comprising a compound of
the invention and a composition comprising another therapeutic
agent, e.g., to minimize the toxicity associated with a particular
drug. The duration of administration of each drug or therapeutic
agent can be, e.g., one month, three months, six months, or a year.
In certain embodiments, when a composition of the invention is
administered concurrently with another therapeutic agent that
potentially produces adverse side effects including but not limited
to toxicity, the therapeutic agent can advantageously be
administered at a dose that falls below the threshold at which the
adverse side is elicited.
[0278] The present compositions can be administered together with a
statin. Statins for use in combination with the compounds and
compositions of the invention include but are not limited to
atorvastatin, pravastatin, fluvastatin, lovastatin, simvastatin,
and cerivastatin.
[0279] The present compositions can also be administered together
with a PPAR agonist, for example a thiazolidinedione or a fibrate.
Thiazolidinediones for use in combination with the compounds and
compositions of the invention include but are not limited to 5 ((4
(2 (methyl 2 pyridinylamino)ethoxy)phenyl)methyl)2,4
thiazolidinedione, troglitazone, pioglitazone, ciglitazone, WAY
120,744, englitazone, AD 5075, darglitazone, and rosiglitazone.
Fibrates for use in combination with the compounds and compositions
of the invention include but are not limited to gemfibrozil,
fenofibrate, clofibrate, or ciprofibrate. As mentioned previously,
a therapeutically effective amount of a fibrate or
thiazolidinedione often has toxic side effects. Accordingly, in a
preferred embodiment of the present invention, when a composition
of the invention is administered in combination with a PPAR
agonist, the dosage of the PPAR agonist is below that which is
accompanied by toxic side effects.
[0280] The present compositions can also be administered together
with a bile acid binding resin. Bile acid binding resins for use in
combination with the compounds and compositions of the invention
include but are not limited to cholestyramine and colestipol
hydrochloride. The present compositions can also be administered
together with niacin or nicotinic acid. The present compositions
can also be administered together with a RXR agonist. RXR agonists
for use in combination with the compounds of the invention include
but are not limited to LG 100268, LGD 1069, 9-cis retinoic acid, 2
(1 (3,5,5,8,8 pentamethyl 5,6,7,8 tetrahydro 2
naphthyl)cyclopropyl)pyridine 5 carboxylic acid, or 4 ((3,5,5,8,8
pentamethyl 5,6,7,8 tetrahydro 2 naphthyl)2 carbonyl)benzoic acid.
The present compositions can also be administered together with an
anti-obesity drug. Anti-obesity drugs for use in combination with
the compounds of the invention include but are not limited to
.beta.-adrenergic receptor agonists, preferably .beta.-3 receptor
agonists, fenfluramine, dexfenfluramine, sibutramine, bupropion,
fluoxetine, and phentermine. The present compositions can also be
administered together with a hormone. Hormones for use in
combination with the compounds of the invention include but are not
limited to thyroid hormone, estrogen and insulin. Preferred
insulins include but are not limited to injectable insulin,
transdermal insulin, inhaled insulin, or any combination thereof.
As an alternative to insulin, an insulin derivative, secretagogue,
sensitizer or mimetic may be used. Insulin secretagogues for use in
combination with the compounds of the invention include but are not
limited to forskolin, dibutryl cAMP or isobutylmethylxanthine
(IBMX).
[0281] The present compositions can also be administered together
with a phosphodiesterase type 5 ("PDE5") inhibitor to treat or
prevent disorders, such as but not limited to, impotence. In a
particular, embodiment the combination is a synergistic combination
of a composition of the invention and a PDE5 inhibitor.
[0282] The present compositions can also be administered together
with a tyrophostine or an analog thereof. Tyrophostines for use in
combination with the compounds of the invention include but are not
limited to tryophostine 51.
[0283] The present compositions can also be administered together
with sulfonylurea-based drugs. Sulfonylurea-based drugs for use in
combination with the compounds of the invention include, but are
not limited to, glisoxepid, glyburide, acetohexamide,
chlorpropamide, glibomuride, tolbutamide, tolazamide, glipizide,
gliclazide, gliquidone, glyhexamide, phenbutamide, and
tolcyclamide. The present compositions can also be administered
together with a biguanide. Biguanides for use in combination with
the compounds of the invention include but are not limited to
metformin, phenformin and buformin.
[0284] The present compositions can also be administered together
with an .alpha.-glucosidase inhibitor. .alpha.-glucosidase
inhibitors for use in combination with the compounds of the
invention include but are not limited to acarbose and miglitol.
[0285] The present compositions can also be administered together
with an apo A-I agonist. In one embodiment, the apo A-I agonist is
the Milano form of apo A-I (apo A-IM). In a preferred mode of the
embodiment, the apo A-IM for administration in conjunction with the
compounds of the invention is produced by the method of U.S. Pat.
No. 5,721,114 to Abrahamsen. In a more preferred embodiment, the
apo A-I agonist is a peptide agonist. In a preferred mode of the
embodiment, the apo A-I peptide agonist for administration in
conjunction with the compounds of the invention is a peptide of
U.S. Pat. No. 6,004,925 or U.S. Pat. No. 6,037,323 to Dasseux.
[0286] The present compositions can also be administered together
with apolipoprotein E (apo E). In a preferred mode of the
embodiment, the apoE for administration in conjunction with the
compounds of the invention is produced by the method of U.S. Pat.
No. 5,834,596 to Ageland.
[0287] In yet other embodiments, the present compositions can be
administered together with an HDL-raising drug; an HDL enhancer; or
a regulator of the apolipoprotein A-I, apolipoprotein A-IV and/or
apolipoprotein genes. In one embodiment, the other therapeutic
agent can be an antiemetic agent. Suitable antiemetic agents
include, but are not limited to, metoclopromide, domperidone,
prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron, hydroxyzine, acethylleucine
monoethanolamine, alizapride, azasetron, benzquinamide,
bietanautine, bromopride, buclizine, clebopride, cyclizine,
dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,
metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine,
sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine
and tropisetron.
[0288] In another embodiment, the other therapeutic agent can be an
hematopoietic colony stimulating factor. Suitable hematopoietic
colony stimulating factors include, but are not limited to,
filgrastim, sargramostim, molgramostim and erythropoietin alfa. In
still another embodiment, the other therapeutic agent can be an
opioid or non-opioid analgesic agent. Suitable opioid analgesic
agents include, but are not limited to, morphine, heroin,
hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon,
apomorphine, normorphine, etorphine, buprenorphine, meperidine,
lopermide, anileridine, ethoheptazine, piminidine, betaprodine,
diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil,
levorphanol, dextromethorphan, phenazocine, pentazocine,
cyclazocine, methadone, isomethadone and propoxyphene. Suitable
non-opioid analgesic agents include, but are not limited to,
aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac,
fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin,
ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen,
piroxicam and sulindac.
4.13. Combination Therapy of Cardiovascular Diseases
[0289] The present compositions can be administered together with a
known cardiovascular drug. Cardiovascular drugs for use in
combination with the compounds of the invention to prevent or treat
cardiovascular diseases include but are not limited to peripheral
antiadrenergic drugs, centrally acting antihypertensive drugs
(e.g., methyldopa, methyldopa HCl), antihypertensive direct
vasodilators (e.g., diazoxide, hydralazine HCl), drugs affecting
renin-angiotensin system, peripheral vasodilators, phentolamine,
antianginal drugs, cardiac glycosides, inodilators (e.g., aminone,
milrinone, enoximone, fenoximone, imazodan, sulmazole),
antidysrhythmic drugs, calcium entry blockers, ranitine, bosentan,
and rezulin.
4.14. Combination Therapy of Cancer
[0290] The present invention includes methods for treating cancer,
comprising administering to an animal in need thereof an effective
amount of a Compound of the Invention and another therapeutic agent
that is an anti-cancer agent. Suitable anticancer agents include,
but are not limited to, those listed in Table 3. TABLE-US-00003
TABLE 3 Alkylating agents Nitrogen mustards: Cyclophosphamide
Ifosfamide trofosfamide Chlorambucil Treos Nitrosoureas: carbustine
(BCNU) Lomustine (CCNU) Alkylsulphonates Busulfan Treosulfan
Triazenes: Dacarbazine Platinum containing compounds: Cisplatin
carboplatin Plant Alkaloids Vinca alkaloids: Vicristine Vinblastine
Vindesine Vinorelbine Taxoids: paclitaxel Docetaxol DNA
Topoisomerase Inhibitors Epipodophyllins: Etoposide Teniposide
Topotecan 9-aminocamptothecin camptothecin crisnatol mitomycins:
Mitomycin C Anti-metabolites Anti-folates: DHFR inhibitors:
METHOTREXATE Trimetrexate IMP dehydrogenase Inhibitors:
Mycophenolic acid Tiazofurin Ribavirin EICAR Ribonuclotide
reductase Inhibitors: Hydroxyurea deferoxamine Pyrimidine analogs:
Uracil analogs 5-Fluorouracil Floxuridine Doxifluridine Ratitrexed
Cytosine analogs cytarabine (ara C) Cytosine arabinoside
fludarabine Purine analogs: mercaptopurine Thioguanine Hormonal
therapies: Receptor antagonists: Anti-estrogen Tamoxifen Raloxifene
megestrol goscrclin Leuprolide acetate LHRH agonists: flutamide
bicalutamide Retinoids/Deltoids Vitamin D3 analogs: EB 1089 CB 1093
KH 1060 Photodynamic therapies: vertoporfin (BPD-MA) Phthalocyanine
photosensitizer Pc4 Demethoxy-hypocrellin A (2BA-2-DMHA) Cytokines:
Interferon-.alpha. Interferon-.gamma. Tumor necrosis factor Others:
Isoprenylation inhibitors: Lovastatin Dopaminergic neurotoxins:
1-methyl-4-phenylpyridinium ion Cell cycle inhibitors:
staurosporine Actinomycines: Actinomycin D Dactinomycin Bleomycins:
bleomycin A2 Bleomycin B2 Peplomycin Anthracyclines: daunorubicin
Doxorubicin (adriamycin) Idarubicin Epirubicin Pirarubicin
Zorubicin Mitoxantrone MDR inhibitors verapamil Ca.sup.2+ ATPase
inhibitors: thapsigargin
[0291] In a specific embodiment, a composition of the invention
further comprises one or more chemotherapeutic agents and/or is
administered concurrently with radiation therapy. In another
specific embodiment, chemotherapy or radiation therapy is
administered prior or subsequent to administration of a present
composition, preferably at least an hour, five hours, 12 hours, a
day, a week, a month, more preferably several months (e.g., up to
three months), subsequent to administration of a composition of the
invention.
[0292] In other embodiments, the invention provides methods for
treating or preventing cancer, comprising administering to an
animal in need thereof an effective amount of a Compound of the
Invention and a chemotherapeutic agent. In one embodiment the
chemotherapeutic agent is that with which treatment of the cancer
has not been found to be refractory. In another embodiment, the
chemotherapeutic agent is that with which the treatment of cancer
has been found to be refractory. The Compounds of the Invention can
be administered to an animal that has also undergone surgery as
treatment for the cancer.
[0293] In one embodiment, the additional method of treatment is
radiation therapy. In a specific embodiment, the Compound of the
Invention is administered concurrently with the chemotherapeutic
agent or with radiation therapy. In another specific embodiment,
the chemotherapeutic agent or radiation therapy is administered
prior or subsequent to administration of a Compound of the
Invention, preferably at least an hour, five hours, 12 hours, a
day, a week, a month, more preferably several months (e.g., up to
three months), prior or subsequent to administration of a Compound
of the Invention.
[0294] A chemotherapeutic agent can be administered over a series
of sessions, any one or a combination of the chemotherapeutic
agents listed in Table 3 can be administered. With respect to
radiation, any radiation therapy protocol can be used depending
upon the type of cancer to be treated. For example, but not by way
of limitation, x-ray radiation can be administered; in particular,
high-energy megavoltage (radiation of greater that 1 MeV energy)
can be used for deep tumors, and electron beam and orthovoltage
x-ray radiation can be used for skin cancers. Gamma-ray emitting
radioisotopes, such as radioactive isotopes of radium, cobalt and
other elements, can also be administered. Additionally, the
invention provides methods of treatment of cancer with a Compound
of the Invention as an alternative to chemotherapy or radiation
therapy where the chemotherapy or the radiation therapy has proven
or can prove too toxic, e.g., results in unacceptable or unbearable
side effects, for the subject being treated. The animal being
treated can, optionally, be treated with another cancer treatment
such as surgery, radiation therapy or chemotherapy, depending on
which treatment is found to be acceptable or bearable.
[0295] The Compounds of the Invention can also be used in an in
vitro or ex vivo fashion, such as for the treatment of certain
cancers, including, but not limited to leukemias and lymphomas,
such treatment involving autologous stem cell transplants. This can
involve a multi-step process in which the animal's autologous
hematopoietic stem cells are harvested and purged of all cancer
cells, the patient's remaining bone-marrow cell population is then
eradicated via the administration of a high dose of a Compound of
the Invention with or without accompanying high dose radiation
therapy, and the stem cell graft is infused back into the animal.
Supportive care is then provided while bone marrow function is
restored and the animal recovers.
4.15. Surgical Uses
[0296] Cardiovascular diseases such as atherosclerosis often
require surgical procedures such as angioplasty. Angioplasty is
often accompanied by the placement of a reinforcing a metallic tube
shaped structure known as a "stent" into a damaged coronary artery.
For more serious conditions, open heart surgery such as coronary
bypass surgery may be required. These surgical procedures entail
using invasive surgical devices and/or implants, and are associated
with a high risk of restenosis and thrombosis. Accordingly, the
compounds and compositions of the invention may be used as coatings
on surgical devices (e.g., catheters) and implants (e.g., stents)
to reduce the risk of restenosis and thrombosis associated with
invasive procedures used in the treatment of cardiovascular
diseases.
4.16. Veterinary and Livestock Uses
[0297] A composition of the invention can be administered to a
non-human animal for a veterinary use for treating or preventing a
disease or disorder disclosed herein. In a specific embodiment, the
non-human animal is a household pet. In another specific
embodiment, the non-human animal is a livestock animal. In a
preferred embodiment, the non-human animal is a mammal, most
preferably a cow, horse, sheep, pig, cat, dog, mouse, rat, rabbit,
or guinea pig. In another preferred embodiment, the non-human
animal is a fowl species, most preferably a chicken, turkey, duck,
goose, or quail.
[0298] In addition to veterinary uses, the compounds and
compositions of the invention can be used to reduce the fat content
of livestock to produce leaner meats. Alternatively, the compounds
and compositions of the invention can be used to reduce the
cholesterol content of eggs by administering the compounds to a
chicken, quail, or duck hen. For non-human animal uses, the
compounds and compositions of the invention can be administered via
the animals' feed or orally as a drench composition.
4.17. Therapeutic/Prophylactic Administration and Compositions
[0299] Due to the activity of the compounds and compositions of the
invention, they are useful in veterinary and human medicine. As
described above, the compounds and compositions of the invention
are useful for the treatment or prevention of aging, Alzheimer's
Disease, cancer, cardiovascular disease, diabetic nephropathy,
diabetic retinopathy, a disorder of glucose metabolism,
dyslipidemia, dyslipoproteinemia, hypertension, impotence,
inflammation, insulin resistance, lipid elimination in bile,
modulating C reactive protein, obesity, oxysterol elimination in
bile, pancreatitis, Parkinson's disease, a peroxisome proliferator
activated receptor-associated disorder, phospholipid elimination in
bile, renal disease, septicemia, metabolic syndrome disorders
(e.g., Syndrome X), a thrombotic disorder, enhancing bile
production, enhancing reverse lipid transport, inflammatory
processes and diseases like gastrointestinal disease, irritable
bowel syndrome (IBS), inflammatory bowel disease (e.g., Crohn's
Disease, ulcerative colitis), arthritis (e.g., rheumatoid
arthritis, osteoarthritis), autoimmune disease (e.g., systemic
lupus erythematosus), scleroderma, ankylosing spondylitis, gout and
pseudogout, muscle pain: polymyositis/polymyalgia
rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid
arthritis, tendonitis, bursitis and other soft tissue
rheumatism.
[0300] The invention provides methods of treatment and prophylaxis
by administration to a patient of a therapeutically effective
amount of a compound or a composition comprising a compound of the
invention. The patient is an animal, including, but not limited, to
an animal such a cow, horse, sheep, pig, chicken, turkey, quail,
cat, dog, mouse, rat, rabbit, guinea pig, etc., and is more
preferably a mammal, and most preferably a human.
[0301] The compounds and compositions of the invention, are
preferably administered orally. The compounds and compositions of
the invention may also be administered by any other convenient
route, for example, by intravenous infusion or bolus injection, by
absorption through epithelial or mucocutaneous linings (e.g., oral
mucosa, rectal and intestinal mucosa, etc.) and may be administered
together with another biologically active agent. Administration can
be systemic or local. Various delivery systems are known, e.g.,
encapsulation in liposomes, microparticles, microcapsules,
capsules, etc., and can be used to administer a compound of the
invention. In certain embodiments, more than one compound of the
invention is administered to a patient. Methods of administration
include but are not limited to intradermal, intramuscular,
intraperitoneal, intravenous, subcutaneous, intranasal, epidural,
oral, sublingual, intranasal, intracerebral, intravaginal,
transdermal, rectally, by inhalation, or topically, particularly to
the ears, nose, eyes, or skin. The preferred mode of administration
is left to the discretion of the practitioner, and will depend
in-part upon the site of the medical condition. In most instances,
administration will result in the release of the compounds of the
invention into the bloodstream.
[0302] In specific embodiments, it may be desirable to administer
one or more compounds of the invention locally to the area in need
of treatment. This may be achieved, for example, and not by way of
limitation, by local infusion during surgery, topical application,
e.g., in conjunction with a wound dressing after surgery, by
injection, by means of a catheter, by means of a suppository, or by
means of an implant, said implant being of a porous, non-porous, or
gelatinous material, including membranes, such as sialastic
membranes, or fibers. In one embodiment, administration can be by
direct injection at the site (or former site) of an atherosclerotic
plaque tissue.
[0303] In certain embodiments, for example, for the treatment of
Alzheimer's Disease, it may be desirable to introduce one or more
compounds of the invention into the central nervous system by any
suitable route, including intraventricular, intrathecal and
epidural injection. Intraventricular injection may be facilitated
by an intraventricular catheter, for example, attached to a
reservoir, such as an Ommaya reservoir.
[0304] Pulmonary administration can also be employed, e.g., by use
of an inhaler or nebulizer, and formulation with an aerosolizing
agent, or via perfusion in a fluorocarbon or synthetic pulmonary
surfactant. In certain embodiments, the compounds of the invention
can be formulated as a suppository, with traditional binders and
vehicles such as triglycerides.
[0305] In another embodiment, the compounds and compositions of the
invention can be delivered in a vesicle, in particular a liposome
(see Langer, 1990, Science 249:1527 1533; Treat et al., in
Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353 365
(1989); Lopez Berestein, ibid., pp. 317 327; see generally
ibid.).
[0306] In yet another embodiment, the compounds and compositions of
the invention can be delivered in a controlled release system. In
one embodiment, a pump may be used (see Langer, supra; Sefton,
1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980,
Surgery 88:507 Saudek et al., 1989, N. Engl. J. Med. 321:574). In
another embodiment, polymeric materials can be used (see Medical
Applications of Controlled Release, Langer and Wise (eds.), CRC
Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,
Drug Product Design and Performance, Smolen and Ball (eds.), Wiley,
New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev.
Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228:190;
During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J.
Neurosurg. 71:105). In yet another embodiment, a controlled-release
system can be placed in proximity of the target area to be treated,
e.g., the liver, thus requiring only a fraction of the systemic
dose (see, e.g., Goodson, in Medical Applications of Controlled
Release, supra, vol. 2, pp. 115 138 (1984)). Other
controlled-release systems discussed in the review by Langer, 1990,
Science 249:1527 1533) may be used.
[0307] The present compositions will contain a therapeutically
effective amount of a compound of the invention, optionally more
than one compound of the invention, preferably in purified form,
together with a suitable amount of a pharmaceutically acceptable
vehicle so as to provide the form for proper administration to the
patient.
[0308] In a specific embodiment, the term "pharmaceutically
acceptable" means approved by a regulatory agency of the Federal or
a state government or listed in the U.S. Pharmacopeia or other
generally recognized pharmacopeia for use in animals, and more
particularly in humans. The term "vehicle" refers to a diluent,
adjuvant, excipient, or carrier with which a compound of the
invention is administered. Such pharmaceutical vehicles can be
liquids, such as water and oils, including those of petroleum,
animal, vegetable or synthetic origin, such as peanut oil, soybean
oil, mineral oil, sesame oil and the like. The pharmaceutical
vehicles can be saline, gum acacia, gelatin, starch paste, talc,
keratin, colloidal silica, urea, and the like. In addition,
auxiliary, stabilizing, thickening, lubricating and coloring agents
may be used. When administered to a patient, the compounds and
compositions of the invention and pharmaceutically acceptable
vehicles are preferably sterile. Water is a preferred vehicle when
the compound of the invention is administered intravenously. Saline
solutions and aqueous dextrose and glycerol solutions can also be
employed as liquid vehicles, particularly for injectable solutions.
Suitable pharmaceutical vehicles also include excipients such as
starch, glucose, lactose, sucrose, gelatin, malt, rice, flour,
chalk, silica gel, sodium stearate, glycerol monostearate, talc,
sodium chloride, dried skim milk, glycerol, propylene, glycol,
water, ethanol and the like. The present compositions, if desired,
can also contain minor amounts of wetting or emulsifying agents, or
pH buffering agents.
[0309] The present compositions can take the form of solutions,
suspensions, emulsion, tablets, pills, pellets, capsules, capsules
containing liquids, powders, sustained-release formulations,
suppositories, emulsions, aerosols, sprays, suspensions, or any
other form suitable for use. In one embodiment, the
pharmaceutically acceptable vehicle is a capsule (see e.g., U.S.
Pat. No. 5,698,155). Other examples of suitable pharmaceutical
vehicles are described in "Remington's Pharmaceutical Sciences" by
E. W. Martin.
[0310] In a preferred embodiment, the compounds and compositions of
the invention are formulated in accordance with routine procedures
as a pharmaceutical composition adapted for intravenous
administration to human beings. Typically, compounds and
compositions of the invention for intravenous administration are
solutions in sterile isotonic aqueous buffer. Where necessary, the
compositions may also include a solubilizing agent. Compositions
for intravenous administration may optionally include a local
anesthetic such as lignocaine to ease pain at the site of the
injection. Generally, the ingredients are supplied either
separately or mixed together in unit dosage form, for example, as a
dry lyophilized powder or water free concentrate in a hermetically
sealed container such as an ampoule or sachette indicating the
quantity of active agent. Where the compound of the invention is to
be administered by intravenous infusion, it can be dispensed, for
example, with an infusion bottle containing sterile pharmaceutical
grade water or saline. Where the compound of the invention is
administered by injection, an ampoule of sterile water for
injection or saline can be provided so that the ingredients may be
mixed prior to administration.
[0311] Compounds and compositions of the invention for oral
delivery may be in the form of tablets, lozenges, aqueous or oily
suspensions, granules, powders, emulsions, capsules, syrups, or
elixirs. Compounds and compositions of the invention for oral
delivery can also be formulated in foods and food mixes. Orally
administered compositions may contain one or more optionally
agents, for example, sweetening agents such as fructose, aspartame
or saccharin; flavoring agents such as peppermint, oil of
wintergreen, or cherry; coloring agents; and preserving agents, to
provide a pharmaceutically palatable preparation. Moreover, where
in tablet or pill form, the compositions may be coated to delay
disintegration and absorption in the gastrointestinal tract thereby
providing a sustained action over an extended period of time.
Selectively permeable membranes surrounding an osmotically active
driving compound are also suitable for orally administered
compounds and compositions of the invention. In these later
platforms, fluid from the environment surrounding the capsule is
imbibed by the driving compound, which swells to displace the agent
or agent composition through an aperture. These delivery platforms
can provide an essentially zero order delivery profile as opposed
to the spiked profiles of immediate release formulations. A time
delay material such as glycerol monostearate or glycerol stearate
may also be used. Oral compositions can include standard vehicles
such as mannitol, lactose, starch, magnesium stearate, sodium
saccharine, cellulose, magnesium carbonate, etc. Such vehicles are
preferably of pharmaceutical grade.
[0312] The amount of a compound of the invention that will be
effective in the treatment of a particular disorder or condition
disclosed herein will depend on the nature of the disorder or
condition, and can be determined by standard clinical techniques.
In addition, in vitro or in vivo assays may optionally be employed
to help identify optimal dosage ranges. The precise dose to be
employed in the compositions will also depend on the route of
administration, and the seriousness of the disease or disorder, and
should be decided according to the judgment of the practitioner and
each patient's circumstances. However, suitable dosage ranges for
oral administration are generally about 0.001 milligram to 2000
milligrams of a compound of the invention per kilogram body weight.
In specific preferred embodiments of the invention, the oral dose
is 0.01 milligram to 1000 milligrams per kilogram body weight, more
preferably 0.1 milligram to 100 milligrams per kilogram body
weight, more preferably 0.5 milligram to 25 milligrams per kilogram
body weight, and yet more preferably 1 milligram to 10 milligrams
per kilogram body weight. In a most preferred embodiment, the oral
dose is 5 milligrams of a compound of the invention per kilogram
body weight. The dosage amounts described herein refer to total
amounts administered; that is, if more than one compound of the
invention is administered, the preferred dosages correspond to the
total amount of the compounds of the invention administered. Oral
compositions preferably contain 10% to 95% active ingredient by
weight.
[0313] Suitable dosage ranges for intravenous (i.v.) administration
are 0.01 milligram to 1000 milligrams per kilogram body weight, 0.1
milligram to 350 milligrams per kilogram body weight, and 1
milligram to 100 milligrams per kilogram body weight. Suitable
dosage ranges for intranasal administration are generally about
0.01 pg/kg body weight to 1 mg/kg body weight. Suppositories
generally contain 0.01 milligram to 50 milligrams of a compound of
the invention per kilogram body weight and comprise active
ingredient in the range of 0.5% to 10% by weight. Recommended
dosages for intradermal, intramuscular, intraperitoneal,
subcutaneous, epidural, sublingual, intracerebral, intravaginal,
transdermal administration or administration by inhalation are in
the range of 0.001 milligram to 200 milligrams per kilogram of body
weight. Suitable doses of the compounds of the invention for
topical administration are in the range of 0.001 milligram to 1
milligram, depending on the area to which the compound is
administered. Effective doses may be extrapolated from
dose-response curves derived from in vitro or animal model test
systems. Such animal models and systems are well known in the
art.
[0314] The invention also provides pharmaceutical packs or kits
comprising one or more containers filled with one or more compounds
of the invention. Optionally associated with such container(s) can
be a notice in the form prescribed by a governmental agency
regulating the manufacture, use or sale of pharmaceuticals or
biological products, which notice reflects approval by the agency
of manufacture, use or sale for human administration. In a certain
embodiment, the kit contains more than one compound of the
invention. In another embodiment, the kit comprises a compound of
the invention and another lipid-mediating compound, including but
not limited to a statin, a thiazolidinedione, or a fibrate.
[0315] The compounds of the invention are preferably assayed in
vitro and in vivo, for the desired therapeutic or prophylactic
activity, prior to use in humans. For example, in vitro assays can
be used to determine whether administration of a specific compound
of the invention or a combination of compounds of the invention is
preferred for lowering fatty acid synthesis. The compounds and
compositions of the invention may also be demonstrated to be
effective and safe using animal model systems.
[0316] Other methods will be known to the skilled artisan and are
within the scope of the invention.
[0317] The following examples are provided by way of illustration
and not limitation.
5. EXAMPLES
5.1. Keto-substituted .alpha.-Cycloalkyldicarboxylic Acids
[0318] The cycloalkyl substituted keto-derivatives II are prepared
as shown in Scheme 14 by methods already described in Dasseux,
J.-L. H. et al. Ketone compounds and compositions for cholesterol
management and related uses. U.S. patent application publication
20030078239, Oct. 11, 2001. The key step in the syntheses of most
of the compounds of the invention is the alkylation of the
formaldehyde synthon: Tosylmethyl Isocyanide (TosMIC) (Possel, O.
et al. Tetrahedron Lett., 1977, 17, 4229-4232; Kurosawa, K. et al.
Tetrahedron Lett., 1982, 23, 5335-5338; Yadav, J. S. et al.
Tetrahedron Lett., 1990, 31, 6217-6218; van Leusen, D. et al.
Synthetic Uses of Tosylmethyl Isocyanide (TosMIC). In Organic
Reactions, Vol. 57; Overman, L. E., Editor-in-Chief; John Wiley and
Sons, Inc.: New York, 2001; pp 417-666) with a properly
functionalized halo-ester, which is available commercially (e.g.,
Aldrich Chemical Co., Milwaukee, Wis.) or can be prepared by
well-known methods such as halogenation or sulfonation of
butanediol. ##STR518##
[0319] In a typical procedure, a halo-ester is prepared via
alkylation of commercially available or known esters of type 101
with a dihaloalkane of type 102 of proper length as described in
Scheme 15. Cycloakyl carboxylic esters of type 101 prepared for
this invention are used for the preparation of haloesters described
in Table 1. Ethyl, butyl and t-butyl ester analogues of 101 could
be used as starting material. As an example, ethyl
cyclopropylcarboxylate, which is known to self-condensate on
treatment with various bases, as described in Pinnick, H. W. et al.
J. Org. Chem., 1980, 45, 4505-4507, cannot be used for this
reaction, and the corresponding t-butyl analogue is used instead,
which is prepared as described in the literature (Haener, R. et al.
Helv. Chim. Acta, 1986, 69, 1655-1665). In a typical procedure,
bromo-esters 103a-g are prepared via treatment of 101 with LDA and
a large excess of a dibromoalkane (102, X=Br) or bromo-chloroalkane
(102, X=Cl) in THF at low temperatures. The crude product 104 is
separated from excess of 102 via fractional distillation. If
iododerivatives are needed due to the lack of reactivity of the
chloro-ester derivatives (104a-c), the latter are converted to the
corresponding iodides (105a-c) by methods known in the literature
prior to their reaction with TosMIC. In the case of the
bromo-esters (103a-g) treatment with a catalytic amount of
Bu.sub.4NI suffices to form the corresponding iodo compounds in
situ. ##STR519## TABLE-US-00004 TABLE 1 Synthesis of halo-esters
103a-g, 104a-c and 105a-c. Compound m R R1 R2 X Yield (%) 103a 4 Et
Me Me Br .sup.a 103b 4 tBu cyclo-Propyl Br 34.sup.b 103c 4 Bu
cyclo-Pentyl Br 49 103d 4 Et CO.sub.2Et Me Br .sup.c 103e 5 Et Me
Me Br .sup.a 103f 5 Bu cyclo-Pentyl Br 61.sup.b 103g 7 Et Me Me Br
45 104a 4 tBu cyclo-Propyl Cl 52 104b 4 Et cyclo-Butyl Cl 86 104c 5
tBu cyclo-Propyl Cl 73 105a 4 tBu cyclo-Propyl I 94.sup.b 105b 4 Et
cyclo-Butyl I 99 105c 5 tBu cyclo-Propyl I 99 .sup.aSee: Ackerley,
N. et al. J. Med. Chem., 1995, 38, 1608-1628. .sup.bPurity >90%.
.sup.cSee: Astles, P. C. et al. J. Med. Chem., 1996, 39,
1423-1432.
[0320] Symmetrical ketones are prepared by Method A (e.g. TosMIC,
NaH, 3, Bu.sub.4NI in DMSO) as described in Scheme 16. The
intermediate dialkylated TosMIC derivatives is treated with conc
HCl in CH.sub.2Cl.sub.2 to provide keto-diesters 106d,g-h,j,m-n in
moderate to good yield as shown in Scheme 15 and Table 2. For the
preparation of keto-diacids 106c,e-f,k-l Method B is applied (e.g.,
KOtBu, 105 in N,N-dimethylacetamide at temperatures between
-10.degree. C. to 35.degree. C., preferably room temperature),
which is similar to the one described by Haener, R. et al. Helv.
Chim. Acta, 1986, 69, 1655-1665 and products are obtained as
described in Table 2. ##STR520##
[0321] For the preparation of asymmetrical ketones 106c,e,k a set
of mono-alkylated TosMIC derivatives (108a,b) are used as starting
materials that are prepared as described in Scheme 17. As such
intermediates could only be produced in low yield via Method A the
more selective conditions (K.sub.2CO.sub.3, DMAc) are applied,
providing 108a,b in good yield (Table 3). Subsequent treatment of
108a,b as reported for Method A or B afforded the asymmetrical
ketones 106c,e,k (Table 2). The target keto-diacids (107) were
prepared from the corresponding ester analogues (106) by
saponification of the linear alkane esters (Et, Bu), treatment of
the t-butyl esters with HCO.sub.2H or a combination of the two
(Schemes 3 and 4). Preparations are similar for compounds with
other terminal groups than acids, as described in Dasseux, J.-L. H.
et al. Ketone compounds and compositions for cholesterol management
and related uses. U.S. patent application 20030078239, Oct. 11,
2001 ##STR521## TABLE-US-00005 TABLE 2 Syntheses of keto-esters
(106) and corresponding keto-acids (107) using TosMIC chemistry.
Compound 107 Elemental Analysis Compound 6 106.fwdarw. 107 Found
(Calculated) Yield Meth- Yield mp 106 m n R R1 R2 R3 R4 R5
Method.sup.6 (%) od.sup.6 (%) C H (.degree. C.) c 4 4 CO.sub.2Et
CO.sub.2tBu Me Me cyclo-Propyl C 43.sup.b F 80.sup.b 65.06 (65.36)
9.02 (9.03) 49-52 d 4 4 CO.sub.2tBu CO.sub.2tBu cyclo-Propyl
cyclo-Propyl A 49 E 99 65.40 (65.78) 8.37 (8.44) 132-134 e 4 4
CO.sub.2Et CO.sub.2Et Me Me cyclo-Butyl C 75.sup.b D 76 53-55 f 4 4
CO.sub.2Et CO.sub.2Et cyclo-Butyl cyclo-Butyl B 82 D 56 67.19
(67.43) 8.97 (8.93) 69-70 g 4 4 CO.sub.2Bu CO.sub.2Bu cyclo-Pentyl
cyclo-Pentyl A 56 D 94.sup.b 68.78 (68.82) 9.47 (9.35) 104-106 h 4
4 CO.sub.2Et CO.sub.2Et Me CO.sub.2Et Me CO.sub.2Et A 71 .sup.c 81
-- -- -- k 5 5 CO.sub.2Et CO.sub.2tBu Me Me cyclo-Propyl C 57.sup.b
F 84 66.86 (67.03) 9.50 (9.47) 65-66 I 5 5 CO.sub.2tBu CO.sub.2tBu
cyclo-Propyl cyclo-Propyl B 46.sup.b E 99 67.20 (67.43) 9.05 (8.93)
122-123 m 5 5 CO.sub.2Bu CO.sub.2Bu cyclo-Pentyl cyclo-Pentyl A
68.sup.b D 83 70.37 (70.02) 9.72 (9.71) 78-85 n 7 7 CO.sub.2Et
CO.sub.2Et Me Me Me Me A 57 D 74 69.41 (69.31) 10.73 (10.62) 74-77
.sup.aSee ref 6. .sup.bPurity >90%. .sup.cKOH, EtOH, rt.
[0322] TABLE-US-00006 TABLE 3 Synthesis of 108a-b. Yield Compound m
R R1 R2 (%) 8a 4 Et Me Me 67 8b 5 Et Me Me 61
[0323] t-Butyl 1-(4-bromo-butyl)-cyclopropanecarboxylate (103b).
Under a N.sub.2 atmosphere at -60.degree. C., a solution of t-butyl
cyclopropanecarboxylate (80.05 g, 0.507 mol) and 1,4-dibromobutane
(219.3 g, 1.01 mol) in dry THF (800 mL) was added dropwise to a
solution of LDA (2 M in THF/heptane/ethylbenzene, 380 mL, 0.76 mol)
in 1.5 h. Stirring was continued for 5 h, during which the reaction
mixture was allowed to slowly reach rt. After that, the reaction
mixture was poured into saturated aqueous NH.sub.4Cl (1 L). The
organic layer was separated and concentrated in vacuo to a smaller
volume. The aqueous layer was extracted with Et.sub.2O (3.times.200
mL). The combined organic layers were washed with saturated aqueous
NH.sub.4Cl (2.times.400 mL) and brine (400 mL) and dried. The
remaining residue was purified by fractional distillation under
reduced pressure to give 103b (51.4 g, 94% pure by GC, 34%) as a
slightly yellow oil. bp: T=93-96.degree. C. (p=0.075-0.087 Torr).
.sup.1H NMR: .delta. 3.40 (t, J=6.8 Hz, 2H), 1.85 (quintet, J=7.1
Hz, 2H), 1.65-1.46 (m, 4H), 1.43 (s, 9H), 1.12 (q, J=3.5 Hz, 2H),
0.60 (q, J=3.5 Hz, 2H). .sup.13C NMR: .delta. 174.0, 79.8, 33.6,
33.2, 32.8, 27.9 (3.times.), 26.3, 23.9, 15.1 (2.times.). HRMS
calcd for C.sub.12H.sub.21BrO.sub.2 (MH.sup.+): 277.0803, found:
277.0807.
[0324] Butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (103c).
Compound 103c was prepared, likewise the procedure described for
103b, starting from butyl cyclopentanecarboxylate (Payne, G. B. et
al. J. Org. Chem., 1957, 22, 1680-1682) (80.0 g, 0.42 mol),
1,4-dibromobutane (183.3 g, 0.84 mol) and LDA (2 M in
THF/heptane/ethylbenzene, 250 mL, 0.50 mol) to give, after
purification by fractional distillation under reduced pressure,
103c (62.8 g, 49%) as a light yellow liquid. bp: T=116-117.degree.
C. (p=0.040-0.051 Torr). .sup.1H NMR: .delta. 4.07 (t, J=6.6 Hz,
2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet,
J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2
Hz, 3H). .sup.13C NMR: .delta. 177.6, 64.1, 53.9, 38.2, 36.0
(2.times.), 33.3, 33.0, 30.6, 24.8 (2.times.), 24.6, 19.1, 13.6.
HRMS calcd for C.sub.14H.sub.25BrO.sub.2 (M.sup.+): 304.1038,
found: 304.1042.
[0325] Butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate (103f).
Compound 103f was prepared, likewise the procedure described for
103b, starting from butyl cyclopentanecarboxylate (40.2 g, 0.236
mol), 1,5-dibromopentane (64 mL, 0.45 mol) and LDA (2 M in
THF/heptane/ethylbenzene, 200 mL, 0.40 mol) to give, after
purification by fractional distillation under reduced pressure, 3f
(49.1 g, 93% pure by GC, 61%) as a bright yellow liquid. bp:
T=123.degree. C. (p=0.001 Torr). .sup.1H NMR: .delta. 4.06 (t,
J=6.6 Hz, 2H), 3.38 (t, J=6.9 Hz, 2H), 2.15-2.07 (m, 2H), 1.89-1.79
(quintet, J=7.1 Hz, 2H), 1.69-1.56 (m, 8H), 1.49-1.32 (m, 6H),
1.28-1.17 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). .sup.13C NMR: .delta.
177.7, 64.0, 54.0, 39.0, 36.0 (2.times.), 33.6, 32.5, 30.7, 28.5,
25.1, 24.8 (2.times.), 19.1, 13.6. HRMS calcd for
C.sub.15H.sub.27BrO.sub.2 (M.sup.+): 318.1195, found: 318.1192.
[0326] Ethyl 2,2-dimethyl-9-bromononanoate (103g). Under a N.sub.2
atmosphere at 0.degree. C., LDA (2 M in THF/heptane/ethylbenzene,
13.0 mL, 26.0 mmol) was added dropwise to a mixture of ethyl
isobutyrate (3.5 mL, 25.9 mmol) and 1,7-dibromoheptane (9.84 g,
38.2 mmol) in dry THF (50 mL) in 1.5 h, while keeping the
temperature below 5.degree. C. After 3 h, the mixture was poured
into ice-cold saturated aqueous NH.sub.4Cl (150 mL). The layers
were separated and the aqueous phase was extracted with Et.sub.2O
(3.times.100 mL). The combined organic layers were washed with
aqueous HCl (1 M, 100 mL), saturated aqueous NaHCO.sub.3 (100 mL)
and brine (100 mL) and dried. The remaining residue was purified by
column chromatography (heptane:EtOAc=40:1) twice to give 103g (3.42
g, 45%) as a colorless liquid. .sup.1H NMR: .delta. 4.11 (q, J=7.2
Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.85 (quintet, J=6.9 Hz, 2H),
1.52-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.35-1.20 (m, 6H), 1.24 (t,
J=7.2 Hz, 3H), 1.15 (s, 6H). .sup.13C NMR: .delta. 177.8, 60.0,
42.0, 40.5, 33.7, 32.7, 29.7, 28.5, 28.0, 25.0 (2.times.), 24.7,
14.1. HRMS calcd for C.sub.13H.sub.25BrO.sub.2 (M.sup.+): 292.1038,
found: 292.1034.
[0327] t-Butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (104a).
Compound 104a was prepared, likewise the procedure described for
103b, starting from t-butyl cyclopropanecarboxylate (Kohlrausch, K.
W. F. et al. Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285)
(12.5 g, 88 mmol), 1-bromo-4-chlorobutane (13.7 mL, 117 mmol) and
LDA (prepared from BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) and
iPr.sub.2NH (12.3 mL, 88 mmol, distilled from NaOH)) to give, after
purification by fractional distillation under reduced pressure,
104a (10.73 g 52%) as a colorless oil. bp: T=57-61.degree. C.
(p=0.001 mbar). .sup.1H NMR: .delta. 3.52 (t, J=6.6 Hz, 2H), 1.76
(quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42
(s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz,
2H). .sup.13C NMR: .delta. 173.9, 80.0, 45.1, 33.6, 32.9, 28.2
(3.times.), 25.3, 24.2, 15.4 (2.times.). HRMS calcd for
C.sub.12H.sub.22ClO.sub.2 (MH.sup.+): 233.1308, found:
233.1308.
[0328] Ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (104b).
Compound 104b was prepared, likewise the procedure described for
104c, starting from LDA (prepared from BuLi (2.5M in hexanes, 52.8
mL, 132 mmol) and iPr.sub.2NH (18.52 mL, 132 mmol, distilled from
NaOH)), ethyl 1-cyclobutanecarboxylate (Torok, B. et al. J. Chem.
Soc. Perkin Trans. 1, 1993, 7, 801-804) (14.05 g, 110 mmol) (the
resulting mixture was allowed to warm to 0.degree. C. and cooled
again to -60.degree. C.) and 1-bromo-4-chlorobutane (19.1 mL, 165
mmol) to give, after purification by fractional distillation under
reduced pressure, 104b (20.53 g, 86%) as a thin, colorless oil. bp:
T=64-71.degree. C. (p=0.001 Torr). .sup.1H NMR: .delta. 4.13 (q,
J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70
(m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). .sup.13C NMR:
.delta. 176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2.times.), 22.4,
15.8, 14.4.
[0329] t-Butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (104c).
Under an Ar atmosphere at 0.degree. C., BuLi (2.5M in hexanes, 80
mL, 0.20 mol) was added dropwise to a solution of iPr.sub.2NH (27.2
mL, 194 mmol, distilled from NaOH) in dry THF (200 mL) in 30 min.
The reaction mixture was stirred for 30 min, cooled to -70.degree.
C. and then, t-butyl cyclopropanecarboxylate (25.0 g, 176 mmol) was
added dropwise in 30 min. The resultant mixture was allowed to warm
up to -35.degree. C., cooled again to -70.degree. C. and then
1-bromo-5-chloropentane (36 mL, 50.7 g, 273 mmol) was added
dropwise in 15 min. The reaction mixture was allowed to reach
-5.degree. C., stirred for 3 h, poured into a mixture of ice (100
mL), H.sub.2O (100 mL), brine (200 mL) and aqueous HCl (2 M, 200
mL) and extracted with Et.sub.2O (2.times.300 mL). The combined
organic layers were washed with a mixture of brine and saturated
aqueous NaHCO.sub.3 (10:1, 300 mL) and dried. The remaining oil was
purified by fractional distillation under reduced pressure to give
104c (31.5 g, 73%) as a colorless liquid. bp: T=67-74.degree. C.
(p=0.001 mbar). .sup.1H NMR: 3.52 (t, J=6.6 Hz, 2H), 1.77 (quintet,
J=6.8 Hz, 2H), 1.48-1.38 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.5 Hz,
3.8 Hz, 2H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). .sup.13C NMR: .delta.
174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3.times.), 27.20, 27.17, 24.3,
15.4 (2.times.). HRMS calcd for C.sub.13H.sub.24ClO.sub.2
(MH.sup.+): 247.1465, found: 247.1465.
[0330] t-Butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate (105a). To
a solution of t-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate
(104a, 10.6 g, 45.7 mmol) in 2- butanone (50 mL) was added NaI
(8.23 g, 54.5 mmol). The reaction mixture was stirred under reflux
overnight, diluted with Et.sub.2O (100 mL), washed with a mixture
of H.sub.2O (100 mL) and aqueous Na.sub.2S.sub.2O.sub.4 (0.5 M, 10
mL) and brine (50 mL) and dried to give 105a (14.8 g, 94% pure by
GC, 94%) as a slightly yellow liquid. .sup.1H NMR: .delta. 3.18 (t,
J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.62-1.45 (m, 4H),
1.43 (s, 9H), 1.12 (dd, J=6.7 Hz, 3.8 Hz, 2H), 0.60 (dd, J=6.6 Hz,
3.9 Hz, 2H). .sup.13C NMR: .delta. 173.9, 80.0, 33.8, 33.3, 28.9,
28.2 (3.times.), 24.2, 15.5 (2.times.), 7.2. HRMS calcd for
C.sub.12H.sub.21IO.sub.2 (M.sup.+): 324.0587, found: 324.0587.
[0331] Ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (105b).
Compound 105b was prepared, likewise the procedure described for
5a, starting from ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate
(104b, 21.21 g, 97.0 mmol) and NaI (19.07 g, 127 mmol) to give 105b
(29.91 g, 99%) as a slightly yellow oil. .sup.1H NMR: .delta. 4.14
(q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H),
1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H).
.sup.13C NMR: .delta. 176.5, 60.3, 47.5, 36.9, 33.7, 30.1
(2.times.), 26.0, 15.7, 14.5, 6.8.
[0332] t-Butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (105c).
To a solution of t-butyl
1-(5-chloropentyl)-1-cyclopropanecarboxylate (104c, 31.5 g, 128
mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166 mmol). The
reaction mixture was stirred under reflux for 24 h, diluted with
heptane (220 mL) and filtered through a layer of silicagel
(.about.2 cm) in a glassfilter. The residue was eluted with a
mixture of heptane and EtOAc (3:1, 5.times.100 mL). The combined
filtrate and elutes were evaporated in vacuo to give 5c (42.3 g,
99%) as a slightly yellow liquid. .sup.1H NMR: .delta. 3.18 (t,
J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H),
1.42 (s, 9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz,
2H). .sup.13C NMR: .delta. 174.0, 79.9, 34.1, 33.6, 30.8, 28.2
(3.times.), 26.8, 24.3, 15.4 (2.times.), 7.4. HRMS calcd for
C.sub.13H.sub.23IO.sub.2 (M.sup.+): 338.0743, found: 338.0743.
[0333]
{7-Ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(m-
ethylidyne)ammonium (108a). To a mixture of K.sub.2CO.sub.3 (13.18
g, 95.6 mmol) and Bu.sub.4NI (2.35 g, 6.36 mmol) in dry DMF (50 mL)
was added a solution of 103a (24.00 g, 95.6 mmol) and TosMIC (12.41
g, 63.7 mmol) in dry DMF (50 mL) in 20 min under a N.sub.2
atmosphere while stirring vigorously. After 4 d, H.sub.2O (100 mL)
was added dropwise while keeping the temperature below 25.degree.
C. by cooling with an ice-bath. The resulting mixture was extracted
with Et.sub.2O (3.times.200 mL). The combined organic layers were
washed with saturated aqueous NaHCO.sub.3 (2.times.200 mL) and
dried. The remaining residue was purified by column chromatography
(silica; heptane:EtOAc=6:1; a layer of NaHCO.sub.3 was put on the
base of the column) to give 108a (15.68 g, 42.8 mmol, 67%) as a
slightly yellow oil which slowly solidified on standing. An
analytical sample was obtained after recrystallization (0.43 g)
from iPr.sub.2O/heptane at .about.4.degree. C. to give 108a (0.30
g) as a white solid. mp=38-39.degree. C. .sup.1H NMR: .delta. 7.84
(d, J=8.4 Hz, 2H), 7.40 (d, J=7.8 Hz, 2H), 4.43 (dd, J=3.3, 10.8
Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 2.48 (s, 3H), 2.23-2.12 (m, 1H),
1.90-1.77 (m, 1H), 1.66-40 (m, 4H), 1.38-1.22 (m, 2H), 1.24 (t,
J=7.1 Hz, 3H), 1.15 (s, 6H). .sup.13C NMR: .delta. 177.3, 164.6,
146.3, 131.0, 129.93 (2.times.), 129.87 (2.times.), 72.8, 60.4,
42.2, 40.2, 28.4, 26.0, 25.35, 25.30, 24.2, 22.0, 14.5.
[0334]
{8-Ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl}(me-
thylidyne)ammonium (108b). Under a N.sub.2 atmosphere, TosMIC
(10.01 g, 51.3 mmol) and 103e (20.41 g, 77.0 mmol) were dissolved
in dry DMF (100 mL) and BU4NI (1.89 g, 5.12 mmol) and
K.sub.2CO.sub.3 (10.62 g, 76.8 mmol) were added while stirring
vigorously. After 5 d, the reaction mixture was poured in an
ice/H.sub.2O mixture (500 mL) and extracted with Et.sub.2O
(1.times.200 mL, 2.times.100 mL). The combined organic layers were
washed with brine (2.times.50 mL) and dried. The remaining residue
was purified by column chromatography (silica, heptane:EtOAc=3:1)
to give in order of elution 103e (5.67 g, 90% pure by GC), an
impure batch of 108b (0.94 g), and pure 108b (11.83 g, 61%) as a
colorless oil. .sup.1H NMR: .delta. 7.86 (d, J=8.1 Hz, 2H), 7.43
(d, J=8.1 Hz, 2H), 4.45 (dd, J=10.9, 3.5 Hz, 1H), 4.11 (q, J=7.2
Hz, 2H), 2.49 (s, 3H), 2.22-2.11 (m, 1H), 1.90-1.77 (m, 1H),
1.67-1.57 (m, 1H), 1.53-1.42 (m, 3H), 1.24 (t, J=7.2 Hz, 3H),
1.39-1.20 (m, 4H), 1.15 (s, 6H). .sup.13C NMR: .delta. 177.8,
164.8, 146.5, 131.1, 130.1 (2.times.), 130.0 (2.times.), 72.8,
60.2, 42.0, 40.3, 29.0, 28.3, 25.12, 25.06 (2.times.), 24.5, 21.7,
14.2. HRMS calcd for C.sub.20H.sub.29NNaO.sub.4S (MNa.sup.+):
402.1715, found: 402.1736.
General Procedures for Alkylation of TosMIC
[0335] Method A. t-Butyl
1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarbo-
xylate (106d). Under a N.sub.2 atmosphere, NaH (60% (.sup.w/w) in
mineral oil, 2.91 g, 72.8 mmol) was added portionwise to a solution
of TosMIC (5.85 g, 30.0 mmol) and Bu.sub.4NI (1.10 g, 2.98 mmol) in
dry DMSO (100 mL) while stirring vigorously and cooling with a
water bath. After 10 min, 103b (16.56 g, 94% pure by GC, 56.2 mmol)
was added dropwise in 20 min and stirring was continued for 1 h and
50 min. Then, H.sub.2O (100 mL) was added dropwise and the
resulting mixture was extracted with Et.sub.2O (3.times.100 mL).
The combined organic layers were washed with brine (2.times.100 mL)
and dried. The remaining oil was purified by column chromatography
(silica, heptane:EtOAc=6:1) to give t-butyl
1-{9-[1-(t-butoxycarbonyl)cyclopropyl]-5-isocyano-5-[(4-methylphenyl)sulf-
onyl]nonyl}-1-cyclopropanecarboxylate (10.00 g) as a slightly
yellow oil.
[0336] Acidic hydrolysis of alkylated TosMIC intermediate. The
above mentioned oil (10.00 g) was dissolved in CH.sub.2Cl.sub.2
(200 mL) and conc aqueous HCl (4 mL) was added. After stirring
vigorously for 1 h, H.sub.2O (100 mL) was added and the layers were
separated. The aqueous phase was extracted with CH.sub.2Cl.sub.2
(100 mL) and the combined organic layers were washed with saturated
aqueous NaHCO.sub.3 (3.times.100 mL) and dried. The remaining
residue was purified by column chromatography (silica,
heptane:EtOAc=10:1) to give 106d (5.80 g, 49%) as a colorless oil.
.sup.1H NMR: .delta. 2.39 (t, J=7.3 Hz, 4H), 1.63-1.38 (m, 30H),
1.10 (dd, J=6.6, 3.9 Hz, 4H), 0.59 (dd, J=6.7,3.9 Hz, 4H). .sup.13C
NMR: .delta. 211.1, 174.4 (2.times.), 79.9 (2.times.), 42.7
(2.times.), 33.9 (2.times.), 28.0 (6.times.), 27.4 (2.times.), 24.1
(2.times.), 24.0 (2.times.), 15.2 (4.times.). HRMS calcd for
C.sub.25H.sub.43O.sub.5 (MH.sup.+): 423.3111, found: 423.3111.
[0337] Method B. Ethyl
1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate
(106f). Under a N.sub.2 atmosphere at 0.degree. C., KOtBu (8.61 g,
76.7 mmol) was added portionwise to a solution of 105b (24.83 g,
80.1 mmol) and TosMIC (7.26 g, 36.4 mmol) in N,N-dimethylacetamide
(DMAc, 150 mL). After 30 min, the reaction mixture was allowed to
warm to rt, stirred for 1.5 h and diluted with DMAc (10 mL). Then,
105b (2.01 g, 6.5 mmol) and KOtBu (0.81 g, 7.2 mmol) were added
followed by another portion of 105b (1.00 g, 3.2 mmol) and KOtBu
(0.86 g, 7.7 mmol) after 1 h. After 1 h, the reaction mixture was
poured into a mixture of Et.sub.2O (700 mL) and aqueous NaCl (10%,
500 mL) and the layers were separated. The organic layer was washed
with brine (1.times.500 mL, 1.times.300 mL) and dried. The
remaining residue was purified by column chromatography (silica,
heptane:EtOAc=6:1) to give ethyl
1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl-
]nonyl-1-cyclobutanecarboxylate (18.35 g) as a slightly yellow oil.
Part of this oil (15.62 g, 27.9 mmol) was hydrolyzed with conc
aqueous HCl (75 mL) according to the procedure described for 106d
to give, after purification by column chromatography (silica,
heptane:EtOAc=6:1), 106f (9.99 g, 82%) as a slightly yellow liquid,
after evaporation from CH.sub.2Cl.sub.2 (100 mL). .sup.1H NMR:
.delta. 4.12 (q, J=7.1 Hz, 4H), 2.44-2.32 (m, 8H), 1.93-1.79 (m,
8H), 1.77-1.72 (m, 4H), 1.55 (quintet, J=7.5 Hz, 4H), 1.25 (t,
J=7.1 Hz, 6H), 1.21-1.10 (m, 4H). .sup.13C NMR: .delta. 210.2,
176.7 (2.times.), 60.2 (2.times.), 47.6 (2.times.), 42.6
(2.times.), 37.9 (2.times.), 30.1 (4.times.), 24.7 (2.times.), 24.1
(2.times.), 15.7 (2.times.), 14.4 (2.times.). HRMS calcd for
C.sub.23H.sub.38O.sub.5 (M.sup.+): 394.2719, found: 394.2703.
[0338] Method C. Ethyl
13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate
(106k). Under a N.sub.2 atmosphere at 0.degree. C., a solution of
108b (28.4 g, 75.0 mmol) in N,N-dimethylacetamide (DMAc, 125 mL)
followed by a solution of 105c (25.4 g, 75.0 mmol) in DMAc (125 mL)
were added dropwise in 60 and 30 min, respectively to a solution of
KOtBu (8.83 g, 79.0 mmol) in DMAc (250 mL). The mixture was allowed
to reach rt and stirring was continued for 2 h. Then, the reaction
mixture was quenched by the dropwise addition of H.sub.2O (250 mL)
while cooling with an ice-bath. The resulting mixture was extracted
with Et.sub.2O (3.times.250 mL) and the combined organic layers
were washed with brine (2.times.250 mL) and dried to give a yellow
oil (43.02 g). Part of this oil (42.50 g) was hydrolyzed with conc
aqueous HCl (34 mL) according to the procedure described for 106d
to give, after purification by column chromatography (silica,
heptane:EtOAc=8:1), 106k (19.0 g, 95% pure by .sup.1H NMR, 57%) as
a slightly yellow oil. .sup.1H NMR: .delta. 4.09 (q, J=7.2 Hz, 2H),
2.37 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H), 1.62-1.35 (m, 10H),
1.41 (s, 9H), 1.30-1.21 (m, 6H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (s,
6H), 1.09 (dd, J=6.6, 3.9 Hz, 2H), 0.58 (dd, J=6.3, 3.6 Hz, 2H).
.sup.13C NMR: .delta. 210.8, 177.6, 174.1, 79.8, 60.2, 42.9. 42.8,
42.2, 40.6, 34.1, 29.8, 29.6, 28.2 (3.times.), 27.6, 25.3
(2.times.), 24.9, 24.3, 23.9, 23.8, 15.3 (2.times.), 14.4.
[0339] Ethyl
11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate
(106c). Compound 6c was prepared likewise Method C starting from
108a (20.5 g, 55.9 mmol), 105a (18.11 g, 55.9 mmol) and KOtBu (6.57
g, 58.7 mmol) to give a yellow oil (31.79 g). Part of this oil
(30.63 g) was treated with conc aqueous HCl (23 mL), as described
for 106d, to give, after purification by column chromatography
(silica, heptane:EtOAc=40:1), 106c (9.83 g, >90% pure by NMR,
43%) as a colorless oil. .sup.1H NMR: .delta. 4.09 (q, J=7.2 Hz,
2H), 2.38 (t, J=7.2 Hz, 4H), 1.62-1.35 (m, 10H), 1.41 (s, 9H),
1.26-1.17 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (s, 6H), 1.09 (dd,
J=6.9, 4.2 Hz, 2H), 0.59 (dd, J=6.3, 3.6 Hz, 2H). .sup.13C NMR:
.delta. 210.5, 177.4, 174.0, 79.8, 60.2, 42.8, 42.6, 42.1, 40.5,
34.0, 28.2 (3.times.), 27.5, 25.2 (2.times.), 24.7, 24.3, 24.2,
24.1, 15.3 (2.times.), 14.4.
[0340] Ethyl
11-[1-(ethoxycarbonyl)cyclobutyl]-2,2-dimethyl-7-oxoundecanoate
(106e). Compound 106e was prepared likewise Method C starting from
108a (11.01 g, 30.1 mmol), 105b (10.28 g, 33.1 mmol) and KOtBu
(4.06 g, 36.2 mmol) to give, after purification by column
chromatography (silica, heptane:EtOAc=6:1; a layer of NaHCO.sub.3
was put on the base of the column), ethyl
1-[11-ethoxy-5-isocyano-10,10-dimethyl-5-[(4-methylphenyl)sulfonyl]-11-ox-
oundecyl]-1-cyclobutanecarboxylate (14.11 g) as a colorless oil.
Part of this oil (13.86 g, 25.3 mmol) was treated with conc aqueous
HCl (50 mL), as described for 106d, to give crude 106e, which was
stirred up in heptane (50 mL) and the resulting precipitate was
filtered off and washed with heptane (3.times.50 mL). The combined
filtrates were washed with aqueous NaOH (1M, 2.times.50 mL) and
brine (50 mL) and dried to give 106e (9.44 g, >90% pure by
.sup.1H NMR, 75%) as a slightly yellow oil. .sup.1H NMR: .delta.
4.12 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 2.50-2.29 (m, 2H),
2.37 (t, J=7.4 Hz, 4H), 1.95-1.70 (m, 6H), 1.61-1.44 (m, 6H),
1.30-1.09 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H),
1.14 (s, 6H). .sup.13C NMR: .delta. 210.1, 177.3, 176.6, 60.1
(2.times.), 47.5, 42.57 (2.times.), 42.1, 40.4, 37.8, 30.0
(2.times.), 25.2 (2.times.), 24.7, 24.6, 24.2, 24.1, 15.7, 14.4,
14.3.
[0341] Butyl
1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate
(106g). Compound 106g was prepared likewise Method A starting from
TosMIC (6.58 g, 33.0 mmol), Bu.sub.4NI (1.31 g, 3.55 mmol), NaH
(60% (.sup.w/w) in mineral oil, 3.20 g and 0.56 g after 2 h, 80.0
and 14.0 mmol) and 103c (21.59 g, 67.2 mmol) to give, after
purification by column chromatography (silica, heptane:EtOAc=8:1),
butyl
1-{9-[1-(butoxycarbonyl)cyclopentyl]-5-isocyano-5-[(4-methylphenyl)sulfon-
yl]nonyl}-1-cyclopentanecarboxylate as a yellow oil (13.38 g). This
oil (13.38 g) was treated with conc aqueous HCl (75 mL), as
described for 106d, to give, after purification by column
chromatography (silica, heptane:EtOAc=10:1), 106g (9.05 g, 56%) as
a slightly yellow liquid. .sup.1H NMR: .delta. 4.05 (t, J=6.5 Hz,
4H), 2.36 (t, J=7.5 Hz, 4H), 2.14-2.05 (m, 4H), 1.65-1.32 (m, 28H),
1.24-1.16 (m, 4H), 0.96 (t, J=7.2 Hz, 6H). .sup.13C NMR: .delta.
210.8, 177.8 (2.times.), 64.1 (2.times.), 54.0 (2.times.), 42.6
(2.times.), 39.0 (2.times.), 36.0 (4.times.), 30.7 (2.times.), 25.6
(2.times.), 24.9 (4.times.), 24.1 (2.times.), 19.1 (2.times.), 13.6
(2.times.). HRMS calcd for C.sub.29H.sub.50O.sub.5 (M.sup.+):
478.3658, found 478.3663.
[0342] Tetraethyl 7-oxo-2,2,12,12-tridecanetetracarboxylate (106h).
Compound 106h was prepared likewise Method A starting from TosMIC
(10.63 g, 53.4 mmol), Bu.sub.4NI (3.99 g, 10.7 mmol), NaH (60%
(.sup.w/w) in mineral oil, 4.27 g, 107 mmol) and 103d (30.0 g, 97.0
mmol) to give, after filtration through silica (elute:
heptane:EtOAc=2:1),
7-ethoxy-6-(ethoxycarbonyl)-1-[6-ethoxy-5-(ethoxycarbonyl)-5-methyl-6-oxo-
hexyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl(methylidyne)ammon-
ium (27.9 g) as a yellow oil. Part of this oil (26.9 g) was treated
with conc aqueous HCl (50 mL), as described for 106d, to give,
after purification by column chromatography (silica,
heptane:EtOAc=4:1), 106h (16.21 g, 71%) as a yellow oil. .sup.1H
NMR: .delta. 4.17 (q, J=7.1 Hz, 8H), 2.40 (t, J=7.4 Hz, 4H),
1.87-1.82 (m, 4H), 1.58 (quintet, J=7.4 Hz, 4H), 1.38 (s, 6H),
1.28-1.18 (m, 4H), 1.25 (t, J=7.2 Hz, 12H). .sup.13C NMR: .delta.
210.0, 172.0 (4.times.), 60.8 (4.times.), 53.3 (2.times.), 42.1
(2.times.), 35.0 (2.times.), 23.6 (4.times.), 19.5 (2.times.), 13.8
(4.times.). HRMS calcd for C.sub.25H.sub.43O.sub.9 (MH.sup.+):
487.2907, found: 487.2944.
[0343] t-Butyl
1-11-[1-(t-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxy-
late (1061). Compound 1061 was prepared likewise Method B starting
from TosMIC (13.84 g, 70.9 mmol), 105c (24.0 and 24.0 g after 1.5 h
in 15 min, 71.0 and 71.0 mmol) and KOtBu (8.35 and 8.35 g after 1.5
h, 74.6 and 74.6 mmol) to give, after dissolving the crude product
in EtOAc (100 mL) and filtration through silica (elute:
heptane:EtOAc=1:1, 5.times.80 mL) an oil (42.38 g). This oil (42.38
g) was treated with conc aqueous HCl (11.4 mL), as described for
106d, to give, after purification by column chromatography (silica,
heptane:EtOAc=12:1), 1061(16.3 g, >90% pure by .sup.1H NMR, 46%)
as a colorless oil. .sup.1H NMR: .delta. 2.37 (t, J=7.4 Hz, 4H),
1.62-1.49 (quintet, J=7.4 Hz, 4H), 1.48-1.36 (m, 8H), 1.41 (s,
18H), 1.33-1.20 (m, 4H) 1.09 (dd, J=6.5, 3.8 Hz, 4H), 0.58 (dd,
J=6.6, 3.9 Hz, 4H). .sup.13C NMR: .delta. 210.9, 174.1 (2.times.),
79.8 (2.times.), 42.9 (2.times.), 34.1 (2.times.), 29.6 (2.times.),
28.2 (6.times.), 27.7 (2.times.), 24.4 (2.times.), 24.0 (2.times.),
15.4 (4.times.).
[0344] Butyl
1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxy-
late (106m). Compound 106m was prepared likewise Method A starting
from TosMIC (12.48 g, 62.6 mmol), Bu.sub.4NI (2.56 g, 6.93 mmol),
NaH (60% (.sup.w/w) in mineral oil, 7.55 g and 1.20 g after 2 h,
189 mmol and 30.0 mmol) and 103f (44.46 g, 93% pure by GC, 129
mmol) to give, after purification by column chromatography (silica,
heptane/EtOAc=8:1), butyl
1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-isocyano-6-[(4-methylphenyl)sulfo-
nyl]undecyl}-1-cyclopentanecarboxylate as a yellow oil (32.79 g).
This oil (32.79 g) was treated with conc aqueous HCl (150 mL), as
described for 106d, to give, after purification by column
chromatography (silica, heptane:EtOAc=6:1), 106m (24.11 g, 90% pure
by .sup.1H NMR, 68%) as a slightly yellow liquid. .sup.1H NMR:
.delta. 4.06 (t, J=6.6 Hz, 4H), 2.36 (t, J=7.4 Hz, 4H), 2.15-2.06
(m, 4H), 1.65-1.52 (m, 20H), 1.49-1.32 (m, 8H), 1.27-1.19 (m, 8H),
0.94 (t, J=7.4 Hz, 6H). .sup.13C NMR: .delta. 210.9, 177.6
(2.times.), 63.8 (2.times.), 54.0 (2.times.), 42.5 (2.times.), 38.9
(2.times.), 35.8 (4.times.), 30.6 (2.times.), 29.5 (2.times.), 25.6
(2.times.), 24.7 (4.times.), 23.4 (2.times.), 19.0 (2.times.), 13.5
(2.times.). HRMS calcd for C.sub.31H.sub.54O.sub.5 (M.sup.+):
506.3971, found: 506.3981.
[0345] Diethyl 10-oxo-2,2,18,18-tetramethyl-nonadecanedioate
(106n). Compound 106n was prepared likewise Method A starting from
TosMIC (2.43 g, 12.5 mmol), Bu.sub.4NI (0.462 g, 1.25 mmol), NaH
(60% (.sup.w/w) in mineral oil, 1.21 g, 30.3 mmol) and 103g (7.65
g, 88% pure by GC, 23.0 mmol) to give, after purification by column
chromatography (silica, heptane:EtOAc=6:1),
{10-ethoxy-1-(9-ethoxy-8,8-dimethyl-9-oxononyl)-9,9-dimethyl-1-[(4-methyl-
phenyl)sulfonyl]-10-oxodecyl}(methylidyne)ammonium (5.41 g) as a
yellow oil. Part of this oil (5.03 g) was treated with conc aqueous
HCl (30 mL), as described for 106d, to give, after purification by
column chromatography (silica, heptane:EtOAc=7:1), 106n (3.21 g,
57%) as a colorless oil. .sup.1H NMR: .delta. 4.11 (q, J=7.2 Hz,
4H), 2.37 (t, J=7.4 Hz, 4H), 1.57-1.46 (m, 8H), 1.28-1.23 (m, 16H),
1.24 (t, J=7.1 Hz, 6H), 1.15 (s, 12H). .sup.13C NMR: .delta. 211.5,
178.0 (2.times.), 60.08 (2.times.), 60.07 (2.times.), 42.7
(2.times.), 42.1 (2.times.), 40.7 (2.times.), 29.9 (2.times.),
29.21 (2.times.), 29.15 (2.times.), 25.1 (2.times.), 24.8
(2.times.), 23.8 (2.times.), 14.2 (2.times.). HRMS calcd for
C.sub.27H.sub.50O.sub.5 (M.sup.+): 454.3658, found: 454.3663.
General Procedures for Ester Hydrolysis
[0346] Method D.
1-[9-(1-Carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic
acid (107f). LiOH.H.sub.2O (3.94 g, 93.9 mmol) and H.sub.2O (30 mL)
were added to a solution of 106f (9.20 g, 23.3 mmol) in EtOH (90
mL) and the resulting mixture was stirred at reflux temperature for
17 h, allowed to cool to rt and concentrated in vacuo to a smaller
volume. H.sub.2O (150 mL) was added and the resulting mixture was
extracted with Et.sub.2O (50 mL), acidified with aqueous HCl (6 M,
25 mL) and extracted with Et.sub.2O (1.times.100 mL, 2.times.50
mL). The latter organic layers were combined, washed with brine (50
mL) and dried. The remaining residue was recrystallized from
iPr.sub.2O/heptane to give 7f (4.41 g, 56%) as small, white
granules. mp 69-70.degree. C. .sup.1H NMR: .delta. 11.2 (br s, 2H),
2.50-2.37 (m, 4H), 2.39 (t, J=7.2 Hz, 4H), 1.96-1.84 (m, 8H),
1.81-1.75 (m, 4H), 1.57 (quintet, J=7.4 Hz, 4H), 1.26-1.12 (m, 4H).
.sup.13C NMR: .delta. 210.6, 183.4 (2.times.), 47.6 (2.times.),
42.7 (2.times.), 37.8 (2.times.), 30.1 (4.times.). 24.7 (2.times.),
24.1 (2.times.), 15.7 (233 ). Anal. calcd for
C.sub.19H.sub.30O.sub.5: C, 67.43; H, 8.93, found: C, 67.19; H,
8.97.
[0347] Method E.
1-[9-(1-Carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic
acid (107d). A solution of 106d (5.31 g, 12.6 mmol) in HCO.sub.2H
(50 mL) was stirred for 3 h, evaporated in vacuo and coevaporated
from toluene (3.times.25 mL) to give 107d (3.89 g, 99%) as a white
solid. An analytical sample was obtained after recrystallization
from iPr.sub.2O/heptane. mp 132-134.degree. C. .sup.1H NMR:
(CD.sub.3OD) .delta. 2.45 (t, J=6.9 Hz, 4H), 1.58-1.39 (m, 12H),
1.14 (dd, J=6.6, 3.7 Hz, 4H), 0.70 (dd, J=6.8, 3.9 Hz, 4H).
.sup.13C NMR: (CD.sub.3OD) .delta. 214.4, 179.4 (2.times.), 43.5
(2.times.), 34.9 (2.times.), 28.5 (2.times.), 25.1 (2.times.), 24.2
(2.times.), 16.2 (4.times.). Anal. calcd for
C.sub.17H.sub.26O.sub.5: C, 65.78; H, 8.44, found: C, 65.40; H,
8.37.
[0348] Method F.
11-(1-Carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid (107c).
A solution of 106c (9.27 g, >90% pure by NMR, 21.0 mmol) in
HCO.sub.2H (50 mL) was stirred for 1.5 h, evaporated in vacuo and
coevaporated from toluene (10 mL). The remaining residue was
dissolved in EtOH:H.sub.2O (2:1, 100 mL) and NaOH (5.33 g, 132
mmol) was added. The resulting clear solution was warmed to
80.degree. C. and after 5 h, EtOH was evaporated in vacuo. The
remaining solution was diluted with H.sub.2O to .about.100 mL,
extracted with Et.sub.2O (3.times.100 mL), acidified to pH.about.1
with conc aqueous HCl (.about.9 mL) and extracted with Et.sub.2O
(3.times.100 mL). The latter organic layers were combined and
dried. The remaining residue was purified by column chromatography
(heptane:EtOAc=2:1 (containing 1% (.sup.v/v) HOAC)) to give 7c
(5.83 g, >90% pure by 1H-NMR, 80%) as a slightly yellow oil
which turns solid when stored at -18.degree. C. for several days.
mp=49-52.degree. C. .sup.1H NMR: (CD.sub.3OD) .delta. 2.44 (t,
J=7.2 Hz, 4H), 1.57-1.42 (m, 10H), 1.30-1.19 (m, 2H), 1.17-1.07 (m,
2H), 1.14 (s, 6H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). .sup.13C NMR:
(CD.sub.3OD) .delta. 213.5, 181.4, 178.9, 43.5, 43.4, 43.0, 41.7,
34.9, 28.5, 25.9 (3.times.), 25.5, 25.2, 24.3, 16.4 (2.times.).
[0349] 11-(1-Carboxycyclobutyl)-2,2-dimethyl-7-oxoundecanoic acid
(107e). Compound 107e was prepared likewise Method D starting from
106e (8.83 g, >90% pure by .sup.1H NMR, 20.8 mmol) and
LiOH.H.sub.2O (2.91 and 1.94 g after 18 h, 69.4 and 46.2 mmol) to
give, after recrystallized from iPr.sub.2O/heptane, 7e (5.19 g,
76%) as a white solid. mp=53-55.degree. C. .sup.1H NMR: .delta.
10.80 (br s, 2H), 2.50-2.35 (m, 2H), 2.39 (t, J=7.2 Hz, 4H),
1.98-1.74 (m, 6H), 1.65-1.49 (m, 6H), 1.31-1.11 (m, 4H), 1.18 (s,
6H). .sup.13C NMR: .delta. 210.6, 184.3, 183.4, 47.6, 42.7, 42.6,
42.2, 40.5, 37.8, 30.1 (2.times.), 25.1 (2.times.), 24.8, 24.7,
24.2, 24.1, 15.7.
[0350]
1-[9-(1-Carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic
acid (107g). Compound 107g was prepared likewise Method D starting
from 106g (7.25 g, 15.0 mmol) and LiOH.H.sub.2O (3.21 g, 76.4 mmol)
to give 107g (5.46 g, 95% pure by .sup.1H NMR, 94%,
mp=99-103.degree. C.) as a white solid. An analytical sample was
obtained after recrystallization from iPr.sub.2O/heptane.
mp=104-106.degree. C. .sup.1H NMR: .delta. 2.39 (t, J=6.9 Hz, 4H),
2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). .sup.3C
NMR: .delta. 211.1, 184.6 (2.times.), 53.9 (2.times.), 42.5
(2.times.), 39.0 (2.times.), 35.9 (4.times.), 25.7 (2.times.), 24.9
(4.times.), 24.0 (2.times.). Anal. calcd for
C.sub.21H.sub.34O.sub.5: C, 68.82; H, 9.35, found: C, 68.78; H,
9.47.
[0351] 2,12-Di(ethoxycarbonyl)-2,12-dimethyl-7-oxotridecanedioic
acid (107h). A solution of KOH (2.44 g, >85%, >37.0 mmol) in
EtOH (80 mL) was added to 106h (9.00 g, 18.5 mmol). After stirring
for 54 h, another portion of KOH (1.21 g, >85%, >18.5 mmol)
was added and stirring was continued for 16 h. The reaction mixture
was evaporated in vacuo and Et.sub.2O (250 mL) and H.sub.2O (250
mL) were added. The aqueous layer was separated, acidified with
aqueous HCl (2 M, 50 mL) and extracted with Et.sub.2O (250 mL) and
CH.sub.2Cl.sub.2 (250 mL). The combined organic layers were dried
and the remaining residue was purified by column chromatography
(silica, heptane:EtOAc:HOAc=3:2:0.01) and vacuum dried at
50.degree. C. to give 107h (6.43 g, 81%) as a yellow oil. .sup.1H
NMR: .delta. 10.40 (br s, 2H), 4.21 (q, J=7.1 Hz, 4H), 2.42 (t,
J=7.4 Hz, 4H), 1.90-1.84 (m, 4H), 1.59 (quintet, J=7.4 Hz, 4H),
1.43 (s, 6H), 1.32-1.19 (m, 4H), 1.27 (t, J=7.2 Hz, 6H). .sup.13C
NMR: .delta. 210.9, 177.7 (2.times.), 172.1 (2.times.), 61.5
(2.times.), 53.5 (2.times.), 42.2 (2.times.), 35.3 (2.times.), 23.8
(2.times.), 23.7 (2.times.), 19.8 (2.times.), 13.9 (2.times.). HRMS
calcd for C.sub.21H.sub.35O.sub.9 (MH.sup.+): 431.2281, found:
431.2298.
[0352] 13-(1-Carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid
(107k). Compound 107k was prepared likewise Method F starting from
6k (18.34 g, 95% pure by .sup.1H NMR, 41.0 mmol) to give
1-(11-ethoxy-10,10-dimethyl-5,11-dioxoundecyl)-1-cyclopropanecarboxylic
acid, which was treated with NaOH (9.68 g, 241 mmol) to give, after
recrystallized from iPr.sub.2O/heptane, 107k (9.47 g, 68%) as a
white solid. The mother liquor was evaporated in vacuo and the
remaining residue was purified by column chromatography
(heptane:EtOAc=2:1 (containing 1% (.sup.v/v) HOAc)) and
recrystallization from iPr.sub.2O/heptane to give a second batch
107k (2.23 g, 16%) as a white solid. mp=65-66.degree. C. .sup.1H
NMR: (CD.sub.3OD) .delta. 2.43 (t, J=7.2 Hz, 4H), 1.58-1.42 (m,
10H), 1.35-1.20 (m, 6H), 1.14 (s, 6H), 1.15-1.06 (m, 2H), 0.70 (dd,
J=6.6, 3.9 Hz, 2H). .sup.13C NMR: (CD.sub.3OD) .delta. 213.8,
181.6, 179.0, 43.6, 43.5, 43.1, 41.9, 35.1, 31.0, 30.6, 28.7, 26.2,
25.9 (2.times.), 25.02, 24.96, 24.4, 16.4 (2.times.).
[0353]
1-[11-(1-Carboxycyclopropyl)-6-oxoundecyl]-1-cyclopropanecarboxyli-
c acid (1071). Compound 1071 was prepared likewise Method E
starting from 1061 (7.50 g, >90% pure by .sup.1H NMR, 15.0 mmol)
to give, after recrystallized from toluene, 1071 (5.06 g, 99%) as
colorless crystals. mp=122-123.degree. C. .sup.1H NMR: (DMSO-d6)
.delta. 11.96 (br s, 2H), 2.39 (t, J=7.4 Hz, 4H), 1.50-1.33 (m,
12H), 1.25-1.15 (m, 4H), 1.03 (dd, J=6.5, 3.5 Hz, 4H), 0.68 (dd,
J=6.6, 3.6 Hz, 4H). .sup.13C NMR: (DMSO-d6) .delta. 209.9, 175.7
(2.times.), 41.8 (2.times.), 33.2 (2.times.), 28.8 (2.times.), 27.2
(2.times.), 23.3 (2.times.), 22.9 (233 ), 14.8 (433 ). Anal. calcd
for C.sub.19H.sub.30O.sub.5: C, 67.43; H, 8.93, found: C, 67.20; H,
9.05.
[0354]
1-[11-(1-Carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxyli-
c acid (107m). Compound 107m was prepared likewise Method D
starting from 106m (21.03 g, 90% pure by .sup.1H NMR, 37.3 mmol)
and LiOH.H.sub.2O (7.83 g, 187 mmol) to give, after
recrystallization from iPr.sub.2O/heptane, 107m (12.15 g, 83%) as
white granules. mp=78-85.degree. C. .sup.1H NMR: .delta. 2.37 (t,
J=7.4 Hz, 4H), 2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H), 1.29-1.25 (m,
8H). .sup.13C NMR: .delta. 211.5, 184.8 (2.times.), 54.0
(2.times.), 42.4 (2.times.), 38.9 (2.times.), 35.9 (4.times.), 29.2
(2.times.), 25.5 (2.times.), 24.9 (4.times.), 23.5 (2.times.).
Anal. calcd for C.sub.23H.sub.38O.sub.5: C, 70.02; H, 9.71, found:
C, 70.37; H, 9.72.
[0355] 10-Oxo-2,2,18,18-tetramethyl-nonadecanedioic acid (107n).
Compound 107n was prepared likewise Method D starting from 106n
(11.63 g, 25.6 mmol) and KOH (4.31 g, 77.0 mmol) to give, after
recrystallization from iPr.sub.2O/heptane, 107n (7.56 g, 74%) as
white crystals. mp=74-77.degree. C. .sup.1H NMR: (CD.sub.3OD)
.delta. 2.43 (t, J=7.3 Hz, 4H), 1.57-1.50 (m, 8H), 1.33-1.21 (m,
16H), 1.14 (s, 12H). .sup.13C NMR: .delta. 214.5, 182.1 (2.times.),
43.6 (2.times.), 43.2 (2.times.), 42.0 (2.times.), 31.2 (2.times.),
30.4 (2.times.), 30.38 (2.times.), 26.2 (2.times.), 25.9
(4.times.), 25.0 (2.times.). Anal. calcd for
C.sub.23H.sub.42O.sub.5: C, 69.31; H, 10.62, found: C, 69.41; H,
10.73.
5.2. Synthesis of
9-hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-one
[0356] ##STR522##
[0357]
2,2-Bis-[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic
acid diethyl ester. Under nitrogen atmosphere, to a solution of
2-(6-bromo-2,2-dimethyl-hexyloxy)-tetrahydropyran (17.6 g, 60 mmol)
and diethyl malonate (4.8 g, 30 mmol) in anhydrous DMSO (145 mL)
was added sodium hydride (60% dispersion in mineral oil, 2.88 g, 72
mmol ) under cooling with a water-bath. Tetra-n-butylammonium
iodide (2.1 g, 3.6 mmol) was then added. The mixture was stirred
for 16 h at room temperature. Water (140 mL) was added carefully to
the reaction mixture under cooling with water-bath. The product was
extracted with diethyl ether (3 60 mL) and the combined organic
layers were washed with water (4 50 mL) and brine (50 mL). The
solution was dried over sodium sulfate and concentrated in vacuo to
give
2,2-bis-[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic
acid diethyl ester (17.3 g, 82.3%) as an oil. .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): (ppm) 4.41 (t, J=3.1 Hz, 2H), 4.01 (q, J=7.0 Hz,
4H), 3.82-3.70 (m, 2H), 3.50-3.30 (m, 4H), 2.87 (d, J=9.1 Hz, 2H),
1.80-1.35 (m, 16H), 1.30-0.95 (m, 18H), 0.88-0.74 (m, 12H).
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): (ppm) 172.0, 99.1, 76.6,
61.9, 60.9, 57.6, 39.2, 34.3, 32.3, 30.7, 25.7, 25.0, 24.6, 24.6,
24.3, 19.5, 14.2.
[0358] 2,2-Bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl
ester. A solution of
2,2-bis-[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic
acid diethyl ester (2.92 g, 5mmol) in concentrated HCl (2.4 mL) and
water (1.6 mL) was refluxed for 1 h. Ethanol (8.2 mL) was added and
the reaction mixture was heated to reflux for 3 h. The reaction
mixture was diluted with water (20 mL) and extracted with diethyl
ether (3.times.20 mL). The combined organic layers were washed with
water (20 mL), brine (20 mL), and dried over Na.sub.2SO.sub.4. The
solution was concentrated to furnish
2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester
(1.74 g, 84%). .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): (ppm) 4.13
(q, J=7.2 Hz, 4H), 3.25 (s, 4H), 2.42 (s, 2H), 1.90-1.75 (m, 4H),
1.30-1.12 (m, 18H), 0.84 (s, 12H). .sup.13C NMR (75 MHz,
CDCl.sub.3/TMS): (ppm) 172.0, 71.7, 60.9, 57.4, 38.2, 34.9, 32.1,
24.8, 24.0, 23.7, 14.0.
[0359] 2,2-Bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid. To a
stirred solution of KOH (4.83 g, 75 mmol) in water (4.2 mL) and
ethanol (15 mL) was added
2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester
(15 g). The reaction mixture was heated to reflux for 14 h, then
concentrated in vacuo, and extracted with chloroform. The aqueous
layer was acidified with HCl until pH 1 and extracted with diethyl
ether (3.times.50 mL). The ethereal solution was dried over
anhydrous MgSO.sub.4 and concentrated in vacuo to afford get
2,2-bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid (7.8 g, 82.3%)
as a yellow solid. .sup.1H NMR (300 MHz, CD.sub.3OD/TMS): (ppm)
4.86 (s, 4H), 3.22 (s, 4H), 1.9-1.8 (m, 4H), 1.36-1.10 (m, 12H),
0.84 (s, 12H). .sup.13C NMR (75 MHz, CD.sub.3OD/TMS): (ppm) 176.0,
72.0, 58.7, 39.8, 36.0, 34.1, 26.5, 25.5, 24.5. Mp.: 178-180 C.
[0360]
8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic
acid. 2,2-Bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid was
heated to 200 C using an oil-bath. This temperature was kept for 30
minutes until the effervescence ceased.
8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic
acid was obtained as an oil (4.04 g, 98%). .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): (ppm) 4.88 (s, 3H), 3.22 (s, 4H), 2.29 (m, 1H),
1.70-1.40 (m, 4H), 1.4-1.1 (m, 12H), 0.84 (s, 12H). .sup.13C NMR
(75 MHz, CDCl.sub.3/TMS): (ppm) 180.5, 72.1, 47.1, 39.9, 36.0,
33.8, 29.7, 25.0, 24.6.
[0361]
9-Hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-on-
e. 8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic
acid (1.0 g, 3.16 mmol) was dissolved in THF (40 mL) and cooled in
an ice-water bath. Methyl lithium (27 mL) was then added at once.
The reaction was continued for 2 h at 0 C. The reaction mixture was
poured into dilute hydrochloric acid (5 mL concentrated
hydrochloric acid in 60 mL water). The organic layer was separated
and the aqueous layer was extracted with diethyl ether (2.times.50
mL). The combined organic layers were dried over sodium sulfate and
concentrated in vacuo to give the crude product (1.0 g). The crude
product was purified by column chromatography (hexanes:ethyl
acetate=4:1, then 1:1) to give
9-hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-one
(0.41 g, yield 41%) and
7-(1-hydroxy-1-methylethyl)-2,2,12,12-tetramethyltridecan-1,13-diol
(0.4 g, 38%, not shown) as a by-product. .sup.1H NMR (300 MHz,
CDCl.sub.3/TMS): (ppm) 3.46 (s, 4H), 2.65-2.50 (m, 1H), 2.28 (s,
3H), 2.60 (br., 2H), 1.82-1.50 (m, 4H), 1.50-1.25 (m, 12H), 1.02
(s, 12H). .sup.13C NMR (75 MHz, CDCl.sub.3/TMS): (ppm) 213.4, 71.7,
53.2, 38.3, 34.9, 31.6, 28.7, 28.3, 23.8. HRMS (LSIMS, nba): Calcd.
for C.sub.19H.sub.39O.sub.3 (MH.sup.+): 315.2899, found:
315.2866.
5.3. Synthesis of Keto-dialkyldicarboxylic Acids bis-Amides
[0362] 3.1. Synthesis of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic
acid bis-methylamide ##STR523##
[0363]
6-[2-(5-Ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dime-
thyl-hexanoic acid ethyl ester. Under N.sub.2 atmosphere, to a
solution of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl
ester (1.0 g, 2.70 mmol) and 1,3-propanedithiol (361 mg, 361 L,
3.24 mmol) in dichloromethane (20 mL; dried with Aluminum oxide,
activated, neutral, Brockmann I) was added boron trifluoride
diethyl etherate (100 L) at rt. The reaction mixture was stirred
for 3 h, diluted with dichloromethane (100 mL), and extracted with
5% NaOH solution (100 mL) and water (75 mL). The organic phase was
dried over MgSO.sub.4, concentrated in vacuo, and dried in high
vacuo to furnish
6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-he-
xanoic acid ethyl ester (1.0 g, 80%) as a yellowish oil. .sup.1H
NMR (300 MHz, CDCl.sub.3/TMS): (ppm): 4.11 (q, 4H, J=7.1), 2.79 (t,
4H, J=5.6), 1.94 (m, 2H), 1.84 (m, 4H), 1.54 (m, 4H), 1.39 (m, 4H),
1.24 (t, 6H, J=7.1), 1.30-1.20 (m, 4H), 1.16 (s, 12H). .sup.13C NMR
(75 MHz, CDCl.sub.3/TMS): (ppm): 178.08, 60.33, 53.32, 42.27,
40.69, 38.28, 26.14, 25.67, 25.28, 24.71, 14.41. HRMS (LSIMS, nba):
Calcd. for C.sub.24H4.sub.5S.sub.2O.sub.4 (MH.sup.+): 461.2759,
found 461.2774.
[0364]
6-[2-(5-Carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-he-
xanoic acid. A solution of
6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-he-
xanoic acid ethyl ester (870 mg, 1.89 mmol) and potassium hydroxide
(85%, 750 mg, 11.33 mmol) in ethanol (16 mL) and water (4 mL) was
heated under reflux for 3 h. The reaction mixture was diluted with
water (100 mL) and acidified to pH 4 with 1 N HCl (8 mL). The
emulsion was extracted with dichloromethane (3 75 mL). The combined
organic phases were washed with water (50 mL), dried over
MgSO.sub.4, concentrated in vacuo, and dried in high vacuo to
furnish
6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic
acid (730 mg, 95%) as a viscous, yellowish oil. .sup.1H NMR (300
MHz, CDCl.sub.3/TMS): (ppm): 2.80 (m, 4H), 1.94 (m, 2H), 1.85 (m,
4H), 1.56 (m, 4H), 1.41 (m, 4H), 1.30 (m, 4H), 1.19 (s, 12H).
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): (ppm): 185.08, 53.36, 42.28,
40.52, 38.27, 26.18, 25.69, 25.23, 25.11, 24.73. HRMS (LSIMS, nba):
Calcd. for C.sub.20H.sub.37O.sub.4S.sub.2 (MH.sup.+): 405.2133,
found: 405.2115.
[0365]
2,2-Dimethyl-6-[2-(5-methyl-5-methylcarbamoyl-hexyl)-[1,3]dithian--
2-yl]-hexanoic acid methylamide. Under N.sub.2 atmosphere, to a
solution of
6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexano-
ic acid (280 mg, 0.67 mmol) and N-hydroxysuccinimide (170 mg, 1.47
mmol) in dichloromethane (5 mL; dried with Aluminum oxide, neutral,
Brockmann I) was added dicyclohexyl carbodiimide (305 mg, 1.47
mmol). The reaction mixture was stirred and rt for 2 h, the urea
was removed by filtration and washed with dichloromethane (2 mL).
The filtrate was concentrated in vacuo and dried in high vacuo to
give crude
6-{2-[5-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)-5-methyl-hexyl]-[1,3]dithi-
an-2-yl}-2,2-dimethyl-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester
(500 mg, 125%) as a foamy, yellow oil. Under N.sub.2 atmosphere, to
a solution of this crude intermediate (370 mg, 0.62 mmol) in
anhydrous THF (10 mL) was added a solution of methylamine in
anhydrous THF (5 mL, 10 mmol, 2.0 M in THF), resulting in the
immediate formation of a white precipitate. The reaction mixture
was stirred at rt for 1.5 h, then diluted with dichloromethane (100
mL), and extracted with saturated NaHCO.sub.3 solution (2 50 mL),
water (50 mL), 1 N HCl (50 mL), and saturated NaCl solution. The
organic phase was concentrated in vacuo and the residue purified by
flash chromatography (silica, hexanes/ethyl acetate=50/50, then
25/75, then 0/100) to furnish
2,2-dimethyl-6-[2-(5-methyl-5-methylcarbamoyl-hexyl)-[1,3]dithian-2-yl]-h-
exanoic acid methylamide (100 mg, 37%) as a colorless oil. Mp.:
104-106 C. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS): (ppm): 5.92 (m
br, 2H), 2.81 (d, 6H, J=4.6), 2.78 (m, 4H), 1.94 (m, 2H), 1.82 (m,
4H), 1.52 (m, 4H), 1.37 (m, 4H), 1.30-1.14 (m, 4H), 1.17 (s, 12H).
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): (ppm): 178.46, 53.23, 42.10,
41.32, 38.18, 26.56, 26.08, 25.62, 25.56, 25.16, 24.64. HRMS
(LSIMS, nba): Calcd. for C.sub.22H.sub.43N.sub.2S.sub.2O.sub.2
(MH.sup.+): 431.2766, found: 431.2762.
[0366] 2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid
bis-methylamide. A suspension of
2,2-dimethyl-6-[2-(5-methyl-5-methylcarbamoyl-hexyl)-[1,3]dithian-2-yl]-h-
exanoic acid methylamide (3.30 g, 7.66 mmol), paraformaldehyde (6.9
g), and Amberlyst 15 (3.85 g) in acetone (100 mL) and water (10 mL)
was heated to reflux for 16 h. The acetone was removed under
reduced pressure, the reaction mixture was filtered, and the resin
was washed with ethyl acetate (3 75 mL). The combined layers were
extracted with saturated NaHCO.sub.3 solution (30 mL) and saturated
NaCl solution (30 mL), dried over MgSO.sub.4, and concentrated in
vacuo. The residue was purified by flash chromatography (silica;
ethyl acetate, then ethyl acetate/ethanol=50/50) to furnish
2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid bis-methylamide
(2.45 g, 94%) as a colorless, viscous oil that solidified on
standing. Mp.: 91.5-93.5 C. .sup.1H NMR (300 MHz, CDCl.sub.3/TMS):
(ppm): 6.05 (d br., 2H, J=4.6), 2.78 (d, 6H, J=4.6), 2.36 (t, 4H,
J=7.3), 1.58-1.45 (m, 8H), 1.27-1.12 (m, 4H), 1.15 (s, 12H).
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): (ppm): 211.50, 178.43,
42.56, 41.99, 41.03, 26.52, 25.48, 24.48, 24.20. HRMS (LSIMS, nba):
Calcd. for C.sub.19H.sub.37N.sub.2O.sub.3 (MH.sup.+): 341.2804,
found: 341.2804.
5.4. Synthesis of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid
bis-phenylamide
[0367] ##STR524##
[0368] 2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid
bis-phenylamide. Under N.sub.2 atmosphere, to a stirred solution of
2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid (3.40 g, 10.9 mmol)
in acetonitrile (50 ml) was added N-methyl-morpholine (2.42 g, 2.63
ml, 23.9 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (4.20 g,
23.9 mmol) at rt. After 20 h, aniline (5.08 g, 5.0 ml, 54.5 mmol)
was added and the reaction mixture was stirred for 26 h. The
reaction mixture was diluted with ethyl acetate (100 mL) and
extracted with ice-cold 1 N HCl (2 100 mL), saturated NaCl solution
(100 mL), saturated NaHCO.sub.3 solution (2 100 mL), and saturated
NaCl solution (100 mL). The organic layer was dried over
MgSO.sub.4, concentrated in vacuo, and dried in high vacuo to give
a viscous, crude oil (4.50 g).
2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid bis-phenylamide and
2,2,12-trimethyl-7-oxo-12-phenylcarbamoyl-tridecanoic acid were
isolated from this crude product mixture by flash chromatography
(silica; chloroform, then chloroform/acetone=98/2, then
chloroform/acetone=95/5). Additional purification of
2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid bis-phenylamide by
crystallization (1.0 g oil in ca. 7.5 ml
hexanes/chloroform/ethanol=10/4/1) was necessary to give the clean
bis-amide (290 mg, 6%) as a white solid. Mp.: 113-114 C. .sup.1H
NMR (300 MHz, CDCl.sub.3): (ppm): 7.52 (d, 2H, J=7.5), 7.50 (s,
2H), 7.27 (t, 4H, J=7.5), 7.07 (t, 2H, J=7.5), 2.34 (t, 4H, J=7.3),
1.64-1.44 (m, 8H), 1.34-1.14 (m, 4H), 1.24 (s, 12H). .sup.3C NMR
(75 MHz, CDCl.sub.3): (ppm): 211.31, 176.08, 138.09, 128.93,
124.28, 120.36, 42.96, 42.84, 41.13, 25.58, 24.53, 24.20. HRMS
(LSIMS, nba): Calcd. for C.sub.29H.sub.40N.sub.2O.sub.3 (MH.sup.+):
465.3118, found: 465.3129.
[0369] 2,2,12-Trimethyl-7-oxo-12-phenylcarbamoyl-tridecanoic acid.
Viscous oil (1.15 g, 25%). .sup.1H NMR (300 MHz, CDCl.sub.3):
(ppm): 8.90 (m br., 1H), 7.57 (s br, 1H), 7.51 (d, 2H, J=7.9), 7.28
(m, 2H), 7.08 (t, 1H, J=7.3), 2.38 (t, 2H, J=7.2), 2.36 (t, 2H,
J=7.2 H), 1.53 (m, 8H), 1.34-1.20 (m, 4H), 1.26 (s, 6H), 1.16 (s,
6H). .sup.13C NMR (75 MHz, CDCl.sub.3): (ppm): 211.54, 183.74,
176.28, 138.02, 128.92, 124.35, 120.46, 42.97, 42.55, 42.53, 42.06,
41.12, 40.21, 25.56, 25.05, 24.55, 24.52, 24.21, 24.17. HRMS
(LSIMS, nba): Calcd. for C.sub.23H.sub.36NO.sub.4 (MH.sup.+):
390.2644, found: 390.2650.
5.5. Synthesis of 2,2,12,12-tetramethyl-7-oxo-tridecanedoic acid
bis-3-carboxyphenylamide
[0370] ##STR525##
[0371]
6-[2-(5-Carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-he-
xanoic acid. A solution of the ester (AL056-97, 870 mg, 1.89 mmol)
and potassium hydroxide (85%, 750 mg, 11.33 mmol) in ethanol (16
mL) and water (4 mL) was heated under reflux for 3 h. The reaction
mixture was diluted with water (100 mL) and acidified to pH 4 with
1 N HCl (8 mL). The emulsion was extracted with dichloromethane (3'
75 mL). The combined organic phases were washed with water (50 mL),
dried over MgSO4, concentrated in vacuo, and dried in high vacuo to
furnish ET06802 (730 mg, 95%) as a viscous, yellowish oil. 2.80 (m,
4H), 1.94 (m, 2H), 1.85 (m, 4H), 1.56 (m, 4H), 1.41 (m, 4H), 1.30
(m, 4H), 1.19 (s, 12H). Carboxyl proton resonances were not
visible. Estimated purity by 1H NMR: ca. 85%, contains ca. 10%
starting material. 185.08, 42,28, 40.52, 38.27, 26.18, 25.69,
25.31, 25.23, 25.11, 24.73. Calcd. for C20H37O4S2 (MH+): 405.2133,
found: 405.2115.
[0372]
3-(6-2-5-(3-Ethoxycarbonyl-phenylcarbamoyl)-5-methyl-hexyl-1,3
dithian-2-yl-2,2-dimethyl-hexanoylamino)-benzoic acid ethyl ester.
To a solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 12.1
g, 68.6 mmol) and ET06802 (12.1 g, 29.7 mmol) in THF (50 mL),
N-methylmorpholine (NMM, 6.72 g, 66.5 mmol) was added dropwise at
-5.degree. C. The reaction mixture was stirred for 4 h at this
temperature. Ethyl-3-aminobenzoate (39.2 g, 237.8 mmol) was added
at once and the mixture was stirred at rt for 7 days. The reaction
mixture was filtered to remove the solids. The filtrate was diluted
with ethyl acetate (250 mL) and washed with ice-cold 1N HCl (3 180
mL), brine (150 mL), saturated NaHCO3 solution (2 300 mL), and
brine (200 mL). The organic phase was dried over anhydrous Na2SO4,
and concentrated in vacuo to yield a crude solid that was washed
with a solvent mixture of ethyl acetate/hexanes=1/20 (500 mL) to
furnish the product (12.8 g, 61.8%) as a white solid, M.p.
60-70.degree. C. 60-70.degree. C. 8.02 (s, 2H), 7.96 (d, J=7.8 Hz,
2H), 7.78 (d, J=7.8 Hz, 2H), 7.59 (s, 2H), 7.41 (t, J=6.0 Hz, 2H),
4.38 (q, J=7.2 Hz, 4H), 2.76 (t, J=7.2 Hz, 4H), 1.95-1.51 (m, 10H),
1.38 (t, J=7.2 Hz, 6H), 1.40-1.21 (m, 8H), 1.29 (s, 12H). 176.35,
166.41, 138.31, 131.21, 129.18, 125.37, 124.84, 121.03, 61.31,
53.17, 43.17, 41.44, 38.20, 26.10, 25.64, 25.24, 24.74, 14.48.
Calcd. for C38H55N2O6S2 (MH.sup.+): 699.3496, found: 699.3508.
[0373] 2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid
bis-3-carboethoxy-phenylamide. To a solution of
3-(6-2-5-(3-ethoxycarbonyl-phenylcarbamoyl)-5-methyl-hexyl-1,3
dithian-2-yl-2,2-dimethyl-hexanoylamino)-benzoic acid ethyl ester
(430 mg, 0.62 mmol) in dimethoxy ethane (DME, 5 mL) and
concentrated hydrochloric acid (0.74 mL), methyl sulfoxide (DMSO,
0.35 mL) was added dropwise over 5 minutes. The reaction mixture
was stirred for 30 minutes at rt. The resulting mixture was slowly
poured into saturated sodium bicarbonate solution (60 mL) and
extracted with diethyl ether (2 80 mL). The combined organic layers
were washed with water (3 50 mL), dried over sodium sulfate and
concentrated in vacuo. The crude product was washed with hexanes
(60 mL) to yield ET07002 (300 mg, 79.0%) as a colorless oil. 8.05
(s, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.77 (m, 4H), 7.35 (t, J=7.8 Hz,
2H), 4.36 (t, J=6.9 Hz, 4H), 2.37 (t, J=7.2 Hz, 4H), 1.62-1.39 (m,
10H), 1.46 (t, J=6.9 Hz, 6H), 1.37-1.17 (m, 2H), 1.26 (s, 12H).
211.29, 176.33, 166.36, 138.36, 131.07, 129.01, 125.24, 124.86,
121.13, 61.22, 43.06, 42.53, 41.05, 25.55, 25.17, 24.53, 24.16,
14.43. Calcd. for C35H49N2O7 (MH+): 609.3534, found: 609.3569.
[0374] 2,2,12,12-Tetramethyl-7-oxo-tridecanedoic acid
bis-3-carboxyphenylamide. To a homogenous solution of KOH (85%,
1.24 g, 18.66 mmol) and 2,2,12,12-tetramethyl-7-oxo-tridecanedioic
acid bis-carboethoxy-phenylamide (1.9 g, 3.13 mmol) in water (7 ml)
and ethanol (33 ml) was heated to reflux for 5 h. The ethanol was
removed under reduced pressure. The residue was diluted with water
(55 ml). The solution was acidified with concd. hcl (4 ml) to ph 1
and extracted with diethyl ether (2 80 ml). The combined organic
layers were washed with brine (50 ml), dried over anhydrous na2so4
and concentrated in vacuo to yield a crude solid that was washed
with hexanes (200 ml) and a solvent mixture of ethyl
acetate/hexanes=1/40 (200 ml) to furnish a white solid (1.4 g,
81.4% yield, 94.9% pure by hplc), m.p 78-80.degree. C. mp
78-80.degree. C. 12.87 (br, 2h), 9.35 (s, 2h), 8.24 (s, 2h), 7.91
(d, j=8.1 hz, 2h), 7.62 (d, j=7.8 hz, 2h), 7.42 (t, j=7.8 hz, 2h),
2.35 (t, j=4.5 hz, 4h), 1.62-1.50 (m, 4h), 1.45-1.30 (m, 4h),
1.30-1.11 (m, 4h), 1.15 (s, 12h). 210.33 , 176.05, 167.29, 139.58,
131.02, 128.63, 124.38, 124.00, 121.14, 42.55, 40.36, 38.89, 25.11,
23.99, 23.71. calcd. for c31h41n2o7 (mh): 553.2914 , found:
553.2911.
5.6. .alpha.,.alpha.-Dialkyl or -Arylalkyl-substituted
Keto-dialkyldicarboxylic Acids
[0375] Long hydrocarbon chain keto-diols and -acids was synthesized
as described in Schemes 18 and 19, and Table 4 (Dasseux, J.-L. H.
et al. Ketone compounds and compositions for cholesterol management
and related uses. U.S. patent application 20030078239, Oct. 11,
2001). The side chains connected to the central ketone
functionality varied both in length (n, m=3-7) and in the attached
geminal modifying groups (R.sup.1, R.sup.2=Me, Ph, 4-Me-C.sub.6H4,
4-iBu-C.sub.6H.sub.4). The majority of target compounds fell in the
category of either symmetrical ketodiacids (210b-210g, 210i, 210j,
Scheme 18) or symmetrical ketodiols (214a-214i, Scheme 19).
##STR526## ##STR527## TABLE-US-00007 TABLE 4 Synthesis of
Symmetrical Ketodiacids No. n R.sup.1 R.sup.2 Yield (%) 209b 3 Me
Ph 61 209c 4 Me Me 67 209d 4 Me Ph 66 209e 4 Me 4-Me-C.sub.6H.sub.4
54 209f 4 Me 4-iBu--C.sub.6H.sub.4 82 209g 5 Me Me 61 209i 6 Me Me
40 209j 7 Me Me 61.sup.a 210b 3 Me Ph 31 210c 4 Me Me 86 210d 4 Me
Ph 87 210e 4 Me 4-Me-C.sub.6H.sub.4 39 210f 4 Me
4-iBu--C.sub.6H.sub.4 86 210g 5 Me Me 57 210i 6 Me Me 57.sup.b 210j
7 Me Me 74 .sup.aIntermediate 208j was purified by column
chromatography; .sup.b prepared by direct base hydrolysis of
208i.
[0376] ##STR528## TABLE-US-00008 TABLE 5 Synthesis of Symmetrical
Ketodiols. No. n R.sup.1 R.sup.2 Yield (%) 211i 5 Me Me 66 212f 4
Me 4-iBu--C.sub.6H.sub.4 98 213f 4 Me 4-iBu--C.sub.6H.sub.4 94 214a
3 Me Me 30 214b 3 Me Ph 38 214c 4 Me Me 68 214d 4 Me Ph 61 214e 4
Me 4-Me-C.sub.6H.sub.4 21 214f 4 Me 4-iBu--C.sub.6H.sub.4 83 214g 5
Me Me 79 214h 5 Me Ph 56 214i 6 Me Me 35
[0377] A series of unsymmetrical keto-diols and -acids with chains
of different lengths or with a different substitution pattern
(217-219, Scheme 20 and 225, 226, Scheme 21) was included in this
study as well. In addition, the aryl-bridged compounds 231 and 232
with a benzophenone backbone (Scheme 22) were prepared and examined
for comparison. ##STR529## ##STR530## ##STR531##
[0378] The key step in the syntheses of all ketones with aliphatic
chains was the alkylation of tosylmethyl isocyanide (TosMIC)
(Possel, O. et al. Tosylmethyl Isocyanide Employed in a Novel
Synthesis of Ketones. A New Masked Formaldehyde Reagent.
Tetrahedron Lett. 1977, 17, 4229-4232; Kurosawa, K. et al. Facile
Synthesis of [3.sup.n]Cyclophanes in which Aromatic Rings are
Connected with --CH.sub.2--CO--CH.sub.2-- Bridges. Tetrahedron
Lett. 1982, 23, 5335-5338; Yadav, J. S. et al. TosMIC in the
Preparation of Spiroacetals: Synthesis of Pheromone Components of
Olive Fruit Fly. Tetrahedron Lett. 1990, 31, 6217-6218; van Leusen,
D. et al. Synthetic Uses of Tosylmethyl Isocyanide (TosMIC). In
Organic Reactions, Vol. 57; Overman, L. E., Editor-in-Chief; John
Wiley and Sons, Inc.: New York, 2001; pp 417-666) with
appropriately substituted alkyl bromides (Schemes 18-22). These
alkyl bromide building blocks were generally synthesized via
lithiation of commercially available or readily accessible ethyl
esters 201, 202 (Shiner, V. J., Jr. et al. The Arrhenius Parameters
of the Deuterium Isotope Rate Effect in a Base-promoted Elimination
Reaction: Evidence for Proton Tunneling. J. Am. Chem. Soc. 1961,
83, 593-598), 203 (Ghosh, S. et al. Ester Enolates from
.alpha.-Acetoxy Esters. Synthesis of Aryl Malonic and .alpha.-Aryl
Alkanoic Esters from Aryl Nucleophiles and .alpha.-Keto Esters. J.
Org. Chem. 1982, 47, 4692-4702; Chounan, Y. et al. 1,2-Asymmetric
Induction in the Conjugate Addition of Organocopper Reagents to
.gamma.-Aryl .alpha.,.beta.-Unsaturated Carbonyl Derivatives.
Tetrahedron 2000, 56, 2821-2831), and 204 with lithium
diisopropylamide in anhydrous THF in the presence of
N,N'-dimethylpropyleneurea (DMPU) at -78.degree. C. followed by
subsequent reaction with an .alpha.,.omega.-dibromoalkane (a)
Ackerley, N. et al. A Novel Approach to Dual-Acting Thromboxane
Receptor Antagonist/Synthase Inhibitors Based on the Link of
1,3-Dioxane-Thromboxane Receptor Antagonists and -Thromboxane
Synthase Inhibitors. J. Med. Chem. 1995, 38, 1608-1628; Manley, P.
W. et al. Thromboxane Synthase Inhibitors. Synthesis and
Pharmocological Activity of (R)-, (S)-, and
(.+-.)-2,2-Dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)-methoxy-
]ethoxy]hexanoic Acids. J. Med. Chem. 1987, 30, 1812-1818) of the
required chain length (Scheme 18). Thus, bromo esters 205a-205j
were obtained in moderate to good yields (Table 4). Reduction of
bromo esters with lithium borohydride and methanol (Brown, H. C. et
al. 30. Effect of Cation and Solvent on the Reactivity of Saline
Borohydrides for Reduction of Carboxylic Esters. Improved
Procedures for the Conversion of Esters to Alcohols by Metal
Borohydrides. J. Org. Chem. 1982, 47, 4702-4708; Soai, K. et al.
Mixed Solvents Containing Methanol as Useful Reaction Media for
Unique Chemoselective Reductions with Lithium Borohydride. J. Org.
Chem. 1986, 51, 4000-4005) in refluxing dichloromethane afforded
the bromo alcohols 206a-206e, 206g, and 206h in excellent yields
and purities without effecting the bromide moiety. The
chemoselectivity of reduction of similar bromo esters with
LiAlH.sub.4 depended on the conditions. In ether at room
temperature the bromo alcohol was the single product whereas in THF
at reflux the reaction gave the alcohols exclusively. See:
Beckwith, A. L. J. et al. Stereochemistry of the Reversible
Cyclization of .omega.-Formyl Radicals. J. Org. Chem. 1992, 57,
4954-4962. Reduction with lithium aluminum hydride or sodium
borohydride on the other hand was not chemoselective and the
reactions were not reproducible. Another chemoselective reducing
agent was diisobutylaluminum hydride (Brown, H. C. et al. Selective
Reductions. 30. Effect of Cation and Solvent on the Reactivity of
Saline Borohydrides for Reduction of Carboxylic Esters. Improved
Procedures for the Conversion of Esters to Alcohols by Metal
Borohydrides. J. Org. Chem. 1982, 47, 4702-4708). Bromo alcohols
were treated with 3,4-dihydro-2H-pyran and catalytic amounts of
p-toluenesulfonic acid (Brown, H. C. et al. Selective Reductions.
30. Effect of Cation and Solvent on the Reactivity of Saline
Borohydrides for Reduction of Carboxylic Esters. Improved
Procedures for the Conversion of Esters to Alcohols by Metal
Borohydrides. J. Org. Chem. 1982, 47, 4702-4708) to give the THP
ethers 207a-207e, 207g, and 207h (Scheme 18, Table 4) in moderate
to good yields.
[0379] The synthesis of symmetrical ketodiacids 210b-210g, 210i,
and 210j from bromo esters 205b-205g, 205i, and 205j was
accomplished employing TosMIC methodology as described above
(Scheme 2). Accordingly, TosMIC was deprotonated with sodium
hydride in either DMSO or in a DMSO/diethyl ether mixture (Possel,
O. et al. Tosylmethyl Isocyanide Employed in a Novel Synthesis of
Ketones. A New Masked Formaldehyde Reagent. Tetrahedron Lett. 1977,
17, 4229-4232) at room temperature and then reacted with suitable
bromo esters 205b-205g, 205i, and 205j in the presence of catalytic
amounts of tetrabutylammonium iodide to give the corresponding
dialkylated TosMIC intermediates 208a-208g, 208i, and 208j. These
alkylations of TosMIC proceeded also without catalytic amounts of
NBu.sub.4I, but required a slightly longer reaction time. In most
cases, these intermediates were not purified or characterized but
directly treated with concd aqueous HCl in dichloromethane (Prato,
M. et al. Cleavage of the 1,3-Dithiane Protective Group. Synthesis
1982, 679-680) to give ketodiesters 209b-209g, 209i, and 209j in
good yields after chromatographic purification (Table 2). Finally,
hydrolysis of the ester groups with potassium hydroxide in aqueous
ethanol and subsequent acidification with concd HCl (steps c, d)
provided the target diacids 210b-210g, and 210j in variable yields
ranging from 31 to 87%. According to a different protocol,
ketodiacid 210i was prepared by simultaneous hydrolysis of the
tosyl isocyanide and the ester groups in 28i with potassium
hydroxide in aqueous ethanol followed by acidification with dilute
sulfuric acid (steps c, e) in 57% yield.
[0380] Scheme 3 illustrates three different strategies that were
studied for the synthesis of symmetrical ketodiols. The standard
procedure used in most cases employed the dialkylation protocol of
TosMIC as described above. Bromo THP ethers 207a-7e, 7g, and 7h
were used as electrophiles and the resulting TosMIC intermediates
were directly hydrolyzed to give the ketodiols 214a-214e, 214g, and
214h in acceptable yields after purification by column
chromatography (Table 3). An alternative pathway was elected for
the synthesis of ketodiol 214i. In this case, ketodiester 209i was
first reduced to triol 211i by treatment with lithium aluminum
hydride (66%). Selective oxidation of the secondary alcohol moiety
in 211i with aqueous sodium hypochlorite solution in acetic acid
(Stevens, R. V. et al. Further Studies on the Utility of Sodium
Hypochlorite in Organic Synthesis. Selective Oxidation of Diols and
Direct Conversion of Aldehydes to Esters. Tetrahedron Lett. 1982,
23, 4647-4650; Stevens, R. V. et al. Convenient and Inexpensive
Procedure for Oxidation of Secondary Alcohols to Ketones. J. Org.
Chem. 1980, 45, 2030-2032) then produced 214i in low yield (35%).
Better results were obtained when the ketone functionality in a
ketodiester was protected prior to the reduction of the esters.
Thus, protection of 209f with 1,3-propanedithiol and boron
trifluoride diethyl etherate (Hatch, R. P. et al. Studies on Total
Synthesis of the Olivomycins. J. Org. Chem. 1978, 43, 4172-4177)
led to formation of 212f, which was subsequently reduced with
lithium aluminum hydride to 213f. Removal of the 1,3-dithiane
protective group with DMSO in dimethoxyethane and concd HCl (Prato,
M. et al. Cleavage of the 1,3-Dithiane Protective Group. Synthesis
1982, 679-680) afforded ketodiol 214f (63% from 205f). Despite the
superior yields attained, this method was not generally applied for
the synthesis of 214a-214i because of the malodorous reagent
involved.
[0381] The unsymmetrical ketodiols 217-219 were prepared via the
mono-alkylated TosMIC derivative 215 as a common intermediate
(Scheme 21). However, reaction of TosMIC with one equivalent of
207c under the previously utilized reaction conditions (NaH and
NBu.sub.4I in DMSO) gave a mixture of mono- and dialkylated
products 215 and 216 (For similar successive alkylations of TosMIC
with alkyl halides of different chain lengths, see: Rao, A. V. R.
et al. A New Route for the Synthesis of 1,4-Dicarbonyl Compounds:
Synthesis of Jasmone, Dihydrojasmone and a Prostaglandin
Intermediate. Synth. Commun. 1984, 14, 469-475). Contaminant 216
had to be removed by chromatography to prevent formation of
mixtures of 217 or 219, respectively, with 214c in the next step,
which were practically impossible to separate; the yield of this
purification was very low (27%). Modification of the conditions
(K.sub.2CO.sub.3 in DMF) circumvented this problem as 215 was
produced in 69% yield without formation of 216, even when an excess
of 7c was used. Further alkylation of 215 with the respective bromo
THP-ethers 207a, 207d, and 207g, followed by deprotection with
concd HCl in refluxing methanol furnished the unsymmetrical
products 217-219 in respectable yields.
[0382] Similar problems with an unwanted dialkylated by-product
(208c, Scheme 19) were also encountered in the synthetic route to
diacids 225 and 226. Alkylation of TosMIC with 205c by treatment
with NaH and NBu.sub.4I in DMSO led to a mixture of compounds 220
and 208c that was very difficult to separate by chromatographic
means (For similar mono-alkylations of TosMIC with long chain bromo
esters, see: Johnson, D. W. A Synthesis of Unsaturated Very Long
Chain Fatty Acids. Chem. Phys. Lipids 1990, 56, 65-71). As a
result, the yield of pure 220 was only 12%. To ensure the complete
removal of the symmetrical ketodiester 209c that results from
intermediate 208c, compound 220 was reacted with the bromo
THP-ether 207a and subsequently hydrolyzed to give hydroxy ester
221. Purification of 221 from traces of 209c was now easily
accomplished by chromatography (60% yield). Subsequent oxidation of
this alcohol with pyridinium dichromate (PDC) in DMF (Vedejs, E. et
al. J. Am. Chem. Soc. 1987, 109, 5437-5446) afforded diacid
monoester 223 (79%), which was further saponified to provide 225 in
60% yield after crystallization from diethyl ether/hexanes.
[0383] The same strategy was applied for the synthesis of the
unsymmetrical ketodiacid 226. In this case, intermediate 220 was
not isolated, but further alkylated in situ with bromo THP-ether
207g. After deprotecting the ketone group by acid treatment and
purification of the crude product by chromatography, hydroxy ester
222 was isolated in 36% yield. In analogy to its shorter chain
homologue 221, oxidation of compound 222 with PDC in DMF led to
ketodiacid mono-ester 224 (68%). Subsequent hydrolysis of 224 with
potassium hydroxide in aqueous ethanol followed by chromatographic
purification and crystallization furnished 226 in 43% yield.
[0384] Benzophenone derivative 227, prepared similarly to the
method described in Shultz, D. A. et al. The Effect of Phenyl Rin
Torsional Rigidity on the Photophysical Behavior of
Tetraphenylethylenes. J. Am. Chem. Soc. 1989, 111, 6311-6320, was
used as starting material for the synthesis of aryl-bridged ketones
231 and 232. Bromide displacement in 227 by reaction with lithio
ethyl isobutyrate in THF/DMPU at -78.degree. C. produced the
diester 228 in 89% yield. Conversion of 228 to diacid 231 performed
by saponification with KOH resulted in practically quantitative
yield. For the synthesis of the related diol 232, the ketone moiety
in intermediate 228 was first protected as S,S-acetal 229 (87%) as
described in Rao, A. V. R. et al. A New Route for the Synthesis of
1,4-Dicarbonyl Compounds: Synthesis of Jasmone, Dihydrojasmone and
a Prostaglandin Intermediate. Synth. Commun. 1984, 14, 469-475.
Reduction with lithium borohydride and methanol gave diol 230 in
85% yield. Finally, deprotection with copper(II) oxide and
copper(II) chloride in a refluxing acetone/DMF solvent mixture as
described in Stuitz, P. et al. 3-Alkylated and 3-Acylated Indoles
from a Common Precursor: 3-Benzylindole and 3-Benzoylindole. In
Organic Syntheses Collective Volume VI; Noland, W. E.,
Editor-in-Chief; John Wiley and Sons, Inc.: New York, 1988; pp
109-114 afforded ketodiol 232 in 71% yield.
[0385] Representative Procedure for the Synthesis of Ketodiesters:
2,2,12,12-Tetramethyl-7-oxotridecanedioic acid diethyl ester
(209c). Under N.sub.2-atmosphere, to a solution of 205c (22.4 g,
89.2 mmol) in anhydrous DMSO (300 mL) was added TosMIC (8.71 g,
44.6 mmol), NaH (60% w/w in mineral oil, 4.28 g, 107.0 mmol), and
tetrabutylammonium iodide (3.30 g, 8.9 mmol) under cooling with an
ice-bath. After the addition, the reaction mixture was stirred for
23 h at room temperature, then cooled with an ice-bath, and
carefully hydrolyzed with water (300 mL). The solution was
extracted with CH.sub.2Cl.sub.2 (3.times.150 mL). The combined
organic layers were washed with water (100 mL) and half-saturated
aqueous NaCl solution (100 mL), dried over anhydrous MgSO.sub.4,
concentrated in vacuo, and dried in high vacuo to give the crude
intermediate 208c (26.2 g) as an oil [.sup.1H NMR (CDCl.sub.3):
.delta. 7.85 (d, 2H, J=8.3), 7.42 (d, 2H, J=8.3), 4.12 (q, 4H,
J=7.0), 2.49 (s, 3H), 1.94 (m, 4H), 1.60-1.34 (m, 8H), 1.30-1.15
(m, 4H), 1.25 (t, 6H, J=7.0), 1.15 (s, 12H). .sup.3C NMR
(CDCl.sub.3): .delta. 177.77, 164.08, 146.43, 131.20, 130.34,
129.96, 81.78, 60.37, 42.12, 40.27, 33.21, 25.25, 25.19, 24.97,
24.26, 21.86, 14.34]. To a solution of 208c (26.0 g) in
CH.sub.2Cl.sub.2 (400 mL) was added concd HCl (100 mL) and the
reaction mixture was stirred for 45 min at room temperature. The
solution was diluted with water (400 mL) and the layers were
separated. The aqueous layer was extracted with CH.sub.2Cl.sub.2
(300 mL). The combined organic layers were washed with saturated
aqueous NaHCO.sub.3 solution (100 mL) and saturated aqueous NaCl
solution (100 mL). The organic phases were dried over anhydrous
MgSO.sub.4, concentrated in vacuo, and dried in high vacuo. The
residue was purified by flash chromatography (silica gel;
hexanes/ethyl acetate=95/5, then 90/10) to give 209c (11.0 g, 67%)
as an oil. .sup.1H NMR (CDCl.sub.3): .delta. 4.03 (q, 4H, J=7.1),
2.31 (t, 4H, J=7.5), 1.45 (m, 8H), 1.20-1.08 (m, 4H), 1.16 (t, 6H,
J=7.1), 1.07 (s, 12H). .sup.13C NMR (CDCl.sub.3): .delta. 211.14,
178.05, 60.34, 42.69, 42.20, 40.52, 25.24, 24.71, 24.30, 14.35.
HRMS (LSIMS, nba): Calcd for C.sub.21H.sub.39O.sub.5 (MH.sup.+):
371.2797, found: 371.2763.
[0386] 2,10-Dimethyl-6-oxo-2,10-diphenylundecanedioic acid diethyl
ester (209b). According to the procedure described for the
synthesis of 209c, 205b (25.0 g, 76.4 mmol), tetrabutylammonium
iodide (2.78 g, 7.5 mmol) and TosMIC (7.34 g, 37.6 mmol) in
anhydrous DMSO (400 mL) and diethyl ether (150 mL) was reacted with
sodium hydride (60% dispersion in mineral oil, 3.80 g, 95.0 mmol)
first under cooling with an ice-bath, then at room temperature for
24 h. Hydrolysis and extraction afforded the intermediate 208b
(28.0 g) as a brown oil. A portion of this crude intermediate (25.0
g) was then treated with concd aqueous HCl (140 mL) in
CH.sub.2Cl.sub.2 (500 mL) for 2 h at room temperature. Aqueous
workup, extraction, and purification by flash chromatography
(silica gel; ethyl acetate/hexanes=1/20, 1/10) furnished 209b (9.5
g, 61%) as a light yellowish oil. .sup.1H NMR (CDCl.sub.3): .delta.
7.40-7.10 (m, 10H), 4.20-4.05 (m, 4H), 2.38 (m, 4H), 2.05-1.80 (m,
4H), 1.60 (s, 6H), 1.50-1.20 (m, 4H), 1.22 (m, 6H). .sup.13C NMR
(CDCl.sub.3): .delta. 210.24, 176.06, 143.71, 128.42, 126.72,
125.97, 60.83, 50.13, 42.97, 38.91, 22.73, 22.47, 19.09, 14.13.
HRMS (LSIMS, nba): Calcd for C.sub.29H.sub.39O.sub.5 (MH.sup.+):
467.2797, found: 467.2772.
[0387] 7-Oxo-2,12-dimethyl-2,12-diphenyltridecanedioic acid diethyl
ester (209d). In analogy to the procedure described for the
synthesis of 209c, 205d (9.59 g, 30.6 mmol) in anhydrous DMSO (50
mL) was reacted with TosMIC (3.02 g, 15.5 mmol), sodium hydride
(60% w/w in mineral oil, 1.44 g, 36.0 mmol), and tetrabutyl
ammonium iodide (1.10 g, 3.0 mmol), first under cooling with a
water-bath, then for 96 h at room temperature. Hydrolysis and
extraction afforded the crude intermediate 208d (30.0 g) as an oil.
A solution of this oil (30.0 g) in CH.sub.2Cl.sub.2 (300 mL) and
concd aqueous HCl (40 mL) was stirred for 2 h at room temperature.
After extractive workup and flash chromatography (silica gel;
hexanes/ethyl acetate=10/1), 209d (5.0 g, 66%) was obtained as a
clear oil together with a less pure fraction (1.17 g, 16%). .sup.1H
NMR (CDCl.sub.3): .delta. 7.40-7.10 (m, 10H), 4.11 (q, 4H, J=7.0),
2.34 (t, 4H, J=7.1), 2.10-1.70 (m, 4H), 1.6-1.4 (m, 4H), 1.52 (s,
6H), 1.30-1.00 (m, 10H). .sup.13C NMR (CDCl.sub.3): .delta. 210.7,
176.0, 143.8, 128.2, 126.5, 125.8, 60.6, 50.0, 42.4, 38.9, 24.3,
24.1, 22.6, 14.0. HRMS (LSIMS, nba): Calcd for
C.sub.31H.sub.43O.sub.5 (MH.sup.+): 495.3110, found: 495.3106.
HPLC: 94.8% pure.
[0388] 2,12-Dimethyl-7-oxo-2,12-di-p-tolyltridecanedioic acid
diethyl ester (209e). In analogy to the procedure described for the
synthesis of 209c, 205e (21.0 g, 64.2 mmol) was reacted with
tetrabutylammonium iodide (2.37 g, 6.4 mmol), TosMIC (6.26 g, 32.1
mmol) and NaH (60% dispersion in mineral oil, 3.24 g, 81.0 mmol) in
anhydrous DMSO (320 mL) and diethyl ether (110 mL) for 24 h at room
temperature. After hydrolysis and extraction, the crude
intermediate 208e was stirred in CH.sub.2Cl.sub.2 (500 mL) and
concd HCl (140 mL) for 2 h at room temperature. Extraction and
purification by flash chromatography (silica gel; ethyl
acetate/hexanes=1/20, 1/9) afforded 209e (9.0 g, 54%) as a light
yellowish oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.10 (d, 4H,
J=7.9), 7.02 (d, 4H, J=7.9), 4.05 (q, 4H, J=7.0), 2.25 (t, 4H,
J=7.3), 2.20 (s, 6H), 1.95-1.70 (m, 4H), 1.42 (s, 6H), 1.50-1.05
(m, 8H), 1.08 (t, 6H, J=7.0). .sup.13C NMR (CDCl.sub.3): .delta.
211.10, 176.00, 141.00, 135.80, 128.50, 124.51, 60.50, 49.50,
42.01, 39.50, 24.28, 24.05, 22.10, 20.50, 13.00. HRMS (LSIMS, nba):
Calcd for C.sub.33H.sub.47O.sub.5 (MH.sup.+): 523.3423, found:
523.3405.
[0389]
2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-oxotridecanedioic acid
diethyl ester (209f). Similar to the procedure given for 209c, 205f
(14.13 g, 38.3 mmol) was reacted with TosMIC (3.73 g, 19.1 mmol),
tetrabutylammonium iodide (1.30 g, 3.5 mmol), and NaH (2.0 g, 60%,
50.0 mmol) in freshly distilled DMSO (200 mL) for 18 h at room
temperature. The crude intermediate 208f obtained after hydrolysis
and extraction was stirred in CH.sub.2Cl.sub.2 (100 mL) and
concentrated HCl (50 mL) for 1 h at room temperature. Extractive
workup and purification by flash chromatography (silica gel; ethyl
acetate/hexanes=10/90, then 20/80) yielded 209f (9.49 g, 82%) as a
colorless oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.18 (d, 4H,
J=8.0), 7.07 (d, 4H, J=8.0), 4.10 (q, 4H, J=7.0), 2.43 (d, 4H,
J=7.0), 2.34 (t, 4H, J=7.6), 2.10-1.92 (m, 2H), 1.92-1.78 (m, 4H),
1.60-1.50(m, 4H), 1.50(s, 6H), 1.19-1.11 (m, 5H), 1.17(t, 3H,
J=7.0), 0.88(d, 12H, J=6.6). .sup.13C NMR (CDCl.sub.3): .delta.
211.06, 176.39, 141.36, 140.04, 129.16, 125.71, 60.77, 49.90,
45.06, 42.66, 39.18, 30.27, 24.59, 24.35, 22.86, 22.56, 14.23. HRMS
(LSIMS, nba): Calcd for C.sub.39H.sub.59O.sub.5 (MH.sup.+):
607.4362, found: 607.4337.
[0390] 2,2,14,14-Tetramethyl-8-oxopentadecanedioic acid diethyl
ester (209g). According to the procedure described for the
synthesis of 209c, a solution of 205g (32.3 g, 115.3 mmol),
tetrabutylammonium iodide (3.69 g, 10.0 mmol) and TosMIC (9.80 g,
50.2 mmol) in anhydrous DMSO (300 mL) was treated with NaH (4.80 g,
120.0 mmol, 60% in mineral oil) at room temperature for 20 h. The
intermediary dialkylated TosMIC derivative 208g obtained after
aqueous workup (36.8 g) was then hydrolyzed with concd hydrochloric
acid (110 mL) in CH.sub.2Cl.sub.2 (450 mL) at room temperature for
1 h. Extractive workup and purification by column chromatography
(silica gel; hexanes/ethyl acetate=11/1) afforded 209g (12.20 g,
61%) as a colorless oil. .sup.1H NMR (CDCl.sub.3): .delta. 4.11 (q,
4H, J=6.9Hz), 2.37 (t, 4H, J=7.5), 1.58-1.47 (m, 8H), 1.35-1.10 (m,
8H), 1.24 (t, 6H, J=7.2), 1.15 (s, 12H). .sup.13C NMR (CDCl.sub.3):
.delta. 211.6, 178.3, 60.5, 43.1, 42.5, 40.9, 30.1, 25.5, 25.1,
24.1, 14.7. HRMS (LSIMS, gly): Calcd for C.sub.23H4305 (MH.sup.+):
399.3110, found: 399.3129.
[0391] 2,2,18,18-Tetramethyl-10-oxononadecanedioic acid diethyl
ester (209j). Under N.sub.2 atmosphere, NaH (60% w/w in mineral
oil, 1.21 g, 30.2 mmol) was added in portions to a solution of
TosMIC (2.43 g, 12.5 mmol) and tetrabutylammonium iodide (0.462 g,
1.25 mmol) in dry DMSO (100 mL) while stirring vigorously and
cooling with a water bath. After 15 min, 205j (7.65 g, 26.1 mmol)
was added dropwise in 20 min. After 1 h, H.sub.2O (100 mL) was
added dropwise and the resulting mixture was extracted with
Et.sub.2O (3.times.100 mL). The combined organic layers were washed
with brine (2.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated in vacuo. The residue was purified by column
chromatography (silica, heptane:ethyl acetate=6:1) to give 208j
(5.41 g) as a yellow oil. To a portion of this oil (5.03 g),
dissolved in CH.sub.2Cl.sub.2 (100 mL), was added aqueous HCl
(concd, 30 mL) and the resulting mixture was stirred vigorously for
17.5 h. Water (100 mL) was added and the layers were separated. The
aqueous phase was extracted with CH.sub.2Cl.sub.2 (100 mL) and the
combined organic layers were washed with NaHCO.sub.3 solution
(2.times.100 mL) and brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4 and evaporated in vacuo. The residue was purified
by column chromatography (silica, heptane:ethyl acetate=7:1) to
give 209j (3.21 g, 61%) as a colorless oil. .sup.1H NMR
(CDCl.sub.3): .delta. (ppm): 4.11 (q, J=7.2, 4H), 2.37 (t, J=7.4,
4H), 1.57-1.46 (m, 8H), 1.28-1.23 (m, 16H), 1.24 (t, J=7.1, 6H),
1.15 (s, 12H). .sup.13C NMR (CDCl.sub.3): .delta. (ppm): 211.5,
178.0, 60.08, 60.07, 42.7, 42.1, 40.7, 29.9, 29.21, 29.15, 25.1,
24.8, 23.8, 14.2. HRMS: Calcd for C.sub.27H.sub.50O.sub.5
(MH.sup.+): 454.3658, found: 454.3663.
[0392]
9-Isocyano-2,2,16,16-tetramethyl-9-(toluene-4-sulfonyl)-heptadecan-
edioic acid diethyl ester (208i). To a solution of 205i (35.0 g,
125.4 mmol), tetrabutylammonium iodide (4.6 g, 12.5 mmol), and
TosMIC (12.2 g, 62.5 mmol) in anhydrous DMSO (450 mL) was added NaH
(60% dispersion in mineral oil, 6.3 g, 158 mmol) under cooling with
an ice-water bath and under N.sub.2 atmosphere. The reaction
mixture was stirred for 23 h at ambient temperature, then carefully
hydrolyzed with ice-water (500 mL) and extracted with MTBE
(3.times.200 mL). The organic layers were washed with water (300
mL) and brine (150 mL), dried over anhydrous MgSO.sub.4, and
concentrated in vacuo to give crude 8i (37.0 g, 100%) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. (ppm): 7.88 (d, J=7.9, 2H), 7.42
(d, J=7.9, 2H), 4.10 (q, J=7.5, 4H), 2.48 (s, 3H), 2.05-1.75 (m,
3H), 1.65-1.20 (m, 21H), 1.15 (t, J=7.5, 6H), 1.10 (s, 12H).
.sup.13C NMR (CDCl.sub.3): .delta. (ppm): 177.89, 163.75, 146.23,
131.08, 130.28, 129.82, 81.79, 60.17, 42.09, 40.57, 33.09, 29.68,
29.31, 25.17, 24.78, 23.66, 21.08, 14.31. HRMS (LSIMS, gly): Calcd
for C.sub.37H.sub.54NO.sub.6S (MH.sup.+): 592.3672, found:
592.3667.
[0393] 2,2,16,16-Tetramethyl-9-oxoheptadecanedioic acid diethyl
ester (209i). To a solution of 208i (12.0 g, 20.3 mmol) in
CH.sub.2Cl.sub.2 (200 mL) was added concd HCl (47 mL). The reaction
mixture was stirred for 80 min at room temperature and diluted with
water (200 mL). The layers were separated and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 (3.times.70 mL). The combined
organic layers were washed with saturated NaHCO.sub.3 solution
(3.times.40 mL) and brine (50 mL), dried over anhydrous MgSO.sub.4,
and concentrated in vacuo to yield the crude product (7.52 g).
Purification by column chromatography (silica gel, ethyl
acetate/hexanes=1/9) gave 209i (3.5 g, 40.0%) as a colorless oil.
.sup.1H NMR (CDCl.sub.3): .delta. (ppm): 4.14 (q, J=7.1, 4H), 2.41
(t, J=7.0, 4H), 1.66-1.45 (m, 8H), 1.35-1.20 (m, 12H), 1.25 (t,
J=7.1, 6H), 1.17 (s, 12H). .sup.13C NMR (CDCl.sub.3): .delta.
(ppm): 211.24, 177.89, 60.01, 42.69, 42.07, 40.64, 29.86, 29.07,
25.13, 24.73, 23.74, 14.24. HRMS (LSIMS, gly): Calcd for
C.sub.25H.sub.47O.sub.5 (MH.sup.+): 427.3423, found: 427.3430.
[0394] Representative Procedure for the Saponification of
Ketodiesters:
2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-oxotridecanedioic acid
(210f). A solution of 209f (3.0 g, 4.95 mmol) and KOH (85%, 4.4 g,
66.7 mmol) in ethanol (40 mL) and water (10 mL) was heated to
reflux for 6 h. The ethanol was removed under reduced pressure and
the mixture was diluted with water (200 mL). The solution was
extracted with Et.sub.2O (100 mL) and the aqueous layer was
acidified with concentrated HCl (10 mL) to pH 1. The product was
extracted with Et.sub.2O (2.times.100 mL). The ether fractions were
combined, dried over Na.sub.2SO.sub.4, concentrated and dried in
high vacuo to yield 210f (2.35 g, 86%) as a light yellow foam.
.sup.1H NMR (CDCl.sub.3): .delta. 10.02 (br., 2H), 7.24 (d, 4H,
J=8.0), 7.09 (d, 4H, J=8.0), 2.43 (d, 4H, J=7.0), 2.33 (t, 4H,
J=7.3), 2.05-1.88 (m, 2H), 1.96-1.77 (m, 4H), 1.55-1.42 (m, 10H),
1.22-1.08 (m, 4H), 0.88 (d, 12H, J=6.6). .sup.13C NMR (CDCl.sub.3):
.delta. 211.48, 182.94, 140.43, 140.24, 129.27, 125.94, 49.71,
45.06, 42.58, 42.58, 38.91, 30.25, 24.45, 24.24, 22.58, 22.40. HRMS
(LSIMS, nba): Calcd for C.sub.35H.sub.50O.sub.5Na (MNa.sup.+):
573.355, found: 573.3459. HPLC: 86.9% pure. Anal.
(C.sub.35H.sub.50O.sub.5) C, H.
[0395] 2,10-Dimethyl-6-oxo-2,10-diphenylundecanedioic acid (210b).
According to the procedure given for 210f, 209b (14.5 g, 31.1 mmol)
was saponified with KOH (85%, 7.2 g, 108.6 mmol) in water (15 mL)
and ethanol (45 mL) at reflux for 6 h. After the usual extractive
workup, the crude material was purified by flash chromatography
(silica gel; ethyl acetate/hexanes=1/20, 1/10, 1/2) to give 210b
(4.0 g, 31%) as a white solid. Mp 44-46.degree. C. .sup.1H NMR
(CDCl.sub.3): 10.25 (br., 2H), 7.35-7.22 (m, 10H), 2.32 (m, 4H),
1.94-1.86 (m, 4H), 1.57 (s, 6H), 1.51-1.22 (m, 4H). .sup.13C NMR
(CDCl.sub.3): .delta. 210.64, 182.66, 142.69, 128.66, 127.18,
126.29, 50.07, 42.97, 38.62, 22.20, 19.11. HRMS (LSIMS, gly): Calcd
for C.sub.25H.sub.31O.sub.5 (MH.sup.+): 411.2171, found: 411.2144.
HPLC: 95.2% pure.
[0396] 7-Oxo-2,2,12,12-tetramethyltridecanedioic acid (210c).
According to the procedure given for 210f, 209c (30.0 g, 81.0 mmol)
was saponified with KOH (85%, 18.9 g, 286 mmol) in ethanol (143 mL)
and water (48 mL) at reflux for 5 h. The solid product obtained
after extraction and drying was purified by flash chromatography
(silica; hexanes/ethyl acetate=90/10) to afford 210c (22.0 g, 86%)
as a white solid. Mp 60-61.5.degree. C. .sup.1H NMR (CDCl.sub.3):
.delta. 11.40 (br., 2H), 2.41 (t, 4H, J=7.3), 1.62-1.48 (m, 8H),
1.32-1.18 (m, 4H), 1.18 (s, 12H). .sup.13C NMR (CDCl.sub.3=77.0
ppm): .delta. 211.11, 184.74, 42.49, 42.14, 40.42, 24.92, 24.62,
23.99. HRMS (LSIMS, gly): Calcd for C.sub.17H.sub.31O.sub.5
(MH.sup.+): 315.2171, found: 315.2183. HPLC: 94.5% pure. Anal.
(C.sub.17H.sub.30O.sub.5) C, H.
[0397] 2,12-Dimethyl-7-oxo-2,12-diphenyltridecanedioic acid (210d).
According to the procedure given for 210f, 209d (3.93 g, 7.9 mmol)
was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in ethanol (60 mL)
and water (10 mL) at reflux for 3 h and at room temperature
overnight. After the usual workup and drying, 210d (3.0 g, 87%) was
obtained as an oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.40-7.10 (m,
10H), 2.32 (t, 4H, J=7.2), 2.10-1.80 (m, 4H), 1.60-1.45 (m, 4H),
1.54 (s, 6H), 1.25-1.10 (m, 4H). .sup.13C NMR (CDCl.sub.3): .delta.
211.1, 182.5, 142.8, 128.4, 126.9, 126.0, 49.9, 42.3, 38.7, 24.2,
24.0, 22.3. HRMS (LSIMS, nba): Calcd for C.sub.27H.sub.35O.sub.5
(MH.sup.+): 439.2484, found: 439.2497. HPLC: 93.7% pure.
[0398] 2,12-Dimethyl-7-oxo-2,12-di-p-tolyltridecanedioic acid
(210e). According to the procedure given for 210f, 209e (9.0 g,
17.2 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in water
(10 mL) and ethanol (30 mL) at reflux for 6 h. After the usual
extractive workup, the crude material was purified by flash
chromatography (silica gel; ethyl acetate/hexanes=1/10, 1/6, 1/2)
to give 210e (3.1 g, 39%) as a white solid. Mp 48-50.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 10.8-8.8 (br., 2H), 7.22 (d, 4H,
J=8.1), 7.12 (d, 4H, J=8.1), 2.36 (t, 4H, J=7.5), 2.31 (s, 6H),
1.98-1.80 (m, 4H), 1.56-1.44 (m, 4H), 1.51 (s, 6H), 1.24-1.15 (m,
4H). .sup.13C NMR (CDCl.sub.3): .delta. 211.63, 183.07, 140.40,
137.00, 129.58, 126.43, 50.02, 42.82, 39.10, 24.74, 24.50, 22.82,
21.39. HRMS (LSIMS, gly): Calcd for C.sub.29H.sub.39O.sub.5
(MH.sup.+): 467.2797, found: 467.2785. HPLC: 92.4% pure. Anal.
(C.sub.29H.sub.38O.sub.5) C, H.
[0399] 2,2,14,14-Tetramethyl-8-oxopentadecanedioic acid (210g).
According to the procedure given for 210f, 209g (8.54 g, 21.4 mmol)
was saponified with KOH (85%, 4.53 g, 68.6 mmol) in ethanol (13 mL)
and water (5 mL) at reflux for 4 h. The solid product obtained
after usual workup was recrystallized from Et.sub.2O/hexanes (50
mL/50 mL), affording 210g (4.16 g, 57%) as colorless needles. Mp
82-83.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 11.53 (br., 2H),
2.39 (t, 4H, J=7.3), 1.60-1.50 (m, 8H), 1.30-1.20 (m, 8H), 1.18 (s,
12H). .sup.13C NMR (CDCl.sub.3): .delta. 211.7, 185.0, 42.8, 42.3,
40.4, 29.7, 25.1, 24.8, 23.8. HRMS (LSIMS, gly): Calcd for
C.sub.19H.sub.35O.sub.5 (MH.sup.+): 343.2484, found: 343.2444.
HPLC: 92.6% pure. Anal. (C.sub.19H.sub.34O.sub.5) C, H.
[0400] 2,2,16,16-Tetramethyl-9-oxoheptadecanedioic acid (210i). To
a solution of KOH (85%, 8.4 g, 127.3 mmol) in deionized water (3.6
mL) and ethanol (11.5 mL) was added 208i (15.0 g, 25.3 mmol) and
the mixture was heated to reflux for 7 h. The reaction mixture was
diluted with water (40 mL) and extracted with MTBE (2.times.30 mL).
The aqueous layer was cooled with an ice-bath and the pH was
adjusted to 1 by addition of 5 N sulfuric acid (45 mL). The aqueous
layer was extracted with MTBE (3.times.30 mL) and the combined
organic layers were washed with brine (50 mL), dried over anhydrous
MgSO.sub.4, and concentrated in vacuo to give a crude oil (12.5 g).
Purification by chromatography (silica gel, ethyl
acetate/hexanes=10% to 100%) and recrystallization from
MTBE/hexanes (4 mL/50 mL) yielded 210i (5.37 g, 57%) as a white
powder. Mp 74.5-76.0.degree. C. .sup.1H NMR (CDCl.sub.3): .delta.
(ppm): 12.40-11.20 (br, 2H), 2.39 (t, J=7.3, 4H), 1.62-1.48 (m,
8H), 1.38-1.22 (m, 12H), 1.11 (s, 12H). .sup.13C NMR
(CDCl.sub.3=77.02 ppm): .delta. (ppm): 211.88, 184.93, 42.70,
42.19, 40.63, 29.63, 29.09, 24.96, 24.83, 23.83. HRMS (LSIMS, gly):
Calcd for C.sub.21H.sub.39O.sub.5 (MH.sup.+): 371.2797, found:
371.2804.
[0401] 2,2,18,18-Tetramethyl-10-oxononadecanedioic acid (210j). To
a solution of 209j (11.63 g, 25.6 mmol) in EtOH and H.sub.2O (3:1,
200 mL) was added powdered KOH (85%, 4.31 g, 65.3 mmol). The
resulting mixture was refluxed for 19 h and concentrated in vacuo
until all of the EtOH was removed. Water (200 mL) was added and the
resulting mixture was extracted with Et.sub.2O (2.times.200 mL).
The aqueous phase was acidified with aqueous HCl (4 M) to
pH.about.1 and extracted with Et.sub.2O (3.times.200 mL). The
combined Et.sub.2O layers of the latter extraction were dried over
anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo. The remaining
white solid was recrystallized from heptane/iPr.sub.2O to give 210j
(7.56 g, 74%) as white crystals. Mp 74.3-77.3.degree. C. .sup.1H
NMR (CD.sub.3OD): .delta. (ppm): 2.43 (t, J=7.3, 4H), 1.57-1.50 (m,
8H), 1.33-1.21 (m, 16H), 1.14 (s, 12H). .sup.13C NMR (CD.sub.3OD):
.delta. (ppm): 214.5, 182.1, 43.6, 43.2, 42.0, 31.2, 30.4, 30.38,
26.2, 25.9, 25.0. HRMS: Calcd for C.sub.23H.sub.42O.sub.5
(M.sup.+): 398.3028, found: 398.3032.
[0402] 2,2,16,16-Tetramethylheptadecane-1,9,17-triol (211i). Under
N.sub.2-atmosphere, methyl tert-butyl ether (MTBE, 80 mL) was added
to LiAlH.sub.4 (0.67 g, 17.65 mmol) and the suspension was stirred
under cooling with an ice-water bath. A solution of 209i (3.0 g,
7.03 mmol) in MTBE (20 mL) was added dropwise, followed by
additional MTBE (40 mL). After 2 h at 0.degree. C., the reaction
mixture was carefully quenched by addition of ethyl acetate (8 mL)
and allowed to warm to room temperature overnight. The mixture was
cooled with an ice-water bath and carefully hydrolyzed by addition
of crushed ice (15 g) and water (15 mL). The pH was adjusted to 1
by addition of 2 N aqueous sulfuric acid (28 mL) and the solution
was stirred at room temperature for 15 min. The layers were
separated and the aqueous layer was extracted with MTBE (40 mL).
The combined organic layers were washed with deionized water (50
mL), saturated NaHCO.sub.3 solution (40 mL), and brine (40 mL),
dried over anhydrous MgSO.sub.4, concentrated in vacuo and dried in
high vacuo. The crude product (2.65 g) was purified by
recrystallization from hot CH.sub.2Cl.sub.2 (20 mL). The crystals
were filtered, washed with ice-cold CH.sub.2Cl.sub.2 (20 mL) and
dried in high vacuo to furnish 211i (1.59 g, 66%) as a white solid.
Mp 75-77.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. (ppm): 3.57
(m, 1H), 3.30 (s, 4H), 1.72 (br, 2H), 1.50-1.16 (m, 25H), 0.85 (s,
12H). .sup.13C NMR (CDCl.sub.3): .delta. (ppm): 72.09, 38.79,
37.61, 35.21, 30.70, 29.85, 25.78, 24.06, 23.92. HRMS (LSIMS, gly):
Calcd for C.sub.21H.sub.45O.sub.3 (MH.sup.+): 345.3369, found:
345.3364. HPLC: 95.0% pure.
[0403] Representative Procedure for the Dialkylation of TosMIC and
Deprotection to Ketodiols:
1,15-Dihydroxy-2,2,14,14-tetramethylpentadecan-8-one (214g). Under
Argon atmosphere, to a solution of 207g (26.0 g, 84.6 mmol) and
TosMIC (7.8 g, 40.0 mmol) in anhydrous DMSO (200 mL) and THF (10
mL) was added NaH (3.8 g, 95.0 mmol, 60% in mineral oil) in five
portions at 20-30.degree. C. under cooling with a water bath. After
the addition of tetrabutylammonium iodide (3.0 g, 8.1 mmol), the
reaction mixture was stirred at room temperature for 20 h and then
hydrolyzed with water (400 mL). The mixture was extracted with
Et.sub.2O (3.times.100 mL). The combined organic layers were washed
with saturated aqueous NaCl solution (100 mL), dried over
MgSO.sub.4, and concentrated in vacuo to yield the crude
dialkylated intermediate (28.2 g) as an orange oil, which was used
without purification. To a solution of this crude product (28.0 g)
in methanol (115 mL) was added dilute H.sub.2SO.sub.4 (46 g, 12 mL
of concd H.sub.2SO.sub.4 in 24 mL of water) over a period of 10
min, and the mixture was stirred for 80 min at room temperature.
The solution was diluted with water (120 mL) and extracted with
CH.sub.2Cl.sub.2 (150 mL, 100 mL, 50 mL). The combined organic
layers were washed with saturated aqueous Na.sub.2CO.sub.3 solution
(2.times.100 mL), saturated aqueous NaHCO.sub.3 solution (100 mL),
water (200 mL), and saturated aqueous NaCl solution (150 mL). The
organic extract was dried over anhydrous MgSO.sub.4 and
concentrated in vacuo. The residue (18.4 g) was purified by column
chromatography (silica gel; hexanes, then CH.sub.2Cl.sub.2, then
hexanes/ethyl acetate=4/3) to give 214g (9.97 g, 79%) as a
colorless oil. .sup.1H NMR (CDCl.sub.3): .delta. 3.30 (s, 4H), 2.39
(t, 4H, J=7.2), 2.07 (br. s, 2H), 1.60-1.55 (m, 4H), 1.28-1.17 (m,
12H), 0.85 (s, 12H). .sup.13C NMR (CDCl.sub.3): .delta. 212.0,
72.0, 43.0, 38.6, 35.2, 30.3, 24.0, 23.8. HRMS (LSIMS, gly): Calcd
for C.sub.19H.sub.39O.sub.3 (MH.sup.+): 315.2899, found: 315.2886.
HPLC: 94.7% pure.
[0404] 1,11-Dihydroxy-2,2,10,10-tetramethylundecan-6-one (214a). In
analogy to the procedure described for the synthesis of 214g, 207a
(40.0 g, 143.3 mmol) was reacted with TosMIC (13.99 g, 71.7 mmol),
tetrabutylammonium iodide (5.28 g, 14.3 mmol), and NaH (6.86 g,
171.5 mmol) in anhydrous DMSO (400 mL). After extractive workup and
drying, the crude intermediate (47.9 g) was dissolved in methanol
(200 mL) and water (40 mL) and treated with concd sulfuric acid (20
mL) at room temperature. Workup and purification by chromatography
(silica gel; hexanes/ethyl acetate=90/10, 70/30, then 50/50)
afforded 214a (5.6 g, 30%) as an oil. .sup.1H NMR (CDCl.sub.3):
.delta. 3.30 (s, 4H), 2.68 (br. s, 2H), 2.40 (t, 4H, J=7.2), 1.53
(m, 4H), 1.20 (m, 4H), 0.86 (s, 12H). .sup.13C NMR (CDCl.sub.3=77.0
ppm): .delta. 212.25, 70.99, 43.15, 37.69, 34.94, 23.89, 17.91.
HRMS (LSIMS, gly): Calcd for C.sub.15H.sub.29O.sub.2
(MH.sup.+-H.sub.2O): 241.2168, found: 241.2169. HPLC: 96.7%
pure.
[0405] 1,11-Dihydroxy-2,10-dimethyl-2,10-diphenylundecan-6-one
(14b). In analogy to the procedure given for 214g, to a solution of
207b (25.0 g, 73.3 mmol), tetrabutylammonium iodide (3.0 g, 8.2
mmol), and TosMIC (7.23 g, 37.0 mmol) in anhydrous DMSO (350 mL)
was added NaH (60% dispersion in mineral oil, 3.73 g, 93.3 mmol)
while controlling the temperature with an ice bath. After the
addition of Et.sub.2O (100 mL), the mixture was stirred at room
temperature for 24 h, hydrolyzed, extracted, and dried to afford
the dialkylated TosMIC intermediate (28.0 g) as a brown oil. This
crude intermediate was heated to reflux for 3 h in methanol (500
mL), concd HCl (60 mL), and water (120 mL). Extractive workup and
purification by flash chromatography (silica gel; hexanes, then
ethyl acetate/hexanes=1/20, 1/10, 1/2, 1/1) gave 214b (5.3 g, 38%)
as a light yellowish oil. .sup.1H NMR (CDCl.sub.3): .delta. (ppm)
7.38-7.30 (m, 8H), 7.26-7.18 (m, 2H), 3.62 (d, 2H, J=10.5 Hz), 3.48
(d, 2H, J=10.5 Hz), 2.25 (m, 6H), 1.76-1.64 (m, 2H), 1.58-1.16 (m,
6H), 1.32 (s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. (ppm) 211.43,
144.84, 128.32, 126.58, 126.03, 71.79, 43.11, 42.89, 37.61, 21.68,
18.12. HRMS (LSIMS, nba): Calcd for C.sub.25H.sub.33O.sub.2
(MH.sup.+-H.sub.2O): 365.2481, found: 365.2482. HPLC: 89.5%
pure.
[0406] 1,13-Dihydroxy-2,2,12,12-tetramethyltridecan-7-one (214c).
Similar to the procedure given for the synthesis of 214g, 207c
(13.0 g, 44.3 mmol) was treated with TosMIC (4.33 g, 22.17 mmol),
NaH (60% dispersion in mineral oil, 2.13 g, 53.2 mmol), and
tetrabutylammonium iodide (1.64 g, 4.4 mmol) in anhydrous DMSO (100
mL) and anhydrous diethyl ether (50 mL) at room temperature
overnight. Hydrolysis and extraction afforded the dialkylated
TosMIC intermediate (15.5 g) as an oil that was dissolved in
methanol (180 mL), concd HCl (20 mL), and water (40 mL) and heated
to reflux for 2 h. Extractive workup and purification by flash
chromatography (silica gel; hexanes/ethyl acetate=50/50) furnished
214c (4.3 g, 68%) as a colorless oil. .sup.1H NMR (CDCl.sub.3):
.delta. 3.28 (s, 4H), 2.80 (br. m, 2H), 2.42 (t, 4H, J=7.3), 1.54
(m, 4H), 1.25 (m, 8H), 0.84 (s, 12H). .sup.13C NMR (CDCl.sub.3):
.delta. 212.06, 71.24, 42.47, 38.11, 34.76, 24.45, 23.72, 23.25.
HRMS (LSIMS, gly): Calcd for C.sub.17H.sub.35O.sub.5 (MH.sup.+):
287.2556, found: 287.2585. HPLC: 97.5% pure.
[0407] 1,13-Dihydroxy-2,12-dimethyl-2,12-diphenyltridecan-7-one
(214d). According to the procedure described for the synthesis of
214g, 207d (10.0 g, 28.2 mmol) was reacted with tetrabutylammonium
iodide (1.06 g, 2.9 mmol), TosMIC (2.34 g, 12.0 mmol) and NaH (60%
dispersion in mineral oil, 1.42 g, 35.5 mmol) in anhydrous DMSO
(100 mL) and anhydrous Et.sub.2O (50 ml) at room temperature for 24
h. After aqueous workup and extraction, the dialkylated TosMIC
intermediate (11.0 g) was heated to reflux in a mixture of methanol
(180 mL), concd HCl (20 mL), and water (40 mL) for 3 h. After
extraction, the crude oil was purified by flash chromatography
(silica gel; hexanes/ethyl acetate=80/20, then 60/40), affording
214d (3.0 g, 61%) as a colorless oil. .sup.1H NMR (CDCl.sub.3):
7.37-7.28 (m, 8H), 7.24-7.17 (m, 2H), 3.69 (dd, 2H, J=10.9, 5.2),
3.52 (dd, 2H, J=10.9, 7.5), 2.26 (t, 4H, J=7.3), 1.75 (m, 2H), 1.61
(s, 2H), 1.57-1.40 (m, 6H), 1.33 (s, 6H), 1.29-1.06 (m, 2H),
1.04-0.80 (m, 2H). .sup.13C NMR (CDCl.sub.3), .delta. (ppm):
211.21, 144.72, 128.23, 126.50, 125.92, 72.17, 43.14, 42.38, 38.06,
24.27, 23.34, 21.42. HRMS (LSIMS): Calcd for
C.sub.27H.sub.39O.sub.3 (MH.sup.+): 411.2899, found: 411.2899.
HPLC: 92.7% pure.
[0408] 1,13-Dihydroxy-2,12-dimethyl-2,12-di-p-tolyltridecan-7-one
(214e). According to the procedure for the synthesis of 214g, 207e
(21.5 g, 75.3 mmol) was reacted with tetrabutylammonium iodide
(2.36 g, 6.4 mmol), TosMIC (5.68 g, 29.1 mmol) and NaH (60%
dispersion in mineral oil, 2.94 g, 73.5 mmol) in anhydrous DMSO
(300 mL) and anhydrous Et.sub.2O (100 mL) at room temperature for
24 h. The crude intermediate (18.4 g) obtained after aqueous workup
and extraction was then heated to reflux in methanol (300 mL),
concd HCl (36 mL), and water (70 mL) for 3 h. Extractive workup and
purification by flash chromatography (silica gel; hexanes/ethyl
acetate=20/1, 15/1, 10/1, 5/1, and 1/1) gave 214e (2.72 g, 21%) as
a colorless oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.18 (d, 4H,
J=8.1), 7.12 (d, 4H, J=8.1), 3.61 (d, 2H, J=11.0), 3.48 (d, 2H,
J=11.0 Hz), 2.31 (s, 6H), 2.26 (t, 4H, J=7.8), 1.78-1.40 (m, 10H),
1.29 (s, 6H), 1.24-0.82 (m, 4H). .sup.13C NMR (CDCl.sub.3): .delta.
211.51, 141.75, 135.64, 129.23, 126.64, 72.54, 43.06, 42.65, 38.28,
24.53, 23.59, 21.66, 20.98. HRMS (LSIMS, gly): Calcd for
C.sub.29H.sub.43O.sub.3 (MH.sup.+): 439.3212, found: 439.3222.
HPLC: 95.4% pure.
[0409] 1,15-Dihydroxy-2,14-dimethyl-2,14-diphenylpentadecan-8-one
(214h). In analogy to the procedure of 214g, to a solution of 207h
(18.0 g, 63.1 mmol), tetrabutylammonium iodide (2.0 g, 5.4 mmol)
and TosMIC (4.8 g, 24.6 mmol) in anhydrous DMSO (250 mL) and
Et.sub.2O (80 mL) was added NaH (60% dispersion in mineral oil, 2.5
g, 62.5 mmol) while cooling with an ice bath under N.sub.2
atmosphere. After 24 h at room temperature, the mixture was
hydrolyzed and worked up by extraction to give the crude
intermediate (18.0 g) as a brown oil. This crude material was
heated to reflux in methanol (300 mL), concd HCl (36 mL) and water
(70 mL) for 3 h. Extractive workup and purification by flash
chromatography (silica gel; hexanes/ethyl acetate/hexanes=10/1,
5/1, 2/1) yielded 214h (6.1 g, 56%) as a yellowish oil. .sup.1H NMR
(CDCl.sub.3): .delta. 7.32-7.19 (m, 10H), 3.68 (d, 2H, J=10.8),
3.50 (d, 2H, J=10.8), 2.26 (t, 4H, J=7.50H), 1.88-1.42 (m, 10H),
1.25 (s, 6H), 1.22-0.85 (m, 8H). .sup.13C NMR (CDCl.sub.3): .delta.
211.68, 144.94, 128.56, 126.82, 126.23, 72.68, 43.50, 42.79, 38.42,
30.01, 23.74, 23.68, 21.62. HRMS (LSIMS, nba): Calcd for
C.sub.29H.sub.43O.sub.3 (MH.sup.+): 439.3212, found: 439.3207.
HPLC: 95.3% pure.
[0410]
2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-([1,3]dithianyl)-tride-
canedioic acid diethyl ester (212f). Compound 209f (5.50 g, 9.06
mmol) was dissolved in CH.sub.2Cl.sub.2 (freshly distilled from
CaH.sub.2, 60 mL) with boron trifluoride diethyl etherate (0.45 mL,
0.50 g, 3.55 mmol) and 1,3-propanedithiol (1.0 mL, 1.08 g, 9.99
mmol). The solution was stirred for 3 h at room temperature under a
nitrogen atmosphere. An additional volume of CH.sub.2Cl.sub.2 (100
mL) was added and the solution was extracted with 5% sodium
hydroxide solution (2.times.50 mL) and water (100 mL). After drying
with anhydrous Na.sub.2SO.sub.4, filtration, and concentration, the
product was purified by flash chromatography (silica gel; ethyl
acetate/hexanes=10/90), affording 212f (6.16 g, 98%) as a colorless
oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.20 (d, 4H, J=8.0), 7.07
(d, 4H, J=8.0), 4.10 (q, 4H, J=7.0), 2.76 (t, 4H, J=5.3), 2.43 (d,
4H, J=7.0), 2.09-1.95 (m, 2H), 1.94-1.78 (m, 10H), 1.51 (s, 6H),
1.46-1.36 (m, 4H), 1.25-1.12 (m, 4H), 1.18 (t, 6H, J=7.0), 0.88 (d,
12H, J=6.5). .sup.13C NMR (CDCl.sub.3): .delta. 176.42, 141.43,
140.00, 129.14, 125.74, 60.74, 53.30, 49.97, 45.05, 39.22, 38.29,
30.26, 26.10, 25.64, 25.17, 24.76, 22.99, 22.56, 14.26. HRMS (EI):
Calcd for C.sub.42H.sub.64O.sub.4S.sub.2 (M.sup.+): 696.4246,
found: 696.4234. HPLC: 96.2% pure.
[0411]
2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-([1,3]dithianyl)-tride-
cane-1,13-diol (213f). A solution of 212f (5.81 g, 8.33 mmol) in
freshly distilled THF (50 mL) was added dropwise to a suspension of
LiAlH.sub.4 (1.0 g, 26.4 mmol) in THF (50 mL) at -78.degree. C.
under a nitrogen atmosphere. The solution was warmed to room
temperature over 4 h, then cooled back to -78.degree. C., and
quenched with ethyl acetate (5.0 mL). After warming to room
temperature, water (100 mL) was added and the product was extracted
with Et.sub.2O (2.times.100 mL). The ether extracts were combined,
dried with sodium sulfate, filtered, and concentrated. After drying
under high vacuum for 4 h, 213f (4.80 g, 94%) was obtained as a
colorless oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.20 (d, 4H,
J=8.0), 7.09 (d, 4H, J=8.0), 3.64 (d, 2H, J=10.7), 3.48 (d, 2H,
J=10.7), 2.71 (t, 4H, J=5.1), 2.50-2.35 (m br., 2H), 2.43 (d, 4H,
J=7.0), 1.90-1.80 (m, 4H), 1.80-1.68 (m, 6H), 1.58-1.42 (m, 2H),
1.38-1.25 (m, 4H), 1.30 (s, 6H), 1.26-1.10 (m, 2H), 1.10-0.95 (m,
2H), 0.89 (d, 12H, J=6.6). .sup.13C NMR (CDCl.sub.3): .delta.
141.94, 139.39, 129.20, 126.44, 72.48, 53.30, 44.97, 43.09, 38.45,
38.18, 30.21, 26.01, 25.64, 24.84, 24.09, 22.55, 21.64. HRMS
(LSIMS, nba): Calcd for C.sub.38H.sub.61O.sub.2S.sub.2 (MH.sup.+):
613.4113, found: 613.4075. HPLC: 97.6% pure.
[0412]
1,13-Dihydroxy-2,12-bis-(4-isobutylphenyl)-2,12-dimethyltridecan-7-
-one (214f). To a mixture of 213f (4.50 g, 7.34 mmol) in
dimethoxyethane (50 mL) and concentrated HCl (10 mL) was added
dropwise DMSO (5.0 mL) over 5 min. The solution was stirred for 30
min at room temperature, then slowly poured into saturated aqueous
NaHCO.sub.3 solution (100 mL) and extracted with Et.sub.2O
(2.times.100 mL). The ether fractions were combined, dried with
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The product
was purified by flash chromatography (silica gel; ethyl
acetate/hexanes=30/70), affording 214f (3.2 g, 83%) as a colorless
oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.19 (d, 4H, J=8.0), 7.09
(d, 4H, J=8.0), 3.63 (d, 2H, J=11.0), 3.49 (d, 2H, J=11.0), 2.43
(d, 4H, J=7.0), 2.26 (t, 4H, J=7.3), 1.88-1.66 (m, 4H), 1.52-1.41
(m, 8H), 1.29 (s, 6H), 1.15-1.10 (m, 2H), 0.98-0.88 (m, 2H), 0.89
(d, 12H, J=6.6). .sup.3C NMR (CDCl.sub.3): .delta. 211.47, 141.97,
139.51, 129.28, 126.45, 72.53, 45.02, 43.11, 42.69, 38.36, 30.26,
24.57, 23.63, 22.58, 21.72. HRMS (LSIMS, nba): Calcd for
C.sub.35H.sub.55O.sub.3 (MH.sup.+): 523.4151, found: 523.4144.
HPLC: 96.3% pure.
[0413] 1,17-Dihydroxy-2,2,16,16-tetramethylheptadecan-9-one (214i).
To a solution of 211i (2.42 g, 7.02 mmol) in acetic acid (10 mL)
was added dropwise sodium hypochlorite solution (1.76 mL, ca. 3.5
mmol) at 18.degree. C. Additional sodium hypochlorite solution
(3.times.1.0 mL, ca. 6.0 mmol) was added after 20, 40, and 60 min
under monitoring by TLC. The reaction was quenched with 2-propanol
(4 mL) and diluted with deionized water (100 mL). The reaction
mixture was extracted with ethyl acetate (3.times.60 mL). The
combined organic layers were washed with saturated NaHCO.sub.3
solution (3.times.60 mL), water (60 mL) and brine (60 mL), dried
over anhydrous MgSO.sub.4, and concentrated in vacuo. Purification
of the crude product (2.38 g) by column chromatography (silica gel,
ethyl acetate/hexanes=1/1) gave 214i (0.83 g, 35%) as a colorless
wax. .sup.1H NMR (CDCl.sub.3): .delta. (ppm): 3.33 (s, 4H), 2.41
(t, J=7.4, 4H), 1.85 (br, 2H), 1.62-1.45 (m, 4H), 1.35-1.18 (m,
16H), 0.87 (s, 12H). .sup.13C NMR (CDCl.sub.3): .delta. (ppm):
212.09, 72.10, 42.99, 38.75, 35.20, 30.48, 29.42, 24.05, 23.99,
23.82. HRMS (LSIMS, gly): Calcd for C.sub.21H.sub.43O.sub.3
(MH.sup.+): 343.3212, found: 343.3208. HPLC: 96.4% pure.
[0414]
2-[7-Isocyano-2,2-dimethyl-7-(toluene-4-sulfonyl)-heptyloxy]-tetra-
hydropyran (215). Method A. To a solution of TosMIC (9.75 g, 49.9
mmol) and tetrabutylammonium iodide (1.69 g, 4.6 mmol) in anhydrous
DMSO (240 mL) was added NaH (2.2 g, 55.0 mmol, 60% in mineral oil),
while cooling with an ice bath. 207c (14.65 g, 50 mmol) was added
dropwise over 1 h and the reaction mixture was stirred at room
temperature overnight. The mixture was quenched with water (100 mL)
and extracted with CH.sub.2Cl.sub.2 (3.times.100 mL). The combined
organic layers were washed with water (100 mL) and half-saturated
aqueous NaCl solution (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, and concentrated in vacuo to afford the crude
product (30 g), which was purified by column chromatography (silica
gel; hexanes/ethyl acetate=90/10) to obtain 215 (5.4 g, 27%) as a
colorless oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.87 (d, 2H,
J=8.2), 7.43 (d, 2H, J=8.2), 4.56-4.40 (m, 2H), 3.83 (t, 1H,
J=8.1), 3.58-3.38 (m, 1H), 3.46 (d, 1H, J=9.2), 2.97 (d, 1H,
J=9.2), 2.49 (s, 3H), 2.30-1.20 (m, 16H), 0.88 (s, 6H). .sup.13C
NMR (CDCl.sub.3): .delta. 164.7, 146.5, 131.1, 130.1, 99.1, 76.2,
62.0, 38.7, 34.1, 30.6, 28.3, 26.2, 25.5, 24.5, 23.0, 21.8, 19.5.
HRMS (LSIMS, nba): Calcd for C.sub.22H.sub.34NSO.sub.4 (MH.sup.+):
408.2209, found: 408.2205.
[0415] Method B. To a solution of TosMIC (3.9 g, 20.0 mmol) in
anhydrous DMF (100 mL) was added K.sub.2CO.sub.3 (5.52 g, 39.9
mmol), 207c (11.72 g, 40.0 mmol), and tetrabutylammonium iodide
(0.74 g, 1.95 mmol). The reaction mixture was stirred at room
temperature for 20 h and then heated to 50.degree. C. for 4 h. The
reaction mixture was poured into ice water (300 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.60 mL). The combined organic layers
were washed with water (2.times.100 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo to afford the crude
product, which was purified by column chromatography (silica gel;
hexanes/ethyl acetate=90/10) to give 215 (5.6 g, 69%) as a
colorless oil.
[0416] 1,12-Dihydroxy-2,2,11,11-tetramethyldodecan-6-one (217). To
a solution of 215 (6.5 g, 15.9 mmol) in anhydrous DMSO (70 mL) was
added NaH (0.77 g, 19.3 mmol, 60% in mineral oil), 207a (4.91 g,
17.6 mmol), and tetrabutylammonium iodide (0.59 g, 1.6 mmol). The
reaction mixture was stirred at room temperature for 24 h and
hydrolyzed with water (100 mL). The product was extracted with
CH.sub.2Cl.sub.2 (3.times.100 mL). The combined organic layers were
washed with water (3.times.100 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude
intermediate (14.0 g). This crude material was heated to reflux in
concentrated HCl (17 mL) and methanol (100 mL) overnight. The
reaction mixture was poured into ice water (200 mL) and extracted
with Et.sub.2O (3.times.100 mL). The combined organic layers were
washed with 5% NaOH solution (60 mL) and water (2.times.100 mL),
dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel; hexanes/ethyl
acetate=80/20), affording 217 (2.5 g, 58%) as a colorless oil.
.sup.1H NMR (CDCl.sub.3): .delta. 3.31 (s, 2H), 3.28 (s, 2H),
2.42-2.37 (m, 4H), 2.4-1.8 (m br., 2H), 1.56-1.48 (m, 4H),
1.22-1.14 (m, 6H), 0.85 (s, 6H), 0.84 (s, 6H). .sup.13C NMR
(CDCl.sub.3): .delta. 212.0, 71.5, 71.1, 43.0, 42.7, 38.2, 37.7,
35.0, 34.9, 30.8, 24.6, 23.9, 23.8, 23.4, 17.8. HRMS (LSIMS, gly):
Calcd for C.sub.16H.sub.33O.sub.3 (MH.sup.+): 273.2430, found:
273.2422. HPLC: 91.4% pure.
[0417] 1,13-Dihydroxy-2,2,12-trimethyl-12-phenyltridecan-7-one
(218). To a solution of 215 (5.3 g, 13.0 mmol) in anhydrous DMSO
(60 mL) was added NaH (0.62 g, 15.5 mmol, 60% in mineral oil), 207d
(4.6 g, 12.9 mmol), and tetrabutylammonium iodide (0.48 g, 1.3
mmol). The reaction mixture was stirred at room temperature
overnight and hydrolyzed with water (100 mL). The product was
extracted with CH.sub.2Cl.sub.2 (3.times.100 mL) and the combined
organic phases were washed with water (100 mL) and half-saturated
aqueous NaCl solution (100 mL), dried over sodium sulfate and
concentrated in vacuo to get the crude intermediate (9.0 g). This
crude material was heated to reflux in concentrated HCl (13.4 mL)
and methanol (60 mL) overnight. The reaction mixture was poured
into water (200 mL) and the product was extracted with Et.sub.2O
(3.times.60 mL). The combined organic layers were washed with water
(3.times.20 ml), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel; hexanes/ethyl acetate=2/1), affording
218 (3.2 g, 71%) as a colorless oil. .sup.1H NMR (CDCl.sub.3):
.delta. 7.38-7.16 (m, 5H), 3.67 (d, 1H, J=10.9), 3.52 (d, 1H,
J=10.9), 3.26 (s, 2H), 2.40-2.20 (m, 4H), 1.85-1.60 (m, 3H),
1.60-1.40 (m, 5H), 1.33 (s, 3H), 1.28-1.10 (m, 5H), 1.10-0.90 (m,
1H), 0.83 (s, 6H). .sup.13C NMR (CDCl.sub.3=77.0 ppm): .delta.
211.5, 144.6, 128.3, 126.6, 126.0, 72.3, 71.6, 43.3, 42.5, 38.2,
34.9, 24.6, 24.4, 23.8, 23.4, 21.5. HRMS (LSIMS, gly): Calcd for
C.sub.22H.sub.37O.sub.3 (MH.sup.+): 349.2743, found: 349.2731.
HPLC: Alltima C-8 column, 250.times.4.6 mm, 5.mu.; 50%
acetonitrile/50% water, flow rate 1.0 mL/min; RI, retention time
12.87 min, 84.9% pure.
[0418] 1,14-Dihydroxy-2,2,13,13-tetramethyltetradecan-7-one (219).
According to the procedure described for the synthesis of 217, 215
(6.98 g, 17.1 mmol) was reacted with NaH (0.82 g, 20.5 mmol, 60% in
mineral oil), 207g (5.8 g, 18.9 mmol), and tetrabutylammonium
iodide (0.63 g, 1.7 mmol) in anhydrous DMSO (100 mL) for 24 h at
room temperature. The crude intermediate (10.9 g) obtained after
aqueous workup was heated to reflux in concentrated HCl (18 mL) and
methanol (100 mL) overnight. After extraction and column
chromatography (silica gel; hexanes/ethyl acetate=80/20), 219 (2.3
g, 48%) was obtained as a colorless oil. .sup.1H NMR (CDCl.sub.3):
.delta. 3.30 (s, 4H), 2.48-2.34 (m, 4H), 1.85 (br., 2H), 1.66-1.46
(m, 4H), 1.24-1.14 (m, 10H), 0.85 (s, 12H). .sup.13C NMR
(CDCl.sub.3): .delta. 211.8, 71.8, 71.6, 42.7, 42.6, 38.4, 38.2,
34.9, 30.1, 24.6, 23.8, 23.8, 23.7, 23.6, 23.4. HRMS (LSIMS, gly):
Calcd for C.sub.18H.sub.37O.sub.3 (MH.sup.+): 301.2743, found:
301.2745. HPLC: 97.4% pure.
[0419] 7-Isocyano-2,2-dimethyl-7-(toluene-4-sulfonyl)-heptanoic
acid ethyl ester (220). Under nitrogen atmosphere, to a stirred
solution of tetrabutylammonium iodide (4.23 g, 11.5 mmol) and
TosMIC (27.56 g, 141.2 mmol) in anhydrous DMSO (500 mL) was added
NaH (60% w/w in mineral oil, 5.80 g, 145.0 mmol), while keeping the
internal temperature between 10 and 15.degree. C. After the
dropwise addition of 205c (36.60 g, 145.7 mmol), the mixture was
stirred at room temperature for 20 h, then cooled with an ice-bath
and carefully hydrolyzed with water (600 mL). The solution was
extracted with CH.sub.2Cl.sub.2 (4.times.150 mL). The combined
organic layers were washed with water (200 mL) and half-saturated
aqueous NaCl solution (200 mL), dried over anhydrous MgSO.sub.4,
and concentrated in vacuo to obtain the crude product mixture (40.9
g) as an orange oil. A portion of this crude product (13.0 g) was
purified by column chromatography (silica gel; hexanes/ethyl
acetate=10/1, then 9/1), affording 220 (1.92 g, 12%) as a pale
yellow oil, 208c (0.70 g, 3%) as a colorless oil, and a mixture of
both (2.50 g, ratio 9/1). .sup.1H NMR (CDCl.sub.3): .delta. 7.86
(d, 2H, J=8.1), 7.43 (d, 2H, J=8.1), 4.48 (dd, 1H, J=7.2, 3.6),
4.11 (q, 2H, J=7.2), 2.49 (s, 3H), 2.21-2.16 (m, 1H), 1.90-1.78 (m,
1H), 1.56-1.50 (m, 4H), 1.35-1.20 (m, 2H), 1.25 (t, 3H, J=7.2),
1.16 (s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. 177.8, 165.0,
146.7, 131.3, 130.3, 130.2, 72.9, 60.5, 42.2, 40.2, 28.3, 25.8,
25.3, 25.2, 24.2, 21.9, 14.4. HRMS (LSIMS, nba): Calcd for
C.sub.19H.sub.28NO.sub.4S (MH.sup.+): 366.1739, found:
366.1746.
[0420] Ethyl 12-hydroxy-2,2,11,11-tetramethyl-7-oxo-dodecanoate
(221). Under nitrogen atmosphere, to a solution of 220 (1.72 g,
4.68 mmol), tetrabutylammonium iodide (0.17g, 0.46 mmol) and 207a
(1.45 g, 5.19 mmol) in anhydrous DMSO (20 mL) was added NaH (60%
w/w in mineral oil, 0.19 g, 4.75 mmol), while keeping the internal
temperature between 10 and 15.degree. C. The reaction mixture was
stirred for 20 h at room temperature and then carefully hydrolyzed
with ice-water (100 mL). The mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.15 mL). The combined organic layers were
washed with water (40 mL) and saturated aqueous NaCl solution
(2.times.20 mL), dried over anhydrous MgSO.sub.4, and concentrated
in vacuo to obtain the crude intermediate (3.50 g) as brown oil. A
solution of this intermediate in 48% H.sub.2SO.sub.4 (6 mL) and
methanol (12 mL) was stirred for 100 min at room temperature. The
mixture was diluted with water (50 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.15 mL). The combined organic layers were
washed with water (100 mL) and saturated aqueous NaCl solution (100
mL), dried over anhydrous MgSO.sub.4, and concentrated in vacuo to
obtain the crude product (2.70 g) as yellow oil. A portion of the
crude product (2.50 g) was subjected to column chromatography
(silica gel; hexanes/ethyl acetate=80/20, then 75/25) to give 221
(0.82 g, 60%) as a pale yellow oil. .sup.1H NMR (CDCl.sub.3):
.delta. 4.14-4.03 (m, 2H), 3.31 (br. s, 2H), 2.42 (br., 1H), 2.39
(m, 4H), 1.54-1.48 (m, 6H), 1.24-1.18 (m, 7H), 1.14 (s, 6H), 0.86
(s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. 211.7, 178.0, 71.2,
60.3, 43.2, 42.7, 42.1, 40.4, 37.9, 35.1, 25.2, 24.6, 24.2, 24.1,
18.0, 14.3. HRMS (LSIMS, gly): Calcd for C.sub.18H.sub.35O.sub.4
(MH.sup.+): 315.2535, found: 315.2541.
[0421] Ethyl 14-Hydroxy-2,2,13,13-tetramethyl-7-oxotetradecanoate
(222). According to the procedure for the synthesis of 220, 205c
(45.6 g, 182 mmol) was reacted with TosMIC (35.2 g, 180 mmol),
tetrabutylammonium iodide (4.3 g, 11.6 mmol) and NaH (60% w/w in
mineral oil, 7.3 g, 183 mmol) in anhydrous DMSO (500 mL). To this
solution was added tetrabutylammonium iodide (4.3 g, 11.6 mmol) and
207g (43.8 g, 143 mmol) in anhydrous DMSO (20 mL), and then NaH
(7.4 g, 185 mmol, 60% w/w in mineral oil) at 10.degree. C. The
reaction mixture was stirred at room temperature for 20 h, cooled
with an ice-bath, and carefully hydrolyzed with ice-water (1000
mL). The product was extracted with CH.sub.2Cl.sub.2 (5.times.100
mL). The combined organic layers were dried over anhydrous
MgSO.sub.4 and concentrated in vacuo to obtain the crude
intermediate (115 g) as a red oil. This intermediate was dissolved
in 48% H.sub.2SO.sub.4 (147 mL) and methanol (480 mL) and the
mixture was stirred for 100 min at room temperature. After dilution
with water (1500 mL), the product was extracted with
CH.sub.2Cl.sub.2 (2.times.150 mL, 100 mL, 50 mL). The combined
organic layers were washed with saturated aqueous sodium carbonate
solution (150 mL) and saturated aqueous NaCl solution (150 mL),
dried over MgSO.sub.4, filtered through a short column (aluminum
oxide; ethyl acetate), and concentrated in vacuo to obtain the
crude product (89 g) as a yellow oil. The crude product was
subjected to column chromatography (silica gel; hexanes/ethyl
acetate=6:1, then 3:1) to give 222 (17.6 g, 36%) as a pale yellow
oil. .sup.1H NMR (CDCl.sub.3): .delta. 4.10 (q, 2H, J=6.9), 3.30
(br. s, 2H), 2.39 (t, 4H, J=6.9), 1.98 (br., 1H), 1.56-1.48 (m,
6H), 1.27-1.18 (m, 11H), 1.14 (s, 6H), 0.85 (s, 6H). .sup.13C NMR
(CDCl.sub.3): .delta. 211.5, 178.0, 71.9, 60.3, 42.9, 42.7, 42.2,
40.5, 38.6, 35.1, 30.3, 25.2, 24.7, 24.2, 24.0, 23.8, 14.4. HRMS
(LSIMS, gly): Calcd for C.sub.20H.sub.39O.sub.4 (MH.sup.+):
343.2848, found: 343.2846.
[0422] 2,2,11,11-Tetramethyl-7-oxododecanedioic acid 1-ethyl ester
(223). A mixture of 221 (3.26 g, 10.4 mmol) and pyridinium
dichromate (14.0 g, 37.2 mmol) in DMF (45 mL) was stirred at room
temperature for 46 h. The solution was diluted with 48%
H.sub.2SO.sub.4 (30 mL) and water (300 mL) and extracted with ethyl
acetate (5.times.100 mL). The combined organic layers were washed
with saturated aqueous NaCl solution (5.times.100 mL), dried over
anhydrous MgSO.sub.4, and concentrated in vacuo to give the crude
product (3.19 g) as greenish oil. The crude product was subjected
to column chromatography (silica gel; hexanes/ethyl acetate=3:1,
2:1), affording 223 (2.69 g, 79%) as a pale yellow oil. .sup.1H NMR
(CDCl.sub.3): .delta. 11.30 (br., 1H), 4.10 (q, 2H, J=7.2), 2.39
(t, 4H, J=7.2), 1.56-1.48 (m, 8H), 1.25-1.15 (m, 2H), 1.24 (t, 3H,
J=7.2), 1.20 (s, 6H), 1.15 (s, 6H). .sup.13C NMR (CDCl.sub.3):
.delta. 210.9, 184.4, 178.1, 60.4, 43.1, 42.7, 42.2, 40.5, 39.8,
25.3, 25.0, 24.7, 24.3, 19.3, 14.4. HRMS (LSIMS, gly): Calcd for
C.sub.18H.sub.33O.sub.5 (MH.sup.+): 329.2328, found: 329.2330.
[0423] 2,2,13,13-Tetramethyl-7-oxotetradecanedioc acid 1-ethyl
ester (224). A mixture of 222 (10.53 g, 30.7 mmol) and pyridinium
dichromate (32.5 g, 86.4 mmol) in DMF (120 mL) was stirred at
30.degree. C. for 40 h. The mixture was poured into 48% sulfuric
acid (50 mL) and water (700 mL). The product was extracted with
ethyl acetate (3.times.200 mL, 2.times.100 mL). The combined
organic layers were washed with saturated aqueous NaCl solution
(4.times.100 mL), dried over anhydrous MgSO.sub.4, and concentrated
in vacuo to give the crude product (10.3 g) as a pale yellow oil.
This crude material was purified by column chromatography (silica
gel; hexanes/ethyl acetate=75/25) to afford 224 (7.40 g, 68%) as a
yellowish oil. .sup.1H NMR (CDCl.sub.3): .delta. 4.10 (q, 2H,
J=7.5), 2.39 (m, 4H), 1.56-1.49 (m, 8H), 1.26-1.21 (m, 10H), 1.18
(s, 6H), 1.15 (s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. 211.4,
184.2, 178.0, 60.3, 42.8, 42.7, 42.1, 40.5, 40.4, 29.7, 25.2, 24.8,
24.7, 24.3, 23.7, 14.3. HRMS (LSIMS, gly): Calcd for
C.sub.20H.sub.37O.sub.5 (MH.sup.+): 357.2641, found: 357.2641.
[0424] 2,2,11,11-Tetramethyl-6-oxododecanedioc acid (225).
According to the procedure given for 209f, 223 (2.50 g, 7.6 mmol)
was saponified with KOH (1.80 g, 27.3 mmol) in water (3 mL) and
ethanol (8 mL) at reflux for 4 h. After the usual workup, the crude
product (2.17 g) was recrystallized from Et.sub.2O/hexanes (15
mL/25 mL) to give 225 (1.36 g, 60%) as white needles. Mp
72-73.degree. C. .sup.1H NMR (CDCl.sub.3): .delta. 12.0-11.2 (br.,
2H), 2.41 (m, 4H), 1.60-1.52 (m, 8H), 1.29-1.24 (m, 2H), 1.20 (s,
6H), 1.18 (s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. 211.2, 185.1,
184.9, 43.9, 42.7, 42.2, 40.3, 39.8, 25.1, 25.0, 24.7, 24.2, 19.3.
HRMS (LSIMS, gly): Calcd for C.sub.16H.sub.29O.sub.5 (MH.sup.+):
301.2015, found: 301.2023. HPLC: 95.8% pure.
[0425] 2,2,13,13-Tetramethyl-7-oxotetradecanedioc acid (226).
According to the procedure for the synthesis of 209f, a solution of
224 (7.4 g, 20.8 mmol) and KOH (85%, 4.6 g, 69.6 mmol) in water (5
mL) and ethanol (15 mL) was heated to reflux for 4 h. The crude
product (6.8 g) obtained after the usual workup was purified by
repeated column chromatography (silica gel; first: hexanes/ethyl
acetate=2/1, then 1/1. Second: hexanes/ethyl acetate=1/) and
crystallization (Et.sub.2O/hexanes, 20 mL/10 mL), affording 226
(2.95 g, 43%) as colorless needles. Mp 61-62.degree. C. .sup.1H NMR
(CDCl.sub.3): .delta. 11.91 (br., 2H), 2.41 (t, 4H, J=6.9), 2.39
(t, 4H, J=6.9), 1.58-1.52 (m, 8H), 1.30-1.22 (m, 6H), 1.18 (s,
12H). .sup.13C NMR (CDCl.sub.3): .delta. 211.8, 184.5, 185.4, 43.0,
42.9, 42.5, 40.7, 40.6, 29.9, 25.4, 25.1, 25.0, 24.6, 23.9. HRMS
(LSIMS, gly): Calcd for C.sub.18H.sub.33O.sub.5 (MH.sup.+):
329.2328, found: 329.2324. HPLC: 93.5% pure.
[0426]
3-{3-[3-Ethoxycarbonyl-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimeth-
ylpropionic acid ethyl ester (228). Under inert gas atmosphere and
at -78.degree. C., to a stirred solution of ethyl isobutyrate (9.78
g, 84.2 mmol) in anhydrous THF (30 mL) was added dropwise a
solution of lithium diisopropylamide (2.0 M, 42.2 mL, 84.4 mmol).
After 1 h, 227 (10.34 g, 28.1 mmol) was added, followed by addition
of N,N'-dimethylpropyleneurea (DMPU, 2.7 g, 21.1 mmol). The mixture
was stirred for 30 min and then allowed to warm to room temperature
over 30 min. The THF was distilled off under reduced pressure. The
residue was dissolved in saturated aqueous NH.sub.4Cl solution (280
mL) and extracted with ethyl acetate (3.times.100 mL). The combined
organic layers were washed with saturated aqueous NaCl solution
(200 mL), 5% HCl (100 mL) and saturated aqueous NaHCO.sub.3
solution (50 mL). Drying over anhydrous Na.sub.2SO.sub.4 and
concentration in vacuo afforded 228 (11.0 g, 89%) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 7.8-7.2 (m, 8H), 3.98 (q, 4H,
J=6.9), 2.83 (s, 4H), 1.2-0.8 (m, 18H). .sup.13C NMR
(CDCl.sub.3=77.0 ppm): .delta. 196.5, 176.8, 138.1, 137.2, 134.0,
131.4, 128.1, 127.7, 60.3, 45.7, 43.3, 24.8, 13.9.
[0427]
3-(3-{2-[3-(2-Ethoxycarbonyl-2-methylpropyl}-phenyl]-[1,3]dithian--
2-yl}-phenyl)-2,2-dimethylpropionic acid ethyl ester (229). To a
solution of 228 (6.2 g, 14.1 mmol) and 1,3-propanedithiol (1.9 g,
17.6 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added boron trifluoride
diethyl etherate (0.52 mL, 0.58 g, 4.1 mmol). The solution was
stirred at room temperature overnight. After the addition of 5%
NaOH solution (17.5 mL), the organic layer was separated, washed
with water (50 mL), dried over anhydrous Na.sub.2SO.sub.4, and
evaporated to afford 229 (6.5 g, 87%) as an oil. .sup.1H NMR
(CDCl.sub.3): .delta. 7.58-6.96 (m, 8H), 4.10 (q, 4H, J=7.2), 2.85
(s, 4H), 2.76 (t, 4H, J=5.6), 1.98 (m, 2H), 1.22 (t, 6H, J=7.2)
1.13 (s, 12H). .sup.13C NMR (CDCl.sub.3=77.0 ppm): .delta. 177.17,
142.18, 138.07, 131.12, 129.30, 127.84, 127.33, 60.35, 46.16,
43.48, 29.38, 24.90, 14.13.
[0428]
3-(3-{2-[3-(3-Hydroxy-2,2-dimethylpropyl)-phenyl]-[1,3]dithian-2-y-
l}-phenyl)-2,2-dimethylpropan-1-ol (230). To a suspension of
LiBH.sub.4 (0.78 g, 35.8 mmol) in CH.sub.2Cl.sub.2 (55 mL) was
added methanol (1.04 g, 32.5 mmol) at room temperature. After the
addition of 229 (6.5 g, 12.3 mmol), the reaction mixture was heated
to reflux for 6 h. After cooling to room temperature, saturated
aqueous NH.sub.4Cl solution (20 mL) and CH.sub.2Cl.sub.2 (15 mL)
were added and the layers were separated. The aqueous layer was
extracted with CH.sub.2Cl.sub.2 (2.times.10 mL). The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated in vacuo to afford 230 (4.66 g, 85%) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 7.42 (s br., 2H), 7.17 (m, 4H),
6.97 (m, 2H), 3.63 (s, 4H), 3.16 (s, 4H), 2.69 (m, 2H), 2.47 (m,
4H), 1.88 (m, 2H), 0.75 (s, 12H). .sup.13C NMR (CDCl.sub.3):
.delta. 142.39, 139.18, 131.69, 129.88, 128.05, 127.01, 71.12,
44.89, 43.74, 36.70, 29.63, 24.22.
[0429]
3-{3-[3-(2-Carboxy-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethylpr-
opionic acid (231). According to the procedure for the synthesis of
209f, a mixture of 228 (4.38 g, 10.0 mmol) and KOH (85%, 1.57 g,
23.8 mmol) was heated to reflux in water (1.5 mL) and ethanol (5
mL) for 3 h. After extraction and drying in high vacuo, 231 (3.88
g, quantitative) was obtained as a white solid. Mp 46-48.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 11.2-10.6 (br., 2H), 7.8-7.2 (m,
8H), 2.83(s, 4H), 1.25(s, 12H). .sup.13C NMR (CDCl.sub.3): .delta.
198.02, 183.86, 138.61, 137.73, 134.56, 130.54, 128.41, 128.10,
46.69, 43.77, 24.83. HRMS (LSIMS, nba): Calcd for
C.sub.23H.sub.27O.sub.5 (MH.sup.+): 383.1858, found: 383.1858.
HPLC: 88.3% pure.
[0430] Bis[3-(3-hydroxy-2,2-dimethylpropyl)-phenyl]-methanone
(232). A suspension of copper(II) oxide (0.96 g, 12.1 mmol) and
anhydrous copper(II) chloride (3.2 g, 23.8 mmol) in acetone (80 mL)
was heated to reflux. A solution of 230 (4.44 g, 10.0 mmol) in
acetone (20 mL) and DMF (1.2 mL) was added dropwise over 5 min.
After 90 min at reflux temperature, the reaction mixture was cooled
to room temperature and filtered. The insoluble material was washed
with CH.sub.2Cl.sub.2 (3.times.20 mL). The combined organic
solutions were washed with aqueous 2 N Na.sub.2CO.sub.3 solution
(50 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated in
vacuo. The residue was purified by column chromatography (silica
gel; hexanes/acetone=80/20) to give 232 (2.5 g, 71%) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 7.68-7.30 (m, 8H), 3.31 (s, 4H),
3.03 (s br., 2H), 2.65 (s, 4H), 0.88 (s, 12H). .sup.13C NMR
(CDCl.sub.3=77.00 ppm): .delta. 197.42, 139.06, 136.96, 134.60,
131.88, 127.78, 127.55, 70.39, 44.07, 36.30, 23.80. HRMS (LSIMS,
nba): Calcd for C.sub.23H.sub.31O.sub.3 (MH.sup.+): 355.2273,
found: 355.2263. HPLC: 94.5% pure.
Syntheses of Intermediates
[0431] 2-Phenylpropionic acid ethyl ester (202). Under N.sub.2
atmosphere, a solution of ethyl phenylacetate (800.0 g, 4.87 mol)
in anhydrous THF (6.4 L) was cooled to -40.degree. C. and a
solution of LDA (2.0 M in heptane/THF, ethylbenzene, 2.43 L, 4.86
mol) was added dropwise over 30 min. The reaction mixture was
stirred for 1 h, and methyl iodide (968 g, 6.82 mol) was added
dropwise over 20 min, followed by the addition of DMPU (320 mL).
After 1 h, the reaction mixture was allowed to warm to room
temperature and stirred overnight. The reaction mixture was poured
into water (6.4 L) and extracted with ethyl acetate (3.times.1.6
L). The combined organic layers were washed with saturated aqueous
NH.sub.4Cl solution (1.6 L), 1 N HCl (1.6 L), saturated aqueous
NaHCO.sub.3 solution (1.6 L), and saturated aqueous NaCl solution
(1.6 L). The solution was dried over MgSO.sub.4 and concentrated in
vacuo. The residue was distilled in high vacuo to give 202 (620.0
g, 72%) as a colorless oil. Bp 55-60.degree. C./0.2 Torr (lit.
(Shiner, V. J. et al. J. Am. Chem. Soc. 1961, 83, 593-598) bp
59-60.degree. C./0.3 Torr). .sup.1H NMR (CDCl.sub.3): .delta.
7.36-7.18 (m, 5H), 4.11 (m, 2H), 3.69 (q, 1H, J=7.1), 1.49 (d, 3H,
J=7.1), 1.19 (t, 3H, J=7.1). .sup.13C NMR (CDCl.sub.3): .delta.
174.44, 140.73, 128.57, 127.48, 127.04, 60.66, 45.59, 18.66,
14.16.
[0432] Ethyl 2-p-Tolylpropionate (203). According to the procedure
given for the synthesis of 202, ethyl p-tolylacetate (2.72 g, 15.2
mmol) was reacted with LDA (7.6 mL, 15.25 mmol) and methyl iodide
(3.03 g, 21.30 mmol) in anhydrous THF (70 mL) and DMPU (1 mL).
After aqueous workup and extraction, the residue was distilled in
high vacuo to give 203 (2.5 g, 86.0%) as an oil. Bp 59-63.degree.
C./0.2 mmHg. .sup.1H NMR (CDCl.sub.3): .delta. (ppm) 7.18 (d, 2H,
J=8.1), 7.10 (d, 2H, J=8.1), 4.09 (m, 2H), 3.67 (q, 1H, J=7.2),
2.29 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.20 (t, J=5.7 Hz, 3H).
.sup.13C NMR (75 MHz, CDCl.sub.3/TMS): .delta. (ppm) 174.71,
137.80, 136.63, 129.33, 129.14, 127.36, 60.66, 45.18, 21.05, 18.70,
14.15.
[0433] 2-(4-Isobutylphenyl)-propionic acid ethyl ester (204). A
solution of 2-(4-isobutylphenyl)-propionoic acid (Ibuprofen, 9.6 g,
46.5 mmol) and p-toluenesulfonic acid monohydrate (1.52 g, 7.9
mmol) in benzene (100 mL) and ethanol (75 mL) was heated to reflux
using a Dean-Stark apparatus for 4 h. The solvent was removed under
reduced pressure and the residue was taken up in Et.sub.2O (100
mL). The solution was extracted with saturated aqueous NaHCO.sub.3
solution (2.times.100 mL) and water (2.times.100 mL). The organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated, affording 204 (10.44 g, 96%) as a clear oil. .sup.1H
NMR (CDCl.sub.3): .delta. 7.19 (d, 2H, J=8.0), 7.08 (d, 2H, J=8.0),
4.10 (m, 2H), 3.66 (q, 1H, J=7.0), 2.44 (d, 2H, J=7.0), 1.84 (m,
1H), 1.47 (d, 3H, J=7.0), 1.19 (t, 3H, J=7.3), 0.89 (d, 6H, J=7.0).
.sup.13C NMR (CDCl.sub.3): .delta. 174.92, 140.59, 138.07, 129.45,
127.29, 60.79, 45.32, 45.21, 30.35, 22.55, 18.78, 14.29. HRMS
(LSIMS, nba): Calcd for C.sub.15H.sub.23O.sub.2 (MH.sup.+):
235.1698, found: 235.1688.
[0434] Ethyl 5-Bromo-2,2-dimethylpentanoate (205a). Described in
lit. (Kuwahara, M. et al. Chem. Pharm. Bull. 1997, 45, 1447-1457)
Bp 65.0-66.5.degree. C./0.4 mmHg (lit. 71-73.degree. C./0.25 mmHg).
.sup.1H NMR (CDCl.sub.3): 4.12 (q, 2H, J=7.1), 3.38 (t, 2H, J=6.4),
1.88-1.75 (m, 2H), 1.69-1.61 (m, 2H), 1.25 (t, 3H, J=7.1), 1.18 (s,
6H). .sup.13C NMR (CDCl.sub.3): 177.54, 60.49, 41.87, 39.22, 33.97,
28.63, 25.26, 14.34.
[0435] Ethyl 5-Bromo-2-methyl-2-phenyl-pentanoate (205b). Under
Ar-atmosphere, to a solution of ethyl phenylacetate (42.4 g, 0.26
mol) and DMPU (5 mL) in THF (250 mL) was added dropwise a solution
of LDA (2 M, 135 mL, 0.27 mol) at -78.degree. C. The mixture was
stirred for 2 h, before methyl iodide (41.40 g, 0.29 mol) was added
in a single portion. The mixture was stirred overnight and allowed
to warm to room temperature. After cooling to -78.degree. C.,
1,3-dibromopropane (72.7 g, 0.36 mol) was added and the mixture was
allowed to stir overnight, gradually warming to room temperature.
The mixture was hydrolyzed by consecutive addition of ice (200 g),
saturated aqueous NH.sub.4Cl solution (400 mL), and concd HCl (100
mL), and extracted with ethyl acetate (2.times.200 mL). The organic
layers were dried over over anhydrous MgSO.sub.4, and distilled
under vacuum to give 205b as colorless oil (88.6 g, 59%). Bp
123-128.degree. C./0.25 mmHg. .sup.1H NMR (CDCl.sub.3): 7.20-7.10
(m, 5H), 4.12 (q, 2H, J=7.2), 3.35 (t, 2H, J=6.9), 2.18-2.00 (m,
2H), 1.77-1.72 (m, 2H), 1.56 (s, 3H), 1.18 (t, 3H, J=6.9). .sup.13C
NMR (CDCl.sub.3): 175.9, 143.4, 128.5, 126.9, 126.0, 61.0, 49.8,
38.2, 34.0, 28.5, 22.8, 14.2.
[0436] Ethyl 6-Bromo-2,2-dimethylhexanoate (205c). This compound
was prepared as described in lit. (Ackerley, N. et al. J. Med.
Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987,
30, 1812-1818). Bp 65.degree. C./0.15 mmHg (lit. 86.degree. C./0.2
mmHg; lit. 62-64.degree. C./0.40 mmHg). .sup.1H NMR (CDCl.sub.3):
4.15 (q, 2H, J=7.1), 3.41 (t, 2H, J=6.7), 1.85 (qv, 2H, J=6.7),
1.60-1.45 (m, 2H), 1.40-1.30 (m, 2H), 1.28 (t, 3H, J=7.1), 1.20 (s,
6H). .sup.13C NMR (CDCl.sub.3): 177.3, 60.0, 41.8, 39.4, 33.2,
32.9, 24.9, 23.34, 14.02.
[0437] Ethyl 6-Bromo-2-methyl-2-phenylhexanoate (205d). A solution
of LDA (14 mL, 28 mmol, 2.0 M in heptane) was added dropwise to a
stirred solution of 202 (5.0 g, 28.06 mmol) in anhydrous THF (50
mL) at -78.degree. C. After 1 h, the reaction mixture was added to
a -78.degree. C. cold solution of 1,4-dibromobutane (10.06 g, 23.1
mmol) in THF. After the addition of DMPU (5 mL), the reaction
mixture was stirred for 1 h, then warmed to room temperature and
stirred overnight. The mixture was poured into saturated aqueous
NH.sub.4Cl solution (500 mL) and extracted with ethyl acetate
(4.times.100 mL). The combined organic phases were washed with
brine (100 mL), 1 M HCl (50 mL), saturated aqueous NaHCO.sub.3
solution (50 mL), and brine (100 mL). The solution was dried over
anhydrous MgSO.sub.4 and concentrated in vacuo. The residue was
distilled to give 205d as an oil (7.16 g, 99%). Bp 130-131.degree.
C./0.2 mmHg. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.40-7.15 (m,
5H), 4.13 (q, 2H, J=6.7), 3.36 (t, 2H, J=6.7), 2.02 (m, 2H), 1.86
(m, 2H), 1.56 (s, 3H), 1.34 (m, 2H), 1.18 (t, 3H, J=6.7). .sup.13C
NMR (CDCl.sub.3), .delta. (ppm): 176.13, 143.91, 128.51, 126.81,
126.03, 60.93, 50.22, 38.53, 33.56, 33.30, 23.58, 22.77, 14.22.
HRMS (FAB): Calcd for C.sub.15H.sub.21.sup.79BrO.sub.2 (MH.sup.+):
313.0803, found 313.0786.
[0438] Ethyl 6-Bromo-2-methyl-2-p-tolylhexanoate (205e). This
compound was prepared according to the procedure for 205d to give
205e (22.0 g, 90%) as an oil. Bp 128-130.degree. C./0.2 mmHg).
.sup.1H NMR (CDCl.sub.3): .delta. (ppm) 7.19 (d, 2H, J=8.2 Hz),
7.12 (d, 2H, J=8.2 Hz), 4.13 (q, 2H, J=7.2 Hz), 3.37 (t, J=6.6 Hz,
2H), 2.32 (s, 3H), 2.10-1.80 (m, 4H), 1.54 (s, 3H), 1.36 (m, 2H),
1.19 (t, J=7.2 Hz, 3H). .sup.13C NMR (CDCl.sub.3): .delta. (ppm)
176.26, 140.92, 136.35, 129.21, 125.89, 60.88, 49.82, 38.53, 33.61,
33.33, 23.59, 22.78, 21.07, 14.25. HRMS (FAB, nba): Calcd for
(C.sub.16H.sub.23BrO.sub.2) 327.0959, found 327.0975.
[0439] 6-Bromo-2-(4-isobutylphenyl)-2-methylhexanoic acid ethyl
ester (205f). Under nitrogen atmosphere and at -78.degree. C., to a
solution of 204 (10.5 g, 44.8 mmol) in anhydrous THF (150 mL) was
added a solution of LDA (2.0 M, 28 mL, 56 mmol) and the mixture was
stirred for 1 h. 1,4-Dibromobutane (25 mL, 37.5 g, 175 mmol) was
then added dropwise over 30 min and the solution allowed to warm to
room temperature over 5 h. After stirring at room temperature for
an additional 16 h, the reaction was hydrolyzed with water (100 mL)
and extracted with Et.sub.2O (2.times.100 mL). The combined organic
layers were washed with 10% HCl (2.times.100 mL), saturated aqueous
NaHCO.sub.3 solution (100 mL) and water (100 mL). After drying with
Na.sub.2SO.sub.4 (5 g), filtration and concentration, the crude
product was purified by flash chromatography (silica gel; ethyl
acetate/hexanes=5/95) and dried in high vacuo (0.5 mmHg) at
150.degree. C. for 30 min, affording 205f (14.49 g, 88%) as a
clear, viscous oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.19 (d, 2H,
J=8.0), 7.08 (d, 2H, J=8.0), 4.11 (q, 2H, J=7.0), 3.35 (t, 2H,
J=6.8), 2.43 (d, 2H, J=7.3), 2.10-1.92 (m, 1H), 1.92-1.78 (m, 4H),
1.53 (s, 3H), 1.40-1.28 (m, 2H), 1.17 (t, 3H, J=7.0), 0.88 (d, 6H,
J=6.8). .sup.13C NMR (CDCl.sub.3): .delta. 176.17, 141.12, 140.04,
129.14, 125.64, 60.77, 49.80, 44.99, 38.52, 33.51, 33.26, 30.22,
23.55, 22.69, 22.50, 14.19. HRMS (LSIMS, nba): Calcd for
C.sub.19H.sub.30O.sub.2Br (MH.sup.+): 369.1429, found:
369.1445.
[0440] Ethyl 7-Bromo-2,2-dimethylheptanoate (205g). Under argon
atmosphere, a solution of 1,5-dibromopentane (500 g, 2.2 mol) and
ethyl isobutyrate (221 g, 1.9 mol) in anhydrous THF (4 L) was
chilled in a dry ice/acetone bath to -78.degree. C. Over a 40 min
period, LDA solution in THF (1.8 M, 1 L, 1.8 mol) was added
dropwise. After the addition, the solution was allowed to stir
overnight and gradually warm to room temperature. Careful quenching
of the excess base by slow addition of saturated aqueous NH.sub.4Cl
solution (3 L) furnished a two-phase mixture. The organic layer was
separated and evaporated under vacuum to a minimum volume (ca. 1
L). The organic residue was recombined with the aqueous layer and
the resulting mixture was extracted with ethyl acetate (3.times.1
L). The combined ethyl acetate layers were then washed with 1 N HCl
(5 L), water (3 L) and saturated aqueous NaHCO.sub.3 solution (4 L)
before drying over anhydrous MgSO.sub.4. Concentration in vacuo
gave crude material (468.7 g), which was then purified by
distillation affording 205g (208.7 g, 44%) as a colorless oil. Bp
106-108.degree. C./0.01 mmHg. .sup.1H NMR (CDCl.sub.3): .delta.
4.11 (q, 2H, J=7.2), 3.39 (t, 2H, J=6.8), 1.85 (m, 2H), 1.56-1.35
(m, 4H), 1.24 (t, 3H, J=7.2), 1.31-1.19 (m, 2H), 1.16 (s, 6H).
.sup.13C NMR (CDCl.sub.3): .delta. 177.9, 60.2, 42.1, 40.5, 33.8,
32.6, 28.6, 25.2, 24.2, 14.3. HRMS (EI): Calcd for
C.sub.11H.sub.22BrO.sub.2 (MH.sup.+) 265.0803, found 265.0810.
[0441] Ethyl 7-Bromo-2-methyl-2-phenylheptanoate (205h). Under
N.sub.2 atmosphere, a solution of LDA (2.0 M in
heptane/THF/ethylbenzene, 1.85 mL, 3.70 mol) was added dropwise to
a stirred solution of 202 (660 g, 3.70 mol) in anhydrous THF (6.6
L) over 30 min at -78.degree. C. After 1 h, 1,5-dibromopentane
(1390 g, 6.05 mol) was added, followed by the addition of DMPU (660
mL). The reaction mixture was stirred for 1 h, then warmed to room
temperature and stirred overnight. The mixture was poured into
saturated aqueous NH.sub.4Cl solution (24 L) and extracted with
ethyl acetate (4.times.6.7 L). The combined organic layers were
washed with brine (9 L), 1 N HCl (6 L), saturated aqueous
NaHCO.sub.3 solution (6 L), and brine (6 L). The solution was dried
over MgSO.sub.4 and concentrated in vacuo. The residue was
distilled in high vacuo to yield 205h (700 g, 58%) as a yellowish
oil. Bp 140-145.degree. C./0.3 mmHg. .sup.1H NMR (CDCl.sub.3):
.delta. 7.30-7.20 (m, 5H), 4.09 (m, 2H), 3.34 (t, 2H, J=6.9),
2.05-1.80 (m, 4H), 1.53 (s, 3H), 1.43-1.14 (m, 4H), 1.16 (t, 3H,
J=6.6). .sup.13C NMR (CDCl.sub.3): .delta. 176.03, 143.99, 128.33,
126.60, 125.89, 60.68, 50.11, 39.03, 33.75, 32.51, 28.59, 23.93,
22.78, 14.10. HRMS (LSIMS, nba): Calcd for
C.sub.16H.sub.24BrO.sub.2 (MH.sup.+): 327.0960, found: 327.0952.
HPLC: 91.2% pure.
[0442] Ethyl 8-bromo-2,2-dimethyloctanoate (205i). Under N.sub.2
atmosphere, a solution of LDA (2.0 M in heptane/THF/ethylbenzene,
2.94 L, 5.9 mol) was added dropwise to a stirred solution of ethyl
isobutyrate (720 g, 6.2 mol) in anhydrous THF (4.7 L) at-45.degree.
C. After 1 h, 1,6-dibromohexane (2400 g, 9.8 mol) was added
dropwise, followed by the addition of DMPU (320 mL). The reaction
mixture was stirred for 1 h and then allowed to warm to room
temperature overnight. Saturated NH.sub.4Cl solution (3 L) was
added and the mixture was extracted with ethyl acetate (3.times.6
L). The combined organic layers were washed with brine (4.5 L), 1 M
aqueous HCl (6 L), saturated NaHCO.sub.3 solution (6 L), and brine
(4.5 L). The solution was dried over anhydrous MgSO.sub.4 and
concentrated in vacuo. The residue was distilled under high vacuo
to furnish 205i (856 g, 52%) as a light yellowish oil. Bp
95-100.degree. C./0.2 mmHg. .sup.1H NMR (CDCl.sub.3): .delta.
(ppm): 4.13 (q, J=7.1, 2H), 3.39 (t, J=6.9, 2H), 1.92-1.75 (m, 2H),
1.58-1.25 (m, 8H), 1.25 (t, J=7.1, 3H), 1.12 (s, 6H). .sup.13C NMR
(CDCl.sub.3=77.52 ppm): .delta. (ppm): 177.62, 60.01, 42.08, 40.50,
33.63, 32.68, 29.13, 27.93, 25.00, 24.66, 14.22. HRMS (LSIMS, nba):
Calcd for C.sub.12H.sub.24BrO.sub.2 (MH.sup.+): 279.0960, found:
279.0957. GC: 76.4% pure.
[0443] Ethyl 9-bromo-2,2-dimethylnonanoate (205j). Under N.sub.2
atmosphere at 0.degree. C., LDA (2 M solution in
THF/heptane/ethylbenzene, 13.0 mL, 26.0 mmol) was added dropwise to
a mixture of ethyl isobutyrate (3.5 mL, 3.0 g, 25.9 mmol) and
1,7-dibromoheptane (9.84 g, 38.2 mmol) in dry THF (50 mL) over 1.5
h, while keeping the temperature below 5.degree. C. After 3 h, the
mixture was poured into ice-cold saturated aqueous NH.sub.4Cl
solution (150 mL). The layers were separated and the aqueous phase
was extracted with Et.sub.2O (3.times.100 mL). The combined organic
layers were washed with aqueous HCl (1 M, 100 mL), saturated
aqueous NaHCO.sub.3 solution (100 mL) and brine (100 mL), dried
over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The
residue (12.4 g) was purified twice by column chromatography
(heptane: ethyl acetate=40:1) to give 205j (3.42 g, 45%) as a
colorless liquid. .sup.1H NMR (CDCl.sub.3): .delta. (ppm): 4.11 (q,
J=7.2, 2H), 3.40 (t, J=6.9, 2H), 1.85 (quintet, J=6.9, 2H),
1.52-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.35-1.20 (m, 6H), 1.24 (t,
J=7.2, 3H), 1.15 (s, 6H). .sup.13C-NMR (CDCl.sub.3): .delta. (ppm):
177.8, 60.0, 42.0, 40.5, 33.7, 32.7, 29.7, 28.5, 28.0, 25.0
(2.times.), 24.7, 14.1. HRMS: Calcd for C.sub.13H.sub.25BrO.sub.2
(M.sup.+): 292.1038, found: 292.1034.
[0444] Representative Procedure for the Reduction of Ethyl
.omega.-Bromoalkanoates with Lithium Borohydride and Methanol:
6-Bromo-2-methyl-2-p-tolylhexan-1-ol (206e). Methanol (3.14 g, 98.0
mmol) was added dropwise to a stirred suspension of LiBH.sub.4
(2.19 g, 100.6 mmol) in anhydrous CH.sub.2Cl.sub.2 (50 mL) under
N.sub.2 atmosphere. After the addition of 5e (22.0 g, 67.2 mmol),
the reaction mixture was heated to reflux overnight. The reaction
mixture was cooled to 5.degree. C. and hydrolyzed with ice (ca. 40
g) and saturated aqueous NH.sub.4Cl solution (150 mL) for 1 h. The
layers were separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.200 mL). The combined organic layers were
washed with saturated aqueous NH.sub.4Cl solution (3.times.150 mL),
dried over MgSO.sub.4 and concentrated in vacuo to give 206e (18.44
g, 96%) as an oil, which was used without further purification for
the next step. .sup.1H NMR (CDCl.sub.3): .delta. 7.25-7.00 (m, 4H),
3.68-3.50 (m, 1H), 3.49-3.35 (m, 1H), 3.34-3.21 (t, 2H, J=6.9),
2.31 (s, 3H), 1.88-1.51 (m, 4H), 1.51-1.40 (m, 2H), 1.31 (s, 3H),
1.20-1.00 (m, 1H). .sup.13C NMR (CDCl.sub.3): .delta. 141.49,
135.74, 129.47, 126.63, 72.54, 43.03, 37.53, 33.69, 33.51, 22.66,
21.58, 20.98. HRMS (LSIMS, nba): Calcd for C.sub.14H.sub.20Br
(MH.sup.+-H.sub.2O): 267.0748, found: 267.0750.
[0445] 5-Bromo-2,2-dimethylpentan-1-ol (206a). According to the
procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol)
was reduced with LiBH.sub.4 (12.97 g, 0.60 mol) and methanol (19.04
g, 0.60 mol) in CH.sub.2Cl.sub.2 (400 mL) to give 206a (78.0 g,
100%) as an oil. .sup.1H NMR (DMSO-d.sub.6): .delta. 4.42 (s, 1H),
3.45 (t, 2H, J=6.6), 3.08 (s, 2H), 1.84-1.69 (m, 2H), 1.27 (t, 2H,
J=8.3), 0.78 (s, 6H). .sup.13C NMR (DMSO-d.sub.6): .delta. 69.7,
36.9, 35.7, 34.5, 27.4, 24.0.
[0446] 5-Bromo-2-methyl-2-phenylpentan-1-ol (206b). According to
the procedure given for the synthesis of 206e, 205b (23.70 g, 79.21
mmol) was reduced with LiBH.sub.4 (3.45 g, 158.4 mmol) and methanol
(5.24 g, 163.5 mmol) in anhydrous CH.sub.2Cl.sub.2 (150 mL) to give
206b (20.0 g, 98%) as an oil. .sup.1H NMR (CDCl.sub.3): .delta.
7.34-7.14 (m, 5H), 3.60 (m, 1H), 3.48 (m, 1H), 3.29 (t, 2H, J=6.0),
1.96-1.44 (m, 5H), 1.32 (s, 3H). .sup.13C NMR (CDCl.sub.3): .delta.
144.25, 128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58,
21.61. HRMS (LSIMS, nba): Calcd for C.sub.12H.sub.16Br
(MH.sup.+-H.sub.2O): 239.0435, found: 239.0444.
[0447] 6-Bromo-2,2-dimethylhexanol (206c). According to the
procedure described for the synthesis of 206e (Ackerley, N. et al.
J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med.
Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted
with LiBH.sub.4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in
CH.sub.2Cl.sub.2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 3.38 (t, 2H, J=7.4), 3.50-3.40
(br. s, 1H, OH), 3.22 (d, 2H, J=5.6), 1.85 (qv, 2H, J=7.4),
1.50-1.35 (m, 2H), 1.30-1.20 (m, 2H), 0.85 (s, 6H). .sup.13C NMR
(CDCl.sub.3) .delta. 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.
[0448] 6-Bromo-2-methyl-2-phenylhexan-1-ol (206d). According to the
procedure given for the synthesis of 206e, 205d (52.0 g, 166.0
mmol) was reacted with LiBH.sub.4 (5.4 g, 247.9 mmol) and methanol
(8.2 g, 255.9 mmol) in CH.sub.2Cl.sub.2 (180 mL) to afford 206d
(38.0 g, 84%) as an oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.5-7.1
(m, 5H), 3.60 (d, 1H, J=10.8), 3.53 (d, 1H, J=10.8), 3.34 (t, 2H,
J=7.0), 1.90-1.78 (m, 3H), 1.62-1.26 (m, 3H), 1.35 (s, 3H), 1.14
(m, 1H). .sup.13C NMR (CDCl.sub.3): .delta. 144.4, 128.4, 126.5,
126.1, 72.4, 43.2, 37.4, 33.5, 33.3, 22.5, 21.4.
[0449] 7-Bromo-2,2-dimethylheptan-1-ol (206g). According to the
method for the synthesis of 206e, 205g (43.0 g, 0.16 mol) was
treated with LiBH.sub.4 (5.55 g, 0.25 mol) and methanol (7.75 g,
0.24 mol) in CH.sub.2Cl.sub.2 (200 mL) to give 206g (36.2 g, 98%)
as a colorless, viscous oil. .sup.1H NMR (CDCl.sub.3): .delta. 3.41
(t, 2H, J=6.9), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m,
6H), 0.86 (s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. 71.9, 38.6,
35.1, 34.1, 32.9, 29.2, 24.0, 23.2. HRMS (LSIMS, nba): Calcd for
C.sub.9H.sub.18Br (MH.sup.+-H.sub.2O): 205.0592, found:
205.0563.
[0450] 7-Bromo-2-methyl-2-phenylheptan-1-ol (206h). According to
the procedure given for the synthesis of 206e, 205h (60.0 g, 183
mmol) was reduced with LiBH.sub.4 (5.96 g, 274 mmol) and methanol
(8.55 g, 269 mmol) in anhydrous CH.sub.2Cl.sub.2 (390 mL). After
the typical workup, crude 206h (51.0 g, 98%) was obtained as a
yellowish oil, which was used without further purification for the
next step. .sup.1H NMR (CDCl.sub.3): .delta. 7.25-7.08 (m, 5H),
3.64 (d, 1H, J=7.2), 3.50 (d, 1H, J=7.2), 3.35 (t, 2H, J=6 Hz),
1.92-0.95 (m, 9H), 1.28 (s, 3H). .sup.13C NMR (CDCl.sub.3): .delta.
144.77, 128.51, 126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73,
28.96, 23.12, 21.59. HRMS (EI): Calcd for C.sub.14H.sub.21BrO
(M.sup.+): 284.0776, found: 284.0787.
[0451] Representative Procedure for the THP-Protection of
.omega.-Bromoalkanols:
2-(6-Bromo-2-methyl-2-phenylhexyloxy)-tetrahydropyran (207d). Under
N.sub.2 atmosphere and cooling with an ice bath,
3,4-dihydro-2H-pyran (33.86 g, 0.40 mol) was added dropwise to a
stirred solution of 206d (88.0 g, 0.32 mol) and p-toluenesulfonic
acid hydrate (0.05 g, 0.03 mmol) in CH.sub.2Cl.sub.2 (700 mL).
After the addition, the reaction mixture was allowed to warm to
room temperature and stirred overnight. The solution was filtered
through aluminum oxide (160 g) and the aluminum oxide was washed
with CH.sub.2Cl.sub.2 (800 mL). The filtrate was concentrated in
vacuo and purified by flash chromatography on silica gel
(hexanes/ethyl acetate=10/1) to give 207d (80.0 g, 70%) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 7.40-7.14 (m 10H), 4.53 (t, 1H,
J=3.4), 4.49 (t, 1H, J=3.4), 3.82 (d, 1H, J=9.4), 3.81 (t, 1H,
J=9.4), 3.76-3.60 (m, 2H), 3.44 (m, 2H), 3.36 (d, 2H, J=9.4), 3.33
(t, 4H, J=7.0), 1.90-1.42 (m, 14H), 1.79 (t, 4H, J=6.8), 1.37 (s,
6H), 1.34-1.10 (m, 6H). .sup.13C NMR (CDCl.sub.3=77.0 ppm): .delta.
145.67, 127.91, 127.91, 126.39, 126.37, 125.7, 98.95, 98.81, 76.11,
76.07, 62.78, 61.77, 61.66, 41.88, 41.78, 37.93, 37.75, 33.50,
33.44, 30.59, 30.44, 25.41, 25.37, 22.77, 22.71, 22.62, 19.65,
19.23, 19.15. HRMS (LSIMS, nba): Calcd for
C.sub.18H.sub.28BrO.sub.2 (MH.sup.+): 355.1272, found:
355.1272.
[0452] 2-(5-Bromo-2,2-dimethylpentyloxy)-tetrahydropyran (207a).
According to the procedure for the preparation of 207d, 206a (78.0
g, 0.40 mol) was reacted with 3,4-dihydro-2H-pyran (41.5 g, 0.49
mol) and p-toluenesulfonic acid hydrate (0.42 g, 2.2 mmol) in
CH.sub.2Cl.sub.2 (0.5 L) to yield 207a (101.0 g, 90%) as a
pale-yellow oil, which was used without further purification.
.sup.1H NMR (CDCl.sub.3): .delta. 4.55 (t, 1H, J=2.9), 3.83 (m,
1H), 3.51 (m, 1H), 3.47 (d, 1H, J=9.0), 3.38 (t, 2H, J=6.8), 2.98
(d, 1H, J=9.0), 1.94-1.75 (m, 2H), 1.75-1.44 (m, 6H), 1.40 (t, 2H,
J=8.5), 0.91 (s, 3H), 0.90 (s, 3H). .sup.13C NMR (CDCl.sub.3):
.delta. 99.01, 76.17, 61.85, 37.89, 34.66, 34.04, 30.62, 27.92,
25.60, 24.64, 24.56, 19.41. HRMS (LSIMS, nba): Calcd for
C.sub.12H.sub.24BrO.sub.2 (MH.sup.+): 279.0960, found:
279.0955.
[0453] 2-(5-Bromo-2-methyl-2-phenylpentyloxy)-tetrahydropyran
(207b). According to the method described for the synthesis of
207d, 206b (20.0 g, 77.8 mmol) was treated with
3,4-dihydro-2H-pyran (8.2 g, 96.5 mmol) and p-toluenesulfonic acid
hydrate (0.57 g, 3.0 mmol) in CH.sub.2Cl.sub.2 (350 mL) to afford
207b (25.2 g, 95%) as an oil, which was used without further
purification. .sup.1H NMR (CDCl.sub.3): 7.26-7.08 (m, 5H), 4.45 (m,
1H), 3.72 (m, 1H), 3.58 (m, 1H), 3.35-3.05 (m, 2H), 3.28 (t, 2H,
J=6.6), 1.95-1.39 (m, 10H), 1.25 (s, 3H). .sup.13C NMR
(CDCl.sub.3): .delta. 145.38, 128.15, 126.51, 126.03, 99.06, 98.92,
76.20, 61.91, 61.80, 41.82, 41.74, 37.58, 37.43, 34.65, 30.61,
27.88, 25.58, 23.03, 22.90, 19.39, 19.32. HRMS (LSIMS, nba): Calcd
for C.sub.17H.sub.26O.sub.2Br (MH.sup.+): 341.1116, found:
341.1127.
[0454] 2-(6-Bromo-2,2-dimethylhexyloxy)-tetrahydropyran (207c).
According to the procedure for the preparation of 207d, (Ackerley,
N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al.
J. Med. Chem. 1987, 30, 1812-1818) 206c (521.0 g, 2.49 mol) was
reacted with 3,4-dihydro-2H-pyran (278.0 g, 3.30 mol) and
p-toluenesulfonic acid hydrate (3.13 g, 16 mmol) in
CH.sub.2Cl.sub.2 (2.2 L) to yield 207c (603.0 g, 83%) as a
pale-yellow oil, which was used without further purification.
.sup.1H NMR (CDCl.sub.3): .delta. 4.55 (t, 1H, J=3.3), 3.84 (m,
1H), 3.50 (m, 1H), 3.47 (d, 1 H , J=9.0), 3.42 (t, 2H, J=6.7), 2.99
(d, 1H, J=9.0), 1.88 (m, 2H), 1.75-1.33 (m, 10H), 0.91 (s, 3H),
0.90 (s, 3H). .sup.13C NMR (CDCl.sub.3): .delta. 99.37, 76.58,
62.17, 38.56, 34.43, 34.19, 33.90, 30.88, 25.79, 24.80, 24.71,
22.89, 19.67. HRMS (LSIMS, nba): Calcd for
C.sub.13H.sub.25BrO.sub.2 (MH.sup.+): 293.1116, found:
293.1128.
[0455] 2-(6-Bromo-2-methyl-2-p-tolylhexyloxy)-tetrahydropyran
(207e). According to the method described for the synthesis of
207d, 206e (18.2 g, 63.8 mmol) was reacted with
3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) and p-toluenesulfonic acid
hydrate (0.43 g, 2.3 mmol) in CH.sub.2Cl.sub.2 (300 mL) to give
207e (22.0 g, 93%) as an oil, which was used without further
purification. .sup.1H NMR (CDCl.sub.3): .delta. 7.25-7.05 (m, 4H),
4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m,
2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.34 (s, 3H), 1.40-1.08 (m,
1H). .sup.13C NMR (CDCl.sub.3): .delta. 142.78, 135.22, 128.81,
126.39, 99.09, 99.01, 61.93, 61.85, 41.67, 41.56, 38.12, 37.87,
33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41, 19.37. HRMS
(LSIMS, nba): Calcd for C.sub.19H.sub.30O.sub.2Br (MH.sup.+):
369.1429, found: 369.1451.
[0456] 2-(7-Bromo-2,2-dimethylheptyloxy)-tetrahydropyran (207g).
According to the method described for the synthesis of 207d, 206g
(36.0 g, 161 mmol) was treated with 3,4-dihydro-2H-pyran (18.5 g,
220 mmol) and p-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in
CH.sub.2Cl.sub.2 (60 mL). After filtration through neutral aluminum
oxide (200 g) and concentration, the crude product was purified by
column chromatography (silica gel; hexanes/ethyl acetate=50/1),
affording 207g (23.0 g, 46%) as an oil. .sup.1H NMR (CDCl.sub.3):
.delta. 4.54 (t, 1H, J=3.0), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98
(d, 1H, J=9.3), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m,
4H), 0.89 (s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. 99.3, 76.6,
62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6.
HRMS (LSIMS, gly): Calcd for C.sub.14H.sub.28BrO.sub.2 (MH.sup.+):
307.1272, found: 307.1245.
[0457] 2-(7-Bromo-2-methyl-2-phenylheptyloxy)-tetrahydropyran
(207h). According to the method described for the synthesis of
207d, 206h (51.0 g, 179 mmol) was reacted with 3,4-dihydro-2H-pyran
(18.80 g, 223 mmol) and p-toluenesulfonic acid hydrate (1.21 g,
6.36 mmol). Filtration through aluminum oxide (370 g) and
concentration in vacuo afforded 207h (48.75 g, 76%) as a yellowish
oil. .sup.1H NMR (CDCl.sub.3): .delta. 7.35-7.17 (m, 10H), 4.53 (m,
1H), 4.49 (m, 1H), 3.82 (m, 2H), 3.79 (m, 1H), 3.68-3.60 (m, 2H),
3.45-3.35 (m, 2H), 3.32 (t, 4H, J=6.9), 1.82-1.18 (m, 28H), 1.35
(s, 6H). .sup.13C NMR (CDCl.sub.3): .delta. 146.12, 128.11, 126.66,
125.89, 99.18, 99.04, 76.46, 62.02, 61.83, 42.17, 42.07, 38.91,
38.73, 34.12, 32.80, 30.70, 29.04, 25.66, 23.33, 22.97, 22.89,
19.49, 19.39. HRMS (LSIMS, nba): Calcd for
C.sub.19H.sub.30BrO.sub.2 (MH.sup.+): 369.1429, found:
369.1430.
6. BIOLOGICAL ASSAYS
6.1. Effects of Illustrative Compounds of the Invention on the In
Vitro Lipid Synthesis in Isolated Hepatocytes
[0458] Compounds were tested for inhibition of lipid synthesis in
primary cultures of rat hepatocytes. Male Sprague-Dawley rats were
anesthetized with intraperitoneal injection of sodium pentobarbital
(80 mg/kg). Rat hepatocytes were isolated essentially as described
by the method of Seglen (Seglen, P. O. Hepatocyte suspensions and
cultures as tools in experimental carcinogenesis. J. Toxicol.
Environ. Health 1979, 5, 551-560). Hepatocytes were suspended in
Dulbecco's Modified Eagles Medium containing 25 mM D-glucose, 14 mM
HEPES, 5 mM L-glutamine, 5 mM leucine, 5 mM alanine, 10 mM lactate,
1 mM pyruvate, 0.2% bovine serum albumin, 17.4 mM non-essential
amino acids, 20% fetal bovine serum, 100 mM insulin and 20 .mu.g/mL
gentamycin) and plated at a density of 1.5.times.10.sup.5
cells/cm.sup.2 on collagen-coated 96-well plates. Four hours after
plating, media was replaced with the same media without serum.
Cells were grown overnight to allow formation of monolayer
cultures. Lipid synthesis incubation conditions were initially
assessed to ensure the linearity of [1-.sup.14C]-acetate
incorporation into hepatocyte lipids for up to 4 hours. Hepatocyte
lipid synthesis inhibitory activity was assessed during incubations
in the presence of 0.25 .mu.Ci [1-.sup.14C]-acetate/well (final
radiospecific activity in assay is 1 Ci/mol) and 0, 1, 3, 10, 30,
100 or 300 .mu.M of compounds for 4 hours. At the end of the 4-hour
incubation period, medium was discarded and cells were washed twice
with ice-cold phosphate buffered saline and stored frozen prior to
analysis. To determine total lipid synthesis, 170 .mu.l of
MicroScint-E.RTM. and 50 .mu.l water was added to each well to
extract and partition the lipid soluble products to the upper
organic phase containing the scintillant. Lipid radioactivity was
assessed by scintillation spectroscopy in a Packard TopCount NXT.
Lipid synthesis rates were used to determine the IC.sub.50s of the
compounds that are presented in Table 6 and 7. TABLE-US-00009 TABLE
6 Effect of Cyclo-alkyl Ccompounds on Lipid Synthesis in Primary
Rat Hepatocytes. 95% Confidence IC.sub.50 Interval Compound #
(.mu.m) Lower Upper r.sup.2a m n R R1 R2 R3 R4 R5 107c 0.6 0.3 0.9
0.98 4 4 CO.sub.2H CO.sub.2H Me Me cyclo-Propyl 107d 0.3 0.1 5 0.98
4 4 CO.sub.2H CO.sub.2H cyclo-Propyl cyclo-Propyl 107e 6 5 8 0.95 4
4 CO.sub.2H CO.sub.2H Me Me cyclo-Butyl 107f 121 11 1268 0.89 4 4
CO.sub.2H CO.sub.2H cyclo-Butyl cyclo-Butyl 107g 113 7 1794 0.95 4
4 CO.sub.2H CO.sub.2H cyclo-Pentyl cyclo-Pentyl 106d 35 26 48 0.99
4 4 CO.sub.2tBu CO.sub.2tBu cyclo-Propyl cyclo-Propyl 107k 1 0.7
1.4 0.94 5 5 CO.sub.2H CO.sub.2H Me Me cyclo-Propyl 107l 0.5 0.4
0.7 0.99 5 5 CO.sub.2H CO.sub.2H cyclo-Propyl cyclo-Propyl 107m 2 2
2 0.99 5 5 CO.sub.2H CO.sub.2H cyclo-Pentyl cyclo-Pentyl 107n 10 4
21 0.97 7 7 CO.sub.2H CO.sub.2H Me Me Me Me 106n 13 4 46 0.93 7 7
CO.sub.2Et CO.sub.2Et Me Me Me Me .sup.ar.sup.2 is the goodness of
fit of the data to the non-linear sigmoidal model.
[0459] TABLE-US-00010 TABLE 7 Effect of Keto-diacids and -Diols on
Lipid Synthesis in Primary Rat Hepatocytes. 95% Confidence Interval
Compound IC.sub.50 (.mu.M) Lower Upper r.sup.2 210c ##STR532## 3 2
4 0.93 210e ##STR533## 100-300.sup.a 210f ##STR534## 100-300.sup.a
210g ##STR535## 3 3 3 0.99 210i ##STR536## 9 8 9 1 210j ##STR537##
5 2 11 0.98 214a ##STR538## 27 21 35 0.94 214b ##STR539##
100-300.sup.a 214c ##STR540## 4 3 7 0.91 214d ##STR541##
100-300.sup.a 214e ##STR542## 100-300.sup.a 214g ##STR543## 3 3 5
0.94 214h ##STR544## 93 60 144 0.88 214i ##STR545## 2 1 8 0.97 217
##STR546## 3-10.sup.a 218 ##STR547## 1 1 2 0.84 219 ##STR548## 2 2
3 0.94 225 ##STR549## 8 7 11 0.97 226 ##STR550## 3 3 4 0.96 232
##STR551## 52 32 83 0.91 .sup.aThe confidence of the IC.sub.50
estimate is insufficient to assign a value.
6.2. Effects of Illustrative Compounds of the Invention on NonHDL
Cholesterol, HDL Cholesterol, Triglyceride Levels, Glycemic Control
Indicators and Body Weight Control in Obese Female Zucker Rats
[0460] Ten- to twelve-week old (400-500 grams) female Zucker fatty
rats Cr1: (Zuc)-faBR were obtained from Charles River Laboratories.
Animals were acclimated to the laboratory environment for seven
days. During the acclimation and study period, animals were housed
by group in shoebox polycarbonate cages on Cellu-Dri bedding. The
temperature and humidity in the animals' quarters (68-78.degree.
F.; 30-75% RH) were monitored and the airflow in the room was
sufficient to provide several exchanges per hour with 100% fresh
filtered air. An automatic timing device provided an alternating
12-hour cycle of light and dark. Rats received pelleted Purina
Laboratory Rodent Chow.RTM. (5001) prior to and during the drug
intervention period except for a 6-hour phase prior to blood
sampling. Fresh water was supplied ad libitum via an automatic
watering system. Compounds were dissolved, suspended by mixing in a
dosing vehicle consisting of 1.5% carboxymethylcellulose/0.2% Tween
20 or 20% ethanol and 80% polyethylene glycol-200 [v/v]. Dose
volume of vehicle or vehicle plus each compound was set at 0.25% of
body weight in order to deliver the appropriate dose. Doses were
administered daily by oral gavage, approximately between 8-10 AM.
Regarding blood sampling, animals were fasted for 6 hours prior to
all blood collections. Prior to and after 7 days of dosing, a 1.0-
to 2.0-mL sample of blood was collected by administering
O.sub.2/CO.sub.2 anesthesia and bleeding from the orbital venous
plexus. Following 14 days of dosing, blood was collected by cardiac
puncture after euthanasia with CO.sub.2. All blood samples were
processed for separation of serum and stored at -80.degree. C.
until analysis. Commercially available kits were used to determine
serum triglycerides (Roche Diagnostic Corporation, Kit No. 148899
or Boehringer Mannheim, Kit No. 1488872), total cholesterol (Roche
Diagnostic Corporation, Kit No. 450061), non-esterified fatty acids
(Wako Chemicals, Kit No. 994-75409) and .beta.-hydroxybutyrate
(Wako Chemicals, Kit No. 417-73501 or Sigma Kit. No. 310-0) on a
Hitachi 912 Automatic Analyzer (Roche Diagnostic Corporation). In
some instances, an in-house cholesterol reagent was used to
determine total serum cholesterol levels. Serum lipoprotein
cholesterol levels were determined by lipoprotein profile analysis.
Lipoprotein profiles were analyzed using gel-filtration
chromatography on a Superose 6HR (1.times.30 cm) column equipped
with on-line detection of total cholesterol as described by Kieft
et al (Kieft, K. A.; Bocan, T. M.; Krause, B. R. Rapid on-line
determination of cholesterol distribution among plasma lipoproteins
after high-performance gel filtration chromatography. J. Lipid Res.
1991, 32, 859-866.). The total cholesterol content of each
lipoprotein was calculated by multiplying the independent values
determined for serum total cholesterol by the percent area of each
lipoprotein in the profile. The percent body weight gain and the
ratio of liver to body weight is also determined. Selected data are
shown as absolute values or as a percent change of the pretreatment
values in Tables 8 and 9. TABLE-US-00011 TABLE 8 Effect of
Cyclo-alkyl Compounds in Female Obese Zucker Rats. Serum Variables
(Percent Change from Pre-Treatment).sup.a NonHDL- HDL- Compound
Dose No. Cholesterol Cholesterol TG # (mg/kg) animals 1 wk 2 wk 1
wk 2 wk 1 wk 2 wk m n R R1 R2 R3 R4 R5 107c 100 3 -84 -20 104 248
-93 -64 4 4 CO.sub.2H CO.sub.2H Me Me cyclo-Propyl 107d 100 3 22 63
180 260 -51 -28 4 4 CO.sub.2H CO.sub.2H cyclo-Propyl cyclo-Propyl
107e 100 4 4 28 30 60 -54 -51 4 4 CO.sub.2H CO.sub.2H Me Me
cyclo-Butyl 107f 100 4 -32 -40 -1 10 -58 -59 4 4 CO.sub.2H
CO.sub.2H cyclo-Butyl cyclo-Butyl 107g 100 4 -68 -67 36 40 -67 -70
4 4 CO.sub.2H CO.sub.2H cyclo-Pentyl cyclo-Pentyl 107k 100 4 -90
-99 43 84 -93 -98 5 5 CO.sub.2H CO.sub.2H Me Me cyclo-Propyl 107l
100 4 -92 -83 136 171 -95 -94 5 5 CO.sub.2H CO.sub.2H cyclo-Propyl
cyclo-Propyl 107m 100 4 -54 -32 12 27 -63 -48 5 5 CO.sub.2H
CO.sub.2H cyclo-Pentyl cyclo-Pentyl 107n 100 3 -80 -45 44 86 -85
-64 7 7 CO.sub.2H CO.sub.2H Me Me Me Me .sup.a100% represents a
2-fold increase from pre-treatment value
[0461] TABLE-US-00012 TABLE 9 Effect of Keto-diacids and -Diols in
Female Obese Zucker Rats. Serum Variables Percent Change from
Pre-Treatment NonHDL- HDL- Dose Cholesterol Cholesterol TG Compound
(mg/kg) n 1 wk 2 wk 1 wk 2 wk 1 wk 2 wk 210b ##STR552## 100 3 36 65
4 12 10 26 210c ##STR553## 100 5 -62 -41 54 78 -74 -69 210d
##STR554## 100 3 36 79 43 45 -36 -8 210e ##STR555## 30 4 0 47 0 10
-11 12 210f ##STR556## 100 3 -40 -44 11 62 -63 -66 210g ##STR557##
100 4 -98 -99 72 168 -93 -94 210j ##STR558## 100 3 -80 -46 44 86
-85 -63 214a ##STR559## 100 3 -23 28 24 2 -31 0 214b ##STR560## 100
4 -18 -32 -14 -11 -20 -17 214c ##STR561## 100 4 -23 -10 110 126 -54
-29 214d ##STR562## 30 2 -30 30 -1 -27 -24 20 214f ##STR563## 100 3
28 34 -5 6 -11 -15 214g ##STR564## 100 3 -91 -88 76 135 -92 -92
214h ##STR565## 100 5 29 9 2 10 24 1 214i ##STR566## 30 4 -50 -32
85 61 -58 -33 217 ##STR567## 100 2 -26 4 46 48 -40 -11 218
##STR568## 30 4 17 -8 -18 -5 18 -7 219 ##STR569## 100 2 -70 -78 78
78 -85 -87 225 ##STR570## 30 4 -17 92 7 4 -2 -22 226 ##STR571## 100
3 -30 -51 240 72 -65 -62 231 ##STR572## 59 3 -43 34 2 7 -24 7 232
##STR573## 100 4 -15 -5 1 -11 -29 -8
[0462] Select compounds (214c, 210c, and 210g) were further
evalutated in the Zucker rat by performing a full dose response and
measuring additional scrum variables including markers for diabetes
(Tables 10-12). TABLE-US-00013 TABLE 10 Effect of daily 214 c oral
treatment on serum lipid and glycemic control variables in female
obese Zucker rats. Non-HDL-C HDL-C TG Dose (mg/dl) (mg/dl) (mg/dl)
mg/kg n Pre 1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk 2 wk 0 32 25 .+-. 3 36
.+-. 5.sup.a 30 .+-. 4.sup.a 48 .+-. 2 39 .+-. 2.sup.a 41 .+-.
2.sup.a 933 .+-. 69 1114 .+-. 97.sup.a 1099 .+-. 86.sup.a (+144)
(+120) (-19) (-15) (+119) (+118) 3 9 24 .+-. 3 25 .+-. 3 22 .+-. 2
48 .+-. 3 43 .+-. 4.sup.a 39 .+-. 4.sup.a 755 .+-. 89 800 .+-. 75
781 .+-. 65 (-10) (-19) 10 18 25 .+-. 3 21 .+-. 2 25 .+-. 2 46 .+-.
3 52 .+-. 3.sup.a 53 .+-. 4.sup.a 777 .+-. 70 602 .+-. 37.sup.a 730
.+-. 52 (+113) (+115) (-23) 30 26 30 .+-. 3 28 .+-. 2 38 .+-.
5.sup.a 43 .+-. 2 60 .+-. 3.sup.a 61 .+-. 4.sup.a 998 .+-. 85 726
.+-. 49.sup.a 985 .+-. 110 (+127) (+140) (+142) (-27) 100 29 31
.+-. 3 23 .+-. 1 32 .+-. 2 45 .+-. 3 78 .+-. 5.sup.a 79 .+-.
6.sup.a 1051 .+-. 80 485 .+-. 29.sup.a 702 .+-. 53.sup.a (+173)
(+176) (-54) (-33) NEFA Glucose Insulin Dose (mg/dl) (mg/dl)
(ng/ml) mg/kg Pre 1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk 2 wk 0 1.2 .+-.
0.08 1.3 .+-. 0.06 1.6 .+-. 0.12.sup.a 125 .+-. 2 118 .+-. 3 116
.+-. 3 9.1 .+-. 0.6 8.7 .+-. 0.5 7.7 .+-. 0.5 (+133) 3 1.1 .+-.
0.08 1.2 .+-. 0.05 1.6 .+-. 0.13.sup.a 118 .+-. 4 106 .+-. 2 103
.+-. 3 8.8 .+-. 1.5 7.5 .+-. 0.8 7.8 .+-. 0.6 (+145) 10 1.2 .+-.
0.05 0.98 .+-. 0.08.sup.a 1.0 .+-. 0.10 112 .+-. 3 110 .+-. 2 110
.+-. 3 8.4 .+-. 0.6 7.5 .+-. 0.4 7.8 .+-. 0.5 (-18) 30 1.4 .+-.
0.06 1.1 .+-. 0.05.sup.a 1.2 .+-. 0.10 111 .+-. 1 112 .+-. 13 120
.+-. 3 9.3 .+-. 0.8 9.1 .+-. 0.6 9.8 .+-. 0.7 (-21) 100 1.4 .+-.
0.10 0.98 .+-. 0.04.sup.a 0.94 .+-. 0.04.sup.a 114 .+-. 2 120 .+-.
5 118 .+-. 3 9.6 .+-. 0.8 10.9 .+-. 1.0 11.0 .+-. 0.9 (-30) (-33)
.sup.ap < 0.05 compared to pretreatment. Data are represented as
mean .+-. SEM. Numbers in parentheses are the percent increases (+)
or decreases (-) of the pretreatment control values.
[0463] TABLE-US-00014 TABLE 11 Effect of daily 210 c oral treatment
on serum lipid and glycemic control variables in female obese
Zucker rats. Non-HDL-C HDL-C TG Dose (mg/dl) (mg/dl) (mg/dl) mg/kg
n Pre 1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk 2 wk 0 12 40 .+-. 11 43 .+-.
10 29 .+-. 3 39 .+-. 3 39 .+-. 5 38 .+-. 4 1303 .+-. 261 1333 .+-.
231 1140 .+-. 124 3 4 32 .+-. 4 24 .+-. 2 24 .+-. 3 31 .+-. 3 36
.+-. 1 33 .+-. 1 996 .+-. 188 775 .+-. 92 857 .+-. 103 10 4 40 .+-.
8 26 .+-. 4.sup.a 27 .+-. 4 37 .+-. 10 47 .+-. 7 39 .+-. 5 1143
.+-. 373 692 .+-. 180 814 .+-. 205 (-35) 30 4 48 .+-. 4 37 .+-.
4.sup.a 43 .+-. 5 34 .+-. 5 53 .+-. 8.sup.a 50 .+-. 9.sup.a 1242
.+-. 144 826 .+-. 92.sup.a 962 .+-. 118 (-23) (+156) (+147) (-33)
100 11 31 .+-. 4 18 .+-. 3.sup.a 22 .+-. 3.sup.a 38 .+-. 3 66 .+-.
9.sup.a 68 .+-. 10.sup.a 964 .+-. 90 383 .+-. 49.sup.a 440 .+-.
58.sup.a (-42) (-29) (+174) (+179) (-60) (-54) NEFA Glucose Insulin
Dose (mg/dl) (mg/ dl) (ng/ml) mg/kg Pre 1 wk 2 wk Pre 1 wk 2 wk Pre
1 wk 2 wk 0 1.5 .+-. 0.12 1.5 .+-. 0.09 1.4 .+-. 0.10 134 .+-. 6
124 .+-. 7 118 .+-. 3 9.8 .+-. 0.9 8.4 .+-. 0.6 6.8 .+-. 0.7.sup.a
(-31) 3 1.5 .+-. 0.14 1.2 .+-. 0.16 1.5 .+-. 0.27 108 .+-. 6 99
.+-. 4 103 .+-. 3 10.4 .+-. 1.3 10.7 .+-. 0.8 8.6 .+-. 0.5 10 1.6
.+-. 0.15 0.92 .+-. 0.09.sup.a 1.5 .+-. 0.28 113 .+-. 7 105 .+-. 3
113 .+-. 3 10.6 .+-. 1.5 7.7 .+-. 1.0.sup.a 8.9 .+-. 1.3 (-27) 30
1.4 .+-. 0.15 1.0 .+-. 0.11.sup.a 1.1 .+-. 0.20 103 .+-. 2 115 .+-.
4 118 .+-. 8 7.7 .+-. 1.6 9.2 .+-. 1.3 8.5 .+-. 1.8 (-29) 100 1.2
.+-. 0.06 0.81 .+-. 0.07.sup.a 0.66 .+-. 0.06.sup.a 110 .+-. 3 113
.+-. 6 122 .+-. 7 8.1 .+-. 0.9 9.0 .+-. 1.0 9.5 .+-. 0.9 (-33)
(-45) .sup.ap < 0.05 compared to pretreatment. Data are
represented as mean .+-. SEM. Numbers in parentheses are the
percent increases (+) or decreases (-) of the pretreatment control
values.
[0464] TABLE-US-00015 TABLE 12 Effect of daily 210 g oral treatment
on serum lipid and glycemic control variables in female obese
Zucker rats. Non-HDL-C HDL-C TG Dose (mg/dl) (mg/dl) (mg/dl) mg/kg
n Pre 1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk 2 wk 0 27 20 .+-. 2 29 .+-.
3.sup.a 28 .+-. 3.sup.a 76 .+-. 5 66 .+-. 5.sup.a 69 .+-. 5.sup.a
950 .+-. 55 1119 .+-. 82.sup.a 1189 .+-. 92.sup.a (+145) (+140)
(-13) (-9) (+118) (+125) 3 18 22 .+-. 2 23 .+-. 2 25 .+-. 2 77 .+-.
5 75 .+-. 6 77 .+-. 8 905 .+-. 57 995 .+-. 50 833 .+-. 57 10 22 22
.+-. 1 22 .+-. 2 34 .+-. 3.sup.a 86 .+-. 10 136 .+-. 11.sup.a 138
.+-. 8.sup.a 863 .+-. 63 553 .+-. 35.sup.a 865 .+-. 69 (+155)
(+158) (+160) (-36) 30 18 27 .+-. 3 14 .+-. 2.sup.a 30 .+-. 2 62
.+-. 5 159 .+-. 12.sup.a 208 .+-. 14.sup.a 982 .+-. 75 213 .+-.
19.sup.a 475 .+-. 38.sup.a (-48) (+256) (+335) (-78) (-52) 100 15
26 .+-. 2 2 .+-. 1.sup.a 3 .+-. 1.sup.a 66 .+-. 5 100 .+-. 8.sup.a
141 .+-. 12.sup.a 937 .+-. 77 69 .+-. 5.sup.a 78 .+-. 10.sup.a
(-92) (-88) (+151) (+213) (-93) (-92) NEFA Glucose Insulin Dose
(mg/dl) (mg/dl) (ng/ml) mg/kg Pre 1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk
2 wk 0 1.3 .+-. 0.06 1.3 .+-. 0.07 1.3 .+-. 0.07 129 .+-. 4 123
.+-. 2 120 .+-. 2 9.1 .+-. 0.5 10.1 .+-. 0.6 8.1 .+-. 0.6 3 1.3
.+-. 0.09 1 .1 .+-. 0.07.sup.a 1.0 .+-. 0.10.sup.a 114 .+-. 3 117
.+-. 4 124 .+-. 4.sup.a 8.6 .+-. 0.9 10.0 .+-. 1.0 7.3 .+-. 0.5
(-15) (-23) (+108) 10 1.2 .+-. 0.08 1.0 .+-. 0.07.sup.a 0.95 .+-.
0.08.sup.a 120 .+-. 4 122 .+-. 3 125 .+-. 4 9.9 .+-. 0.9 10.5 .+-.
1.1 9.1 .+-. 0.7 (-17) (-21) 30 1.3 .+-. 0.07 0.88 .+-. 0.06.sup.a
0.66 .+-. 0.03.sup.a 119 .+-. 5 108 .+-. 4 130 .+-. 4 9.8 .+-. 0.9
6.4 .+-. 0.6.sup.a 7.7 .+-. 0.9.sup.a (-32) (-49) (-35) (-21) 100
1.4 .+-. 0.06 0.98 .+-. 0.08.sup.a 0.66 .+-. 0.06.sup.a 117 .+-. 3
92 .+-. 4.sup.a 105 .+-. 3.sup.a 11.9 .+-. 1.0 6.4 .+-. 1.3.sup.a
6.0 .+-. 0.8.sup.a (-30) (-52) (-21) (-10) (-46) (-50) .sup.ap <
0.05 compared to pretreatment. Data are represented as mean .+-.
SEM. Numbers in parentheses are the percent increases (+) or
decreases (-) of the pretreatment control values.
[0465] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments which are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the art and are intended to fall
within the appended claims.
* * * * *
References